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The emerging scenario of immunotherapy for T-cell Acute Lymphoblastic Leukemia: advances, challenges and future perspectives


T-cell acute lymphoblastic leukemia (T-ALL) is a challenging pediatric and adult haematologic disease still associated with an unsatisfactory cure rate. Unlike B-ALL, the availability of novel therapeutic options to definitively improve the life expectancy for relapsed/resistant patients is poor. Indeed, the shared expression of surface targets among normal and neoplastic T-cells still limits the efficacy and may induce fratricide effects, hampering the use of innovative immunotherapeutic strategies. However, novel monoclonal antibodies, bispecific T-cell engagers (BTCEs), and chimeric antigen receptors (CAR) T-cells recently showed encouraging results and some of them are in an advanced stage of pre-clinical development or are currently under investigation in clinical trials. Here, we review this exciting scenario focusing on most relevant advances, challenges, and perspectives of the emerging landscape of immunotherapy of T-cell malignancies.


Acute lymphoblastic leukemia (ALL) is a heterogeneous disease characterized by proliferation and accumulation of immature lymphoid cells in bone marrow, peripheral blood, lymphoid tissues, and other extra-nodal sites [1]. In accordance with the definition of the World Health Organization (WHO), ALL can be classified as B or T-cell acute lymphoblastic leukemia (B- or T-ALL) [2, 3]. It occurs more frequently in males than females and in children than in adults [4]. T-ALL aetiology is probably the combination of environmental causes, such as radiation or other agents (benzene, pesticides, bioflavonoids, etc.) exposure and genetic susceptibility. Pathogenetic mechanisms include functional loss of tumor-suppressor genes, activation of oncogenes or translocation events leading to new chimeric proteins, with oncogenic potential in T cell progenitors and driving leukemic transformation. The most common genetic abnormalities of T-ALL are structural chromosomal alterations that lead to secondary somatic DNA copy number variations and mutations [5,6,7]. Also, specific DNA methylation patterns correlate with clinical outcome in ALL patients, suggesting that methylation analysis may be of help for classifying ALL patients’ subtypes [8]. Based on genetic lesions, T-ALL could be classified into type A and type B [9]. In particular, type A mutations involve driver oncogenes or oncogene fusions (HOXA, MYB, TAL/LMO, TLX1, TLX3), while type B mutations activate the NOTCH1 pathway in over than 60% of T-ALL cases, or, in the remaining part of the cases, activate cytokine signalling pathways (IL7R, JAK1 / 3, FLT3, CKIT, PI3K / AKT / PTEN, ABL1, N / KRAS) and factors involved in transcription (RUNX1, ETV6, BCL11B, WT1, TCF7, LEF1, CTNNB1, GATA3, IKZF1), inactivate cell cycle inhibitors (CDKN2A / B, CDKN1B, CDKN1C, CCND3, RB) or deregulate chromatin modifiers and remodelling factors (PHF6, CTCF, KDM6A, SETD2, KMT2A / 2D / 2C, DNMT3A, IDH1 / 2) [10, 11].

Based on the expression of CD1a, CD3, CD5, CD7, and TdT, different immunophenotypic subgroups have been distinguished for T-ALL: pro-T, pre-T, cortical, and mature [12]. Recently, a new provisional entity, which accounts for approximately 10% of pediatric and 40–50% of adult T-ALL cases, was introduced. The early T-cell precursor lymphoblastic leukemia (ETP-ALL) is characterized by the lack of CD1a and CD8, weak expression of CD5, and expression of stem cell (CD34, CD117), and myeloid (CD13, CD33) lineage markers. This entity has been associated with poor prognosis, albeit intensified chemotherapy regimens have improved the outcome [13].

To date, the standard front-line therapy for T-ALL is represented by intensive chemotherapy and central nervous system (CNS) prophylaxis [14]. Vincristine, prednisone, and anthracyclines, sometimes associated with L-asparaginase, are the most active drugs. Cytosine-arabinoside and high-dose methotrexate (MTX) for CNS prophylaxis are also commonly used [15, 16]. Through these approaches, the estimated 5-year EFS and OS of T-ALL patients are 83.8% and 89.5%, respectively [17]. Adult T-ALL patients still have poor outcomes and lower survival than young ones. Survival rate of pediatric patients is around 90%, while in adults it is between 30–40% [18, 19]. Moreover, relapses often occur in adult T-ALL patients (40–75% vs 15–20% in pediatric patient), and cure rates are less than 10% among this group of patients [20, 21]. The minimal residual disease (MRD) is the most relevant prognostic factor of relapse [22]. Nelarabine, the only new therapy recently introduced, is a nucleoside analog indicated for the treatment of pediatric and adult patients who are relapsed and/or refractory (r/r) after at least two chemotherapy regimens. However, it slightly impacts the disease progression in a substantial minority of patients (30%) [23]. Allogeneic haematopoietic cell transplantation (HCT) has a relevant role in patients with high-risk or r/r disease. Nevertheless, also in patients who respond to nelarabine and are consolidated with allogeneic stem cell transplantation (SCT), the outcome remains extremely poor [24]. Finally, γ-Secretase inhibitors hold promise for the treatment of patients with NOTCH1 mutations, and the results of clinical trials investigating these agents are eagerly awaited [25].

We here review the potential immunotherapeutic approaches for T-ALL, focusing on monoclonal antibodies (mAbs), chimeric antigen receptor (CAR) T-cells and Bispecific T-Cell Engagers (BTCEs) as promising and emerging strategies to increase cure rates and reduce the burden of intensive and prolonged maintenance chemotherapy.

Monoclonal antibodies (mAbs) and chimeric antigen receptor (CAR) T-cells for the treatment of T-ALL

Presently, unlike B-ALL, immunotherapeutic attempts for T-ALL patients have been mostly hampered by the shared expression of surface antigens among normal cells and leukemic T cells [26,27,28,29,30]. Indeed, the search and identification of selective targets for T-ALL blasts not expressed by normal T cells remains the main challenge. However, new targets are presently under investigation for novel immunotherapeutic strategies based on mAbs and chimeric antigen receptor (CAR)-T cells.

mAbs bind cell surface antigens and can either prevent the interaction with ligands or inhibit receptor clustering and stimulation, leading to apoptosis of target cells [31]. Moreover, by binding of the Fc regions to Fc gamma receptors (FcγRs) on the surface of immune cells or complement factors, mAb therapeutics activate effector mechanisms (Fig. 1), as antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC), inducing the killing of antigen-expressing cells [32,33,34]. Another mAb-based immunotherapy relies on antibody–drug conjugates (ADCs) that are internalized and release cytotoxic agents into targeted cells [35,36,37,38]. The recent availability of humanized mAbs and the conjugation to powerful drugs have led to the approval by the FDA of ADC targeting CD33 in acute myeloid leukemia (AML) (gemtuzumab ozogamicin, Mylotarg®), CD30 in T-cell lymphoma (TCL) and Hodgkin lymphoma (brentuximab vedotin, Adcetris®), and CD22 in B-ALL patients (inotuzumab ozogamicin, Besponsa®) [39, 40]. Since the approval of Mylotarg® in 2020, a total of 14 ADCs reached the market worldwide [41]. Presently, several ADC are under investigation in clinical trials for T-ALL treatment [39].

Fig. 1
figure 1

Mechanisms of action of antibodies targeting T-ALL cell and CAR-T cell approach. Antibodies induce tumor cell-killing through different mechanisms: (1) initiating the complement cascade [complement-dependent cytotoxicity (CDC)]; (2) delivering cytotoxic drugs to be internalised in tumor cells [antibody–drug conjugation (ADC)]; (3) activating immune effector cells, namely NK cells [antibody-dependent cytotoxicity (ADCC)] or (4) macrophages [antibody-dependent cellular phagocytosis (ADCP)]. On the other hand, CAR-T cells act (5) recognizing and killing cancer cells through the release of inflammatory cytokines and cytolytic molecules

More recently, immunotherapy with CAR-T cells has emerged as a powerful strategy for relapsed/refractory haematopoietic malignancies such as B-ALL [42, 43]. Peripheral blood T-cells are ex vivo engineered to express a receptor specific for a surface antigen/epitope expressed by cancer cells. These engineered immune effectors are finally amplified to be reinfused in the patient. CAR-T cells can recognize and kill tumor cells in a major histocompatibility complex (MHC)-independent manner [44].

BTCEs: a new hope for T-ALL immunotherapy

BTCEs have recently emerged as effective and off-the-shelf therapeutics to induce an immunologic synapse between a tumor-associated antigen (TAAs) expressed by cancer cells and cytotoxic immune effectors. For this aim, a BTCE plays a cell-bridging function completely absent in parent mAbs. There are different species of BTCEs, ranging from small-scale proteins, characterized by two single chain variable fragments (scFv), to longer asymmetric or symmetric immunoglobulin G (IgG)-like molecules [45]. IgG-like constructs offer different pharmacodynamic and pharmacokinetic advantages: a) the presence of neonatal Fc receptor (FcRn) protects IgG-like BTCE from rapid degradation and confers long plasma half-life (days) as compared to the shorter plasma half-life (hours) of Fc-fragment lacking BTCE that, instead, need continuous infusion; b) the presence of bivalent binding domains for TAAs increases the avidity and the selective recognition of antigen-expressing T-ALL cells [45,46,47]. Furthermore, regarding the activation moiety of effector T cells, at least two different IgG-like BTCEs format could be distinguished: bivalent BTCE (2+2), with two arms binding to a TAA and two arms binding to CD3ε, and monovalent BTCE (2+1), with two arms binding to a TAA and one arm binding to CD3ε (Fig. 2). Although both constructs were effective against cancer preclinical models, higher anti-tumor activity has been observed with monovalent BTCEs mainly due to the mitigation of nonspecific T-cell activation by CD3 cross-linking.

Fig. 2
figure 2

Mechanisms of action of BTCEs. (1) Bivalent BTCEs (bBTCEs), characterized by two arms binding CD3Ɛ (2 + 2 format), re-direct T lymphocytes against T-ALL cells expressing the target antigen. (2) Monovalent BTCEs (mBTCEs), constituted by one arm binding CD3Ɛ (2 + 1 format), empower cytotoxic effect on T-ALL cells compared to bBTCEs and limit T-cell exhaustion

The discovery of T-ALL selective antigens might provide effective therapeutic options for the treatment of this orphan disease by a BTCE-based approach.

Challenges in immunotherapy for T-ALL

The above-described strategies have been mostly based on the targeting of the main T lineage targets, such as CD1a, CD5, CD7, CD38, that, indeed, are shared by the normal T cell compartment and produce T-cell fratricide effects and severe T-cell aplasia as consequence of on-target/off-tumor cytotoxicity. These events, together with novel toxicities associated to T-cell activation, such as the Cytokine Release Syndrome (CRS) and the Immune effector Cell-Associated Neurotoxicity Syndrome (ICANS), which is more common in BTCE-treated patients, represent therefore the main issues to be overcome in the next future for a clinically meaningful application of immunotherapy in T-ALL.

Strategies to prevent fratricide effects and T-cell aplasia

While shared expression of B cell lineage antigens between normal and malignant cells results in B cell aplasia, which can be easily managed with immunoglobulin administration, T cell aplasia can result in severe and life-threatening immunosuppression further exacerbated by the absence of effective T cell replacement options.

Currently, to overcome these roadblocks, several strategies are under investigation. To avoid T cell aplasia, CAR-T could be generated by transducing T cells with adeno-associated viral vectors, which confers transient CAR-T expression due to lack of genomic integration [48]. Similarly, non-viral CAR-T delivery through mRNA electroporation confers only transient CAR-T function which can mitigate T cell aplasia with prompt rescue. However, the heterogeneous expression and the low persistence of CAR-T may impair their antitumor activity [49].

The incorporation of suicide genes and safety switches could prevent T cell aplasia, by selective cell-death induction of transduced T cell while sparing normal T lymphocytes. Examples of these approaches are represented by metabolic activation of non-toxic compounds such the herpes simplex virus thymidine kinase (HSV-TK) coupled with the use of ganciclovir [50], use of inducible cas9 (iCas9) [51] or the expression of antigen genes in CAR vectors combined with the use of mAbs resulting in ADCC of transduced cells [52].

Beyond T-cell aplasia, the shared expression of antigens between normal and neoplastic T-cells makes that CAR T cells will inevitably kill themselves, an effect called fratricide, with consequent anti-tumor immunity impairment. To overcome this relevant issue, different approaches have been developed. One of these is based on Tet-OFF inducible expression system, which can be used to circumvent the T cell fratricide activity by temporally controlling CAR-T expression. In this model, the expression of a CAR is repressed in the presence of doxycycline in vitro while is restored with a doxycycline-free environment allowing CAR-mediated cytotoxicity [53].

Another way to prevent the fratricide is the genome editing of the tumor antigen in CAR-T cells using DNA nuclease technology such as CRISPR-Cas9. This approach was successfully used to edit CD7 expression in CAR-T lymphocytes, enabling the expansion of CAR T cells without affecting antitumor function [54].

Protein Expression Blockers (PEBL) technology was also used to limit T cell fratricide by preventing the surface expression of CD7. In detail, CD7 down-regulation on CAR-T was achieved using a scFv directed against CD7 coupled with an ER (endoplasmic reticulum) / Golgi-retention motif which ensures CD7 anchoring in the ER and/or Golgi [55].

Finally, engineering other cytotoxic immune cells such as primary NK (natural killer) or NK-92 cells lines could be another suitable option to prevent T cell fratricide, considering that these cells do not express T cell associated antigen endogenously [56].

T-cell surface antigens as immunotherapeutic target for T-ALL


CD1a is a surface glycoprotein promoting antigen presentation to specialized T cells and it is expressed on approximately 40% of cortical-derived T-ALL patients [57]. On normal tissues, CD1a is present on transient cortical thymocytes, skin Langerhans cells and a subset of circulating myeloid dendritic cells, but it is not expressed by mature T cells [10, 58,59,60,61]. This pattern of expression makes the targeting of CD1a less prone to fratricide effects and potentially reduces the risk of on target/off-tumor side effects [48]. To date, a few studies have contributed to define the in vivo role of CD1a, principally because this CD1 isoform is lacking in mice [62]. However, a recent study performed on CD1a transgenic mice showed that the expression of this molecule is strictly related to the pathogenesis of poison-induced cutaneous diseases [60]. Authors reported the absence of adverse effects following the treatment of induced skin inflammation using anti-CD1a antibodies, thus supporting the idea that CD1a is a safe and attractive target for cortical T-ALL (coT-ALL) subtypes. In this context, an anti-CD1a mAb named CR2113, has been demonstrated to induce potent ADCC in CD1a-expressing cell lines and T-ALL primary samples in vitro, which translated in anti-tumor activity against CD1a-expressing xenografts [63].

Recently, a second-generation (4-1BB costimulatory domain) CD1a CAR-T cells showing no fratricide effects and long-term persistence, was developed [61]. Since CD1a is not expressed by peripheral blood T-cells, the target gene on effector cells did not need to be knocked out. Through in vitro studies, the authors demonstrated the specific cytotoxicity of CD1a CAR-T cells against CD1a+ T-ALL cell lines and primary blasts, while studies on a patient-derived xenograft model of cortical coT-ALL confirmed their potent anti-leukemic activity. Although not applicable to all T-cell malignancies, CAR-T cells for CD1a targeting may represent a successful strategy in the specific subset of coT-ALL patients. A phase I clinical trial is presently ongoing to study its efficacy and safety [48].

More recently, starting from the development of a novel anti-CD1a mAb, named UMG2, a monovalent BTCE that simultaneously binds CD1a on T-ALL cells and CD3ε on T-lymphocytes (CD1a x CD3ε) has been generated [64]. The authors demonstrated that UMG2 binds a previously uncharacterized CD1a epitope, with a strong reactivity on cortical T-ALL cells, while no binding was found on normal peripheral blood cells. CD1a x CD3ε BTCE produced significant in vitro T-cell mediated cytotoxicity against CD1a expressing T-ALL cells and inhibited the growth of human T-ALL xenografts in vivo. These data suggest that CD1a x CD3ε BTCE may be suitable for clinical development as an innovative immunotherapeutic tool for the treatment of CD1a-expressing cortical-derived T-ALL patients.


CD3 is a multimeric protein complex highly expressed in mature T-cell lymphomas and mature T-ALL, and its cytoplasmic expression is considered a diagnostic marker for immature T-ALLs. It is expressed by haematopoietic cells and is involved in the association with the T-cell receptor (TCR) on T-cells and thymocytes surface [65].

The first anti-CD3 mAb available for therapy in humans was Muromonab, approved in 1985 for the treatment of organ transplant rejection [66]. The antitumor activity of anti-CD3 mAbs in T-ALL has been subsequently reported. Indeed, the activation of TCR signalling by the treatment with anti-CD3 mAbs induced leukemic cell death in T-ALL mouse models [67]. A further study demonstrated the preclinical efficacy of humanized non-FcγR-binding anti-CD3 mAbs in xenograft models of T-ALL. The anti-leukemic effects and host survival was increased by the combination of these antibodies with chemotherapy [68].

CD3 was also investigated as a potential target in TCL using immunotoxin-loaded anti-CD3 mAbs: the treatment was well tolerated and induced the partial remission of 2 of 5 patients [69]. The promising results led to the development of anti-CD3 CAR-NK cells. The expression of a third-generation anti-CD3 CAR, incorporating CD28 and 4-1BB costimulatory domains, in the NK-92 cell line induced the in vitro and in vivo killing of CD3+ lymphoma cells, primary T cells and T-ALL cells [70]. A second-generation anti-CD3 CAR, containing a 4-1BB costimulatory domain, demonstrated in vitro antitumor activity against CD3+ primary T cells and childhood T-ALL cells [71]. Finally, a novel strategy, based on the use of a second-generation (4-1BB costimulatory domain) CD3 CAR, was developed to generate allogenic T cells not expressing TCRαβ [72].

Although the encouraging results, the development of a CD3-based immunotherapy against T-ALL is strongly hampered by the risk of severe immune-depression and fratricide effects, due to CD3 wide expression on normal T cells.


CD4 was one of the first targets investigated for therapeutic purposes since it is expressed by a wide range of mature T-cell lymphomas and a subset of T-ALLs [73]. In normal cells, it is expressed by about 80% of thymocytes and in more than 50% of peripheral blood T-lymphocytes [74, 75], and is involved in T-cell activation, acting as a co-receptor for the TCR [76].

Since the use of anti-CD4 mAbs showed a reversible depletion of CD4+ cells in T-cell lymphoma patients without inducing immunosuppression [77,78,79], third-generation anti-CD4 CARs (containing 4-1BB and CD28 costimulatory domains) were then developed, demonstrating in vitro and in vivo preclinical efficacy [73, 80]. A phase I clinical trial (NCT04162340) is evaluating the safety and the antitumor efficacy of anti-CD4 CAR-T cells in T-cell malignancies, including T-ALL. Starting from the same CD4 CAR structure and inserting a natural safety switch based on alemtuzumab (anti-CD52 mAb), Ma et al. extended these studies [81]. Indeed, alemtuzumab, recognizing CD52 on CAR-T cells, was able to remove CD4 CAR-T cells after tumor depletion, thus limiting toxicity. However, further studies are needed to find the best dosage of alemtuzumab that leads to the removal of most CAR-T cells without compromising their antitumor efficacy.


CD5 is a type-I transmembrane glycoprotein of 67 kDa, belonging to scavenger receptor cysteine-rich superfamily [82]. Since it is expressed in about 80% of T-ALLs and T-cell lymphomas, CD5 represents a surface marker of malignant T-cells [83]. In normal cells, its expression is found on thymocytes, peripheral T cells and a subset of B-cells [48, 84]; but it has been reported to be expressed on other immune-cell subtypes such as macrophages and dendritic cells [85, 86]. CD5 participates in T-cell development and function, acting as a negative regulator of TCR signalling [82, 87, 88]. It protects against autoimmunity, preventing T-cells from uncontrolled self-reactivity [88].

Some clinical trials reported tumor cells depletion in patients with T-ALL and cutaneous T-cell lymphoma after treatment with toxin-conjugated anti-CD5 mAbs [89,90,91]. Importantly, no severe side effects were observed during these studies. Thus, the development of CAR-T cells directed against this surface marker seemed a safe and useful strategy for the treatment of T cell malignancies.

As reported in a preclinical work, T cells engineered to express a second-generation CD5 CAR, incorporating the CD28 costimulatory domain, showed low surface CD5 level [92]. This produced poor fratricide and allowed ex vivo expansion. T-ALL and T-cell lymphoma cells were successfully eliminated in vitro, and disease progression was controlled in vivo in two different CD5+ T-ALL models. Considering the promising results of this study, an ongoing clinical trial (NCT03081910) is evaluating the efficacy and safety of these CARs.

Other studies demonstrated that also the use of CD5-negative cells and CD5-CRISPR-Cas9-edited T-cells could overcome the fratricide related to the innate expression of CD5 promoting the antitumor efficacy against T-cell leukemia cell lines [93, 94]. A research group investigated CD5-CAR-edited NK cells, using an approach based on CAR incorporating a costimulatory domain 2B4 (CD25-2B4-CAR NK-92 cells), demonstrating a great efficacy against CD5+ malignant cells either in vitro and in vivo [95].

Recently, a bioepitopic CAR with fully human heavy-chain variable (FHVH) domains for the recognition of different epitopes of CD5, was developed [96]. Also in this case, fratricide in CD5 CAR-T cells was prevented through CD5 knockout via CRISPR-Cas9 genome editing. An enhanced and prolonged efficacy was confirmed through in vitro and in vivo studies.

In another study, T cells were transduced to express third generation CD5 CARs including the CD28 and 4-1BB costimulatory domains [97]. The CD5 CAR-T cells efficiently lysed CD5+ malignant T cell lines and primary cells in vitro, and tumor progression was controlled in vivo. Unfortunately, this construct also induced toxicity against normal T cells.


CD7 is a transmembrane glycoprotein of 40 kDa widely expressed during T-cell differentiation from progenitors or on mature T and NK cells. It is expressed at high levels in lymphoblastic T-cell leukemia, lymphomas and in a subset of peripheral T-cell lymphomas (PTCL) [98, 99]. It plays a significant role in T-cell activation and interactions with other immune cells, but it does not seem to have a pivotal role in T-cell development or function. Indeed, studies performed on murine models showed that T cells lacking in CD7 reported unaltered homeostasis and development, also retaining their short-term effector function and antitumor activity [54, 100]. The activity of an anti-CD7 mAb-ricin A chain immunotoxin in patients with T-cell lymphomas and leukemia, was evaluated [101]. Although no heavy CD7-related toxicity was observed, the antitumor effects were moderate, due to the low activity of murine antibodies on human patients [99].

Further studies have been performed on CD7 as a promising target for CAR-T cell therapies. However, unlike CD5, the incomplete down-regulation of CD7 on engineered CAR-T cells causes fratricide and prevents their ex vivo expansion [102]. Then, to avoid self-antigen targeting in CAR-T cells, CD7 surface expression must be abrogated. To avoid fratricide effect, another intriguing strategy is based on naturally occurred CD7-negative T cells as a source for CAR-T generation. The CD7-negative population can be easily isolated from bulk T cells using a two-step magnetic isolation protocol. This T-cell subpopulation, after the CAR-T engineering, is characterized by a favourable biological profile. Indeed, they are predominantly CD4+ effector memory and CD4+ and terminally differentiated effector memory cells with a preserved expansion activity and viability. Moreover CD7 CAR-T cells are characterized by an effective antitumor immune response, as demonstrated by their ability to kill both CD7 and CD19 expressing haematological malignant cells [103].

Over the past few years, three other groups reported the efficacy of CD7-specific CARs in preclinical models of T-cell malignancies. All these studies considered the abrogation of surface expression of CD7, simply by modifying the CD7 gene or inhibiting the CD7 protein trafficking to the surface of cells [54, 55, 104]. In detail, PEBLs technology prevents CD7 surface expression retaining newly formed CD7 in the ER or Golgi [104,105,106]. TALEN and CRISPR systems are other well-known strategies for the knocking-out of the target gene [102]. This approach has been considered in an ongoing Phase I clinical trial (NCT03690011) which was based on the investigation of the effects related to the presence of CD7-CRISPR-Cas9-edited CD7 CAR-T cells in patients with CD7+ T-cell malignancies, including T-ALL [99]. In another study, anti-CD7 CAR-T cells using CRISPR/Cas9 and lentiviral transduction approaches (TRAC-/-CD7-/-, CD7 UCAR) against T-ALL [107] were developed. The CD7 UCAR-T cells could induce the killing of primary T-ALL cells in vitro, with high degranulation level and proinflammatory cytokines release, and were able to reduce tumor growth and increase mice survival in vivo.

The potential use of a third generation (CD28 and 4-1BB co-stimulatory domains) CD7-specific uCAR for the treatment of r/r T-ALL and non-Hodgkin’s T-cell lymphoma, was described [104]. The abrogation of both CD7 and T-cell receptor alpha chain (TRAC) was induced using CRISPR/Cas9 technology. Since abrogation leads to impaired TCR signalling, this strategy could prevent either fratricide or T-cell-mediated graft-versus-host diseases. CD7 uCAR-T cells proved to be effective against human T-ALL cell lines and primary T-ALL cells. However, a short lifespan is expected from these allogenic CAR-T cells, related to the immune reconstitution of the host. This effect prevents cells aplasia, but it could be not effective in cancer recurrence [102]. Moreover, both strategies based on CRISPR-Cas9 gene editing technology or involving ER retention of CD7 molecules require genetic T-cell engineering, which can lead to long-term side effects [108]. For this reason, current trends involve the culturing of anti-CD7 CAR-T cells with a recombinant anti-CD7 antibody as a safe and cost-effective strategy in T-ALL therapy [109]. Recently, the addition of a blocking antibody has been demonstrated to increase T-cell viability and expansion and prevent cell exhaustion, thus obtaining long-lasting and effective anti-CD7 CAR-T cells for the treatment of T-cell malignancies. In a phase I clinical trial, anti-CD7 CAR-T cells, edited from stem cell transplantation, were administered in 20 patients with r/r T-ALL demonstrating great efficacy and low toxicity [110]. Then, a multicentre phase II trial of CD7 CAR-T cells derived from donors is now ongoing (NCT04689659).

In the last few years, researchers have focused on different targeting domains for CARs, such as nanobodies, peptides and other ligands [111,112,113,114,115]. Thanks to their small size, easy production, high stability and targeting selectivity, nanobodies emerged as promising strategies [112]. In this regard, several pre-clinical and clinical studies have reported a comparable efficacy between scFV-based CAR-Ts and nanobody-based CAR-Ts [116]. Tandem CD7 nanobody combined with an endoplasmic reticulum/Golgi-retention motif peptide able to prevent fratricide thanks to its CD7 blocking effect, was reported [117]. Autologous nanobody-derived fratricide-resistant CD7 CAR-T cells proved a long-lasting antitumor activity in r/r T-ALL with manageable toxic effect. The manufacturing of nanobody derived CD7 CAR-T cells also induced haematological and extramedullary remission in a 11-year-old male with TP53 mutated r/r ETP-ALL/LBL [118]. The patient was enrolled in an anti-CD7 CAR-T clinical trial (NCT04785833) after failure of 4 lines of salvage therapies. Grade 3 CRS and macrophage activation syndrome were observed, but these side effects were reversible.

These approaches often require genetic editing to ablate the CD7 gene or block CD7 cell expression and induce the selective targeting of CD7 on the CAR-T cells. A novel approach focuses on the masking of natural CD7 molecules, by CD7-targeting CAR. The relevant reduction in CD7 accessible epitopes allowed to overcome the fratricide challenge. In a recent study, this approach showed an improved efficacy, compared to that recorded from sorted CD7-negative and CD7 knocked-out CAR-T cells, thanks to the greater amount of CAR+ cells obtained and higher percentages of CD8+ central memory T cells [119]. Based on these results, a first-in-human phase 1 trial (NCT04572308) was performed involving 20 patients, 14 of them with r/r T-ALL. Patients were treated with naturally selected CD7 CAR-T cells, and most of them achieved complete remission reporting no relevant side effects. However, a larger number of patients and longer follow-up are required to validate these results.


CD25, also known as IL2R, represents the alpha chain portion of interleukin 2 receptor. It is expressed on activated T-cells and participates in their proliferation and death, as well as in maintenance of regulatory T-cells. Previous studies reported that this receptor plays a key role in refractory ALL or AML [120, 121]. In a single case-report basiliximab, an anti-CD25 mAb, showed its efficacy on a 5-year-old patient with T-ALL. In detail, the patient reported a clinical status consistent with the febrile ulceronecrotic Mucha-Habermann disease, which prevented the intensification of chemotherapy due to the relative superinfection. In this context, the co-treatment with basiliximab improved cutaneous eruptions, allowing to intensify chemotherapy and proceed with the bone marrow transplantation [122]. This event gave hope for the use of mAbs targeting CD25 as adjuvants for T-ALL therapy. However, to date there are no clinical trials ongoing using this molecule in the treatment of T-ALL patients.


CD30 is a member of the tumor necrosis factor receptor (TNFR) superfamily, expressed not only in Hodgkin's lymphoma but also in other haematological diseases such as anaplastic large cell lymphomas, cutaneous and peripheral T-cell lymphomas, adult T-cell leukemia/lymphoma and diffuse large B-cell lymphomas. In normal cells, it is present on T helper cells, on a subset of CD8+ T cells and on a subset of B lymphocytes [123].

Since in preclinical studies anti-CD30 treatment has been found to be effective in removing cancer cells without affecting normal lymphopoiesis, CD30 could be considered a potential candidate for immunotherapeutic targeting [124, 125]. In this context a CD30 antibody-drug conjugate, brentuximab vedotin (BV), has achieved therapeutic approval for peripheral T cell lymphoma (PTCL) and cutaneous T cell lymphoma (CTCL) and Hodgkin lymphoma, both as monotherapy or in combination with standard chemotherapy [126, 127]. Furthermore, CD30 CAR-T cells have been evaluated in clinical trials for the treatment of r/r Hodgkin lymphoma and anaplastic large cell lymphoma patients, showing good tolerability but modest efficacy [128, 129].

Since CD30 is expressed on 38% of cases of T-ALL and is up-regulated during high-dose chemotherapy [130], anti-CD30-based immunotherapy could be a promising strategy for T-ALL patients. However, to our knowledge no clinical studies are ongoing for the evaluation of CD30 targeting in T-ALL patients.


CD38 is a type II transmembrane glycoprotein of 45 kDa playing a dual role as a receptor and cell surface enzyme (ectoenzyme) [131]. This receptor is expressed at early stages of B and T-cell development, it is downregulated in mature naïve lymphocytes, re-expressed after T-cell activation, and finally lost in the T-cell memory compartment [10, 132]. As an ectoenzyme it enzymatically converts nicotinamide adenine dinucleotide (NAD) to cyclic ADP-ribose, an important calcium-mobilizing second messenger [133]. In T cells, CD38 signalling is associated with TCR function, inducing the activation of intracellular molecules as Zap70, Erk and Akt/PKB [134]. Its ligation induces death of T-cell precursors and contributes to the selection of thymocytes in the thymus. CD38 is also implicated in the regulation of lymphocyte adhesion to endothelial cells and regulates in vitro cytotoxic T-cell activity.

Since it is widely expressed in haematological tumors, CD38 targeting may provide a rationale for novel therapeutic strategies involving CAR-T cells [135, 136].

Recently, CD38 expression has been demonstrated by flow cytometry in different T-ALL subtypes [137]. On these findings, T-ALL patients who relapse or do not respond to conventional therapies could be treated with antiCD38-mAbs. Moreover, the treatment with all-trans retinoic acid (ATRA), clinically used for acute promyelocytic leukemia (APL), can induce CD38 upregulation in CD38low adult T-cell leukemia (ATL) cells, making them susceptible to CD38 CAR-T cells [138]. The combining effect of ATRA and INF-α eradicated more than 95% of these leukemic cells. However, the safety of this treatment still needs to be clarified.

Interestingly, preclinical efficacy of anti-CD38 daratumumab in T-ALL has been reported [139]. CD38 was identified in ETP-ALL and in non-ETP-ALL patient leukemic cells. It was found that almost all T-ALL patient-derived xenografts (PDXs) were sensitive to daratumumab. Furthermore, it was well tolerated by a 19-yr old patient with refractory ETP-ALL and induced a temporary reduction of T-cell lymphoblasts in the bone marrow [140]. Finally, daratumumab eradicated MRD in some T-ALL patients suffering relapse after allogeneic stem cell transplantation [141]. Recently, in vitro and in vivo effects of ATRA in combination with CD38-targeting CAR-T cells or daratumumab, were evaluated [142]. At first, authors proved the robust effect of their CD38 CAR-T cells on lymphoid cells expressing high levels of CD38, such as T-ALL. Interestingly, they found that ATRA significantly increased the expression of CD38 in cancer cell lines with low expression of this marker, thus producing a synergistic effect with CAR-T cells or daratumumab and expanding the possibility of considering CD38 as an efficient target in a wider type of lymphoid malignancies as well. By another approach, combining daratumumab with CD47 inhibitor has been demonstrated to increase phagocytosis of T-ALL cells [143].

The preclinical activity of ISB 1442, a human anti-CD38 and anti-CD47 bispecific antibody currently in a Phase 1/2 clinical trial for r/r MM (NCT05427812), was evaluated in AML and T-ALL [144]. The co-targeting of CD38 and CD47 by a single antibody with increased Fc effector functions led to a strong in vitro phagocytosis, especially in CD38 over-expressing cell lines, and to a potent ADCC.

Two ongoing clinical trials are evaluating the effectiveness of daratumumab (NCT03384654) and isatuximab (NCT03860844) for r/r B or T-ALL. Anti CD38 immunotherapies using ATRA have been evaluated in a recent clinical trial (NCTC02751255) in combination with daratumumab in MM. However, a limited activity emerged in patients due to a temporary increase of CD38 antigen expression (145).

Recently, a novel CD38 x CD3 BTCE with Fc domain engineered to limit Fcγ receptor binding and non-specific T-cell activation, is currently being investigated in a Phase 1 study for patients with r/r T-ALL and AML (NCT05038644) [146].


CD43 is a mucin-like type I transmembrane protein expressed on haematopoietic cells, such as T-lymphocytes, granulocytes, NK cells, monocytes, platelets, and haematopoietic stem cells, but not on mature erythrocytes and B-cell subpopulations. It is involved in a variety of functions including cell activation, proliferation, adhesion, and invasion and may be implicated in immune response by modulating cell growth, survival, and apoptosis [147]. Several studies reported the association between CD43 and cancer: CD43 glycoforms were detected in different tumors also of non-haematopoietic origin but not in the normal tissues [148].

The targeting of a unique epitope of CD43, named UMG1, has been recently proposed as a selective strategy for T-ALL treatment [149]. This epitope was found expressed in approximately 50% of cases of T-ALL patient-derived samples (82% of EGIL TIII patients). Importantly, no antigen expression was found in normal tissues, except for cortical thymocytes and a very small subpopulation of peripheral blood T lymphocytes (<5%), thus excluding the fratricide risk and, also, the targeting of other components of the normal hematopoietic and non-hematopoietic compartments. The expression profile of this specific epitope appears, therefore, highly promising, and significantly differs from the canonical CD43 pattern of expression, as characterized by expression of other epitopes already described, whose targeting, instead, would result in relevant on target/off tumor side effects.

An afucosylated humanized mAb was produced with a long selection process from a previous murine mAb [150,151,152] and, on this basis, two different IgG-like BTCEs against UMG1 have been developed: bivalent UMG1-BTCE (2+2), with two arms binding to CD3ε, and monovalent UMG1-BTCE (2+1), with one arm binding to CD3ε. Importantly, these approaches resulted in significant anti-leukemic in vitro and in vivo activity, which was higher for BTCEs treatment as compared to afucosylated mAb. In particular, both BTCE constructs were effective against T-ALL preclinical models in a clinical range of concentrations similar to Blinatumomab, the first BTCE approved for B neoplasms [153]. However, higher anti-leukemic activity was observed with monovalent BTCE, mainly due to reduced T-lymphocytes exhaustion [149].

These results suggest that the targeting of this epitope may represent a safe and effective new therapeutic option against T-ALL to be explored in the front-line as well as maintenance treatment, in a first in human clinical trial.


CD44 is a type I single-span transmembrane glycoprotein that acts as a cell surface receptor for a component of the extracellular matrix, the hyaluronan. The CD44 gene has various isoforms, differentially expressed in human tissues [154]. The standard isoform (CD44s) is the most abundant in the haematopoietic compartment, whereas variant isoforms (CD44v) are present in some populations of epithelial and haematopoietic cells, particularly during development, in some types of carcinoma and after lymphocyte activation [155]. In cancer cells of epithelial origin, the CD44v6 isoform is usually overexpressed, playing a key role in migration, metastasis and chemoresistance. CD44 was thought to be involved in the homing of lymphocytes into lymph nodes [156] and in the anchoring of haematopoietic precursors [157] and leukemic cells [158] within the bone marrow niche. Moreover, it is highly expressed in the earliest human CD34+ T-cell precursors of thymus and downregulated on T-cell commitment and during T-cell development, while it is preserved in myeloid-primed intra-thymic progenitors with dendritic cell potential [159].

CD44 has been well studied in solid tumors for its function in maintaining cancer-initiating cell properties [160], but its contribution in haematological malignancies has been formally demonstrated very recently [158]. CD44 is a direct transcriptional target of NOTCH1, which was upregulated in NOTCH1-induced preleukemic blasts [161]. Though CD44 expression is aberrant in leukemic blasts of T-ALL patients, no correlation with prognosis and survival has been demonstrated [162]. Since it is also overexpressed in NOTCH1-induced T-ALL leukemic cells treated with chemotherapeutic drugs [163], CD44 may be considered as a valuable target for new therapies against relapsed or chemo resistant T-ALLs. However, to date, no clinical trial has been activated for anti-CD44 therapy in T-ALL patients.


CD52 is a surface glycoprotein, that is not present in normal haematopoietic progenitors but is widely expressed in B- and T-cells, lymphocytes, monocytes, and macrophages [164]. High expression levels of CD52 are also reported in some cases of T-ALL; however, pre-T leukemic blasts showed lower expression than mature cells, indicating that immunotherapeutic approaches involving CD52 might be limited to mature subtypes [164,165,166].

CD52 function is not yet completely understood but some studies reported that it can induce T-cell activation and stimulate the production of CD4+ regulatory T-cells, thus activating immunosuppressive mechanisms [167, 168]. Many trials investigated the efficacy of alemtuzumab (CAMPATH-1H), as a mAb targeting CD52, on T-cell diseases including T-ALL, with poor results [169, 170]. The latest trial, involving patients with more than 10% of CD52+ lymphoblasts, focused on the efficacy and safety of the combination of alemtuzumab with chemotherapy for the eradication of MRD in T-ALL patients. However, these studies demonstrated no advantage over the other available therapies and the occurrence of many side effects that led to the termination of trials involving CD52 [171]. Other approaches involved CD52-knockout CAR-T cells, which were obtained through TALEN technology. A depletion of patient T-cells using alemtuzumab and a subsequent infusion of the engineered T-cells have been proposed in the attempt to enhance their engraftment and retention, thus representing a promising treatment for T-ALL [172, 173].


CD99 is an O-glycosylated transmembrane protein present on leukocytes and involved in cell adhesion, T-cell rosetting and trans-endothelial migration [174]. Preclinical studies reported that anti-CD99 mAbs induced caspase-independent cell death of AML cell lines and primary blasts [175], T-cell lines [176], and TEL/AML1-positive ALL and normal B-cell precursors [177].

CD99 expression is higher in T-ALL cells than in haematopoietic stem cells and normal T-cells [178] and its detection by flow cytometry is useful to detect MRD in T-ALL patients [179], representing a promising target. An in vitro study showed that the treatment of T- and B-cell lines with anti-CD99 antibodies upregulated heat shock protein 70 (HSP70), increasing NK-dependent cytotoxicity [180]. Moreover, Shi et al. demonstrated that CAR-T cells targeting CD99 specifically recognized and eradicated T-ALL cell lines and primary tumor cells without normal blood cells toxicity [181]. Thus, CD99 might represent a candidate for alternative therapeutic approaches against T-ALL to be validated on early clinical setting.


CD194 (CCR4) is the receptor for two chemokines, CCL17 and CCL22, expressed on Type 2 helper T-cells (Th2) and Treg. Its expression is high in mature T-cells, and it has been shown to be implicated in the homing of leukocytes to inflamed sites [182]. Mogamulizumab is an anti-CCR4 humanized antibody, which has been approved in Japan since 2014 for patients with adult T-cell leukemia. This drug showed a great potential in T-ALL therapy as an adjuvant for chemotherapy and it has been considered as a promising strategy for transplant-ineligible patients with adult T-cell leukemia or lymphoma [183]. Furthermore, an interesting approach based on CCR4 CAR-T cells displayed antigen-dependent potent cytotoxicity against patient-derived cell lines of T-cell lymphoma, thus suggesting the feasibility of such approach also for CCR4-expressing T-ALL patients [184].


Another promising target for T-ALL immunotherapy is represented by a chemokine receptor CCR9. Indeed, while CCR9 is expressed only on a small fraction of normal T cells (<5%), it could be found in >70% of cases of T-ALL, including >85% of relapsed/refractory disease. More recently, CAR-T-cells targeting CCR9 have been demonstrated to induce high anti-leukemic in vitro and in vivo activity, without fratricide effects. Thus, such an approach holds the promise to be a highly effective treatment strategy for T-ALL, avoiding detrimental effects of T cell aplasia or an expensive approach of genome engineering for the prevention of fratricide activity [185].


CXCR4 is a chemokine receptor belonging to the superfamily of G protein-coupled receptors and it is implicated in several regulating processes, including hematopoiesis and immune response [186]. CXCR4 interacts with CXCL12 (CXC motif chemokine 12)/Stromal cell-derived factor-1 (SDF-1), that is a chemokine with a critical role for cells escaping from thymus to bone marrow, leukemia initiating cells and trans-endothelial migration [187, 188]. For this reason, studies blocking CXCR4 by mAbs [189] or small molecule [190] have shown a great potential effect on leukemia maintenance and progression [191]. A key role of CXCR4 in T-ALL pathogenesis was demonstrated by the inhibition of the receptor expression on NOTCH1-induced T-ALL mice, using a short hairpin RNA (shRNA) [192]. Authors reported an impaired tumor cells migration and an increased cell death in vitro and efficacy in vivo.

A phase II trial assessing the efficacy and safety of a small synthetic peptide targeting CXCR4, BL8040, in combination with Nelarabine for the treatment of r/r T-ALL patients (NCT02763384), is ongoing.


Interleukin-7 (IL-7) receptor is characterized by a heterodimeric structure with a specific α chain (IL7Rα) and a gamma portion, which is common to numerous cytokine receptors [193]. IL-7 was initially defined as a growth factor for B-cells, but its involvement in cell growth was demonstrated to be also important for T-cells. Through the induction of IL7R signalling, IL-7 defines the maturation of T-cells from the thymus [194, 195]. It also controls naïve and memory T-cells and plays a key role in lymphopoiesis [196]. Impairments in IL7Rs are often reported in T-ALL diseases and they may depend on mutations occurring in exon 5 or exon 6 encoding for IL7Rα. The simultaneous role of IL7R as a target for NOTCH1, a generally mutated gene for T-ALL, also contributed to the pathogenesis [11, 197].

To date, several studies defined a direct relation between the signalling pathway of IL7R and the pathogenesis of T-ALL [194, 198]. One of the most recent investigations, based on a loss-of-function approach, formally demonstrated that the oncogenic programme of NOTCH1 and leukemia-initiating cells (LIC) activity were dependent on IL7R expression [199]. In this context, a fully human anti-IL7R antibody, which impaired IL-7/IL7R-mediated signalling, making T-ALL cells sensitive to chemotherapy, and promoting leukemia cell killing through a NK-mediated cytotoxicity, was generated [200]. In a subsequent study, a new anti-IL7R murine mAb, demonstrating its great efficacy through an ADCC-mediated mechanism against PDX T-ALL cells, was developed. Further in vivo studies proved the efficacy of the mAb on leukemic cell death both through ADCC-dependent and -independent mechanisms [201]. However, the presence of IL7R also in non-haematopoietic tissues makes this strategy still challenging; thus, further investigations are needed to confirm the efficacy and applicability in clinical practice.


The TCRαβ is a heterodimer expressed on T cells, which interacts with molecules presented by the MHC. It contains two variable protein chains, namely TCRα and TCRβ combined with invariant CD3 molecules. TCRβ is composed by variable (V), diversity (D), joining (J), and constant (C) regions, while TCRα lacks the J-region. TCR diversity is strictly dependent by the recombination of the various domains resulting in specific T-cell clonality [202]. TCRβ-chain constant domains 1 and 2 (TRBC1 and TRBC2) are exclusively present on mature T cells while TRBC1 is also expressed in about 50% of TCR+ T-cell lymphomas. On these bases, a recent study focused on the development of third generation anti-TRBC1 CAR T cells, containing CD28 and OX40 co-stimulatory domains, to selectively recognize TRBC1+ cells in vitro and in vivo leukemia models. The selective killing of malignant T cells has been obtained using anti-Vβ8 and Vβ5 CAR-T cells, which preserve Vβ8- and Vβ5- normal T cells [202].

On these premises, an ongoing clinical study (NCT03590574) is investigating the safety and efficacy of a CAR-T cell treatment against TRBC1+ T cell malignancies.

Table 1 summarizes clinical trials involving CAR-T, mAbs or BTCE-based therapies for T-ALL treatment considering the aforementioned targets.

Table 1 CAR-T-, mAbs- or BTCE-based therapies currently under clinical investigation for T-ALL treatment


T-ALL is a highly aggressive and lethal disease in relapsed/refractory patients. Although new molecular insights are driving the development of novel targeted therapy, the prognosis of T-ALL patients still remains poor. In this scenario, harnessing the immune system against leukemic T cells is a promising possibility on the therapeutic horizon for a durable response. Even if the shared expression of targets between normal and neoplastic T cells is the major obstacle to the development of effective strategies for T-ALL for life-threatening T-cell aplasia and severe opportunistic infections, new technologic options with CAR-T and BTCEs (Fig. 3) targeting highly selective T-ALL epitopes/antigens keep the promise to overcome these relevant challenges and improve the prognosis of this still orphan disease. In conclusion, immunotherapy is offering novel opportunities for T-ALL and the ongoing preclinical and clinical research will readily provide a more favorable clinical scenario in the next future.

Fig. 3
figure 3

Schematic representation of immunotherapeutic approaches in T-ALL. Promising approaches based on monoclonal antibodies (mAbs), chimeric antigen receptor (CAR) T-cells and Bispecific T-cell engagers (BTCEs) to increase cure rates in T-ALL

Availability of data and materials

Not applicable.



T-cell acute lymphoblastic leukemia


Bispecific T-cell engagers


Chimeric antigen receptor


Acute lymphoblastic leukemia


World Health Organization


B-cell acute lymphoblastic leukemia


Early T-cell precursor lymphoblastic leukemia


Central nervous system




Minimal residual dose




Haematopoietic cell transplantation


Stem cell transplantation


Monoclonal antibodies


Fc regions to Fc gamma receptors


Antibody-dependent cellular cytotoxicity


Antibody-dependent cellular phagocytosis


Complement-dependent cytotoxicity


Antibody–drug conjugates


Acute myeloid leukemia


T-cell lymphoma


Major histocompatibility complex


Tumor-associated antigen


Single chain variable fragments


Immunoglobulin G


Neonatal Fc receptor


Monovalent BTCEs


Bivalent BTCEs


Cytokine release syndrome


Immune effector cell-associated neurotoxicity syndrome


Herpes simplex virus thymidine kinase


Inducible cas9


Protein expression blockers


Endoplasmic reticulum


Natural killer


Acute respiratory distress syndrome


C-reactive protein


Cortical T-ALL


T-cell receptor


Fully human heavy-chain variable


Peripheral T-cell lymphomas


T-cell receptor alpha chain


Nicotinamide adenine dinucleotide


All-trans retinoic acid


Acute promyelocytic leukemia


Adult T-cell leukemia


Patient-derived xenografts


Heat shock protein 70


Type 2 helper T-cells




Interleukin-7 α chain


Leukemia-initiating cells


  1. Rafei H, Kantarjian HM, Jabbour EJ. Recent advances in the treatment of acute lymphoblastic leukemia. Leuk Lymphoma. 2019;60(11):2606–21.

    Article  CAS  Google Scholar 

  2. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al. WHO classification of tumours of haematopoietic and lymphoid tissues. In: Swerdlow SH, editor. Lyon: International agency for research on cancer; 2008. p. 439.

  3. Zak T, Gao J, Behdad A, Mehta J, Altman JK, Ji P, et al. Clinicopathologic and genetic evaluation of B-lymphoblastic leukemia with intrachromosomal amplification of chromosome 21 (iAMP21) in adult patients. Leuk Lymphoma. 2022:63(13):3200–07.

    Article  CAS  Google Scholar 

  4. Raanani P, Trakhtenbrot L, Rechavi G, Rosenthal E, Avigdor A, Brok-Simoni F, et al. Philadelphia-chromosome-positive T-lymphoblastic leukemia: acute leukemia or chronic myelogenous leukemia blastic crisis. Acta Haematol. 2005;113(3):181–9.

    Article  Google Scholar 

  5. Hernández AF, Menéndez P. Linking pesticide exposure with pediatric leukemia: potential underlying mechanisms. Int J Mol Sci. 2016;17(4):461.

    Article  Google Scholar 

  6. Iacobucci I, Mullighan CG. Genetic basis of acute lymphoblastic leukemia. J Clin Oncol. 2017;35(9):975.

    Article  CAS  Google Scholar 

  7. Pui C-H, Relling MV, Downing JR. Acute lymphoblastic leukemia. N Engl J Med. 2004;350(15):1535–48.

    Article  CAS  Google Scholar 

  8. Milani L, Lundmark A, Kiialainen A, Nordlund J, Flaegstad T, Forestier E, et al. DNA methylation for subtype classification and prediction of treatment outcome in patients with childhood acute lymphoblastic leukemia. Blood, J Am Soc Hematol. 2010;115(6):1214–25.

    CAS  Google Scholar 

  9. Van Vlierberghe P, Pieters R, Beverloo HB, Meijerink JP. Molecular-genetic insights in paediatric T-cell acute lymphoblastic leukaemia. Br J Haematol. 2008;143(2):153–68.

    Article  Google Scholar 

  10. Bayón-Calderón F, Toribio ML, González-García S. Facts and challenges in immunotherapy for T-cell acute lymphoblastic leukemia. Int J Mol Sci. 2020;21(20):7685.

    Article  Google Scholar 

  11. Weng AP, Ferrando AA, Lee W, Morris JP IV, Silverman LB, Sanchez-Irizarry C, et al. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science. 2004;306(5694):269–71.

    Article  CAS  Google Scholar 

  12. Noronha EP, Marques LVC, Andrade FG, Thuler LCS, Terra-Granado E, Pombo-de-Oliveira MS, et al. The profile of immunophenotype and genotype aberrations in subsets of pediatric T-cell acute lymphoblastic leukemia. Front Oncol. 2019;9:316.

    Article  Google Scholar 

  13. Haydu JE, Ferrando AA. Early T-cell precursor acute lymphoblastic leukemia (ETP T-ALL). Curr Opin Hematol. 2013;20(4):369–73.

    Article  CAS  Google Scholar 

  14. Barot SV, Advani AS. Treatment of adult B-and T-cell acute lymphoblastic leukemia: an overview of current treatments and novel advances. In: Litzow MR, Raetz EA, editors. Clin Manag Acute Lymphoblast Leuk. Switzerland: Springer Cham; 2022. p. 105–33.

  15. Hunger SP, Mullighan CG. Acute lymphoblastic leukemia in children. N Engl J Med. 2015;373(16):1541–52.

    Article  CAS  Google Scholar 

  16. Karbasian-Esfahani M, Wiernik PH, Novik Y, Paietta E, Dutcher JP. Idarubicin and standard-dose cytosine arabinoside in adults with recurrent and refractory acute lymphocytic leukemia. Cancer Interdiscip Int J Am Cancer Soc. 2004;101(6):1414–9.

    Google Scholar 

  17. Winter SS, Dunsmore KP, Devidas M, Wood BL, Esiashvili N, Chen Z, et al. Improved survival for children and young adults with T-lineage acute lymphoblastic leukemia: results from the Children’s Oncology Group AALL0434 methotrexate randomization. J Clin Oncol. 2018;36(29):2926.

    Article  CAS  Google Scholar 

  18. Jabbour E, O’Brien S, Konopleva M, Kantarjian H. New insights into the pathophysiology and therapy of adult acute lymphoblastic leukemia. Cancer. 2015;121(15):2517–28.

    Article  Google Scholar 

  19. Terwilliger T, Abdul-Hay M. Acute lymphoblastic leukemia: a comprehensive review and 2017 update. Blood Cancer J. 2017;7(6): e577-e.

    Article  Google Scholar 

  20. Dobson SM, García-Prat L, Vanner RJ, Wintersinger J, Waanders E, Gu Z, et al. Relapse-fated latent diagnosis subclones in acute B lineage leukemia are drug tolerant and possess distinct metabolic programs characterization of relapse-fated clones in diagnosis B-ALL. Cancer Discov. 2020;10(4):568–87.

    Article  CAS  Google Scholar 

  21. Marks DI, Paietta EM, Moorman AV, Richards SM, Buck G, DeWald G, et al. T-cell acute lymphoblastic leukemia in adults: clinical features, immunophenotype, cytogenetics, and outcome from the large randomized prospective trial (UKALL XII/ECOG 2993). Blood, J Am Soc Hematol. 2009;114(25):5136–45.

    CAS  Google Scholar 

  22. Modvig S, Madsen H, Siitonen S, Rosthøj S, Tierens A, Juvonen V, et al. Minimal residual disease quantification by flow cytometry provides reliable risk stratification in T-cell acute lymphoblastic leukemia. Leukemia. 2019;33(6):1324–36.

    Article  CAS  Google Scholar 

  23. DeAngelo DJ, Yu D, Johnson JL, Coutre SE, Stone RM, Stopeck AT, et al. Nelarabine induces complete remissions in adults with relapsed or refractory T-lineage acute lymphoblastic leukemia or lymphoblastic lymphoma: cancer and leukemia Group B study 19801. Blood, J Am Soc Hematol. 2007;109(12):5136–42.

    CAS  Google Scholar 

  24. Gökbuget N, Basara N, Baurmann H, Beck J, Brüggemann M, Diedrich H, et al. High single-drug activity of nelarabine in relapsed T-lymphoblastic leukemia/lymphoma offers curative option with subsequent stem cell transplantation. Blood, J Am Soc Hematol. 2011;118(13):3504–11.

    Google Scholar 

  25. Kaushik B, Pal D, Saha S. Gamma secretase inhibitor: therapeutic target via NOTCH signaling in T cell acute lymphoblastic leukemia. Curr Drug Targets. 2021;22(15):1789–98.

    Article  CAS  Google Scholar 

  26. Goebeler M-E, Bargou R. Blinatumomab: a CD19/CD3 bispecific T cell engager (BiTE) with unique anti-tumor efficacy. Leuk Lymphoma. 2016;57(5):1021–32.

    Article  CAS  Google Scholar 

  27. Goekbuget N, Dombret H, Bonifacio M, Reichle A, Graux C, Havelange V, et al. BLAST: a confirmatory, single-arm, phase 2 study of blinatumomab, a bispecific T-cell engager (BiTE®) antibody construct, in patients with minimal residual disease B-precursor acute lymphoblastic leukemia (ALL). Blood. 2014;124(21):379.

    Article  Google Scholar 

  28. Leonard J, Goldenberg D. Preclinical and clinical evaluation of epratuzumab (anti-CD22 IgG) in B-cell malignancies. Oncogene. 2007;26(25):3704–13.

    Article  CAS  Google Scholar 

  29. Steinfeld SD, Youinou P. Epratuzumab (humanised anti-CD22 antibody) in autoimmune diseases. Expert Opin Biol Ther. 2006;6(9):943–9.

    Article  CAS  Google Scholar 

  30. Zhang C, He J, Liu L, Wang J, Wang S, Liu L, et al. CD19-directed fast CART therapy for relapsed/refractory acute lymphoblastic leukemia: from bench to bedside. Blood. 2019;134:1340.

    Article  Google Scholar 

  31. Golay J, Introna M. Mechanism of action of therapeutic monoclonal antibodies: promises and pitfalls of in vitro and in vivo assays. Arch Biochem Biophys. 2012;526(2):146–53.

    Article  CAS  Google Scholar 

  32. Charles WZ, Faries CR, Street YhT, Flowers LS, McNaughton BR. Antibody‐recruitment as a therapeutic strategy: a brief history and recent advances. Chembiochem. 2022:e202200092.

  33. Chung S, Lin YL, Reed C, Ng C, Cheng ZJ, Malavasi F, et al. Characterization of in vitro antibody-dependent cell-mediated cytotoxicity activity of therapeutic antibodies—impact of effector cells. J Immunol Methods. 2014;407:63–75.

    Article  CAS  Google Scholar 

  34. Taylor RP, Lindorfer MA, editors. Cytotoxic mechanisms of immunotherapy: Harnessing complement in the action of anti-tumor monoclonal antibodies. In: Kroemer G, Mantovani A, editors. Semin Immunol. London: Academic Press; 2016. p. 309–16.

  35. Abdollahpour-Alitappeh M, Lotfinia M, Gharibi T, Mardaneh J, Farhadihosseinabadi B, Larki P, et al. Antibody–drug conjugates (ADCs) for cancer therapy: strategies, challenges, and successes. J Cell Physiol. 2019;234(5):5628–42.

    Article  CAS  Google Scholar 

  36. Hoffmann RM, Coumbe BG, Josephs DH, Mele S, Ilieva KM, Cheung A, et al. Antibody structure and engineering considerations for the design and function of antibody drug conjugates (ADCs). Oncoimmunology. 2018;7(3): e1395127.

    Article  Google Scholar 

  37. Tassone P, Goldmacher VS, Neri P, Gozzini A, Shammas MA, Whiteman KR, et al. Cytotoxic activity of the maytansinoid immunoconjugate B-B4–DM1 against CD138+ multiple myeloma cells. Blood. 2004;104(12):3688–96.

    Article  CAS  Google Scholar 

  38. Tassone P, Gozzini A, Goldmacher V, Shammas MA, Whiteman KR, Carrasco DR, et al. In vitro and in vivo activity of the maytansinoid immunoconjugate huN901-N 2′-deacetyl-N 2′-(3-mercapto-1-oxopropyl)-maytansine against CD56+ multiple myeloma cells. Cancer Res. 2004;64(13):4629–36.

    Article  CAS  Google Scholar 

  39. Goli N, Bolla PK, Talla V. Antibody-drug conjugates (ADCs): potent biopharmaceuticals to target solid and hematological cancers—an overview. J Drug Deliv Sci Technol. 2018;48:106–17.

    Article  CAS  Google Scholar 

  40. Hamann PR, Hinman LM, Hollander I, Beyer CF, Lindh D, Holcomb R, et al. Gemtuzumab ozogamicin, a potent and selective anti-CD33 antibody—calicheamicin conjugate for treatment of acute myeloid leukemia. Bioconjug Chem. 2002;13(1):47–58.

    Article  CAS  Google Scholar 

  41. Fu Z, Li S, Han S, Shi C, Zhang Y. Antibody drug conjugate: the “biological missile” for targeted cancer therapy. Signal Transduct Target Ther. 2022;7(1):1–25.

    Google Scholar 

  42. Mardiana S, Gill S. CAR T cells for acute myeloid leukemia: state of the art and future directions. Front Oncol. 2020;10:697.

    Article  Google Scholar 

  43. Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371(16):1507–17.

    Article  Google Scholar 

  44. Benmebarek MR, Karches CH, Cadilha BL, Lesch S, Endres S, Kobold S. Killing mechanisms of chimeric antigen receptor (CAR) T Cells. Int J Mol Sci. 2019;20(6):1283.

  45. Sedykh SE, Prinz VV, Buneva VN, Nevinsky GA. Bispecific antibodies: design, therapy, perspectives. Drug Des Dev Ther. 2018;12:195.

    Article  CAS  Google Scholar 

  46. Klinger M, Brandl C, Zugmaier G, Hijazi Y, Bargou RC, Topp MS, et al. Immunopharmacologic response of patients with B-lineage acute lymphoblastic leukemia to continuous infusion of T cell–engaging CD19/CD3-bispecific BiTE antibody blinatumomab. Blood, J Am Soc Hematol. 2012;119(26):6226–33.

    CAS  Google Scholar 

  47. Mazor Y, Oganesyan V, Yang C, Hansen A, Wang J, Liu H, et al., editors. Improving target cell specificity using a novel monovalent bispecific IgG design. In: Reichert JM, editor. MAbs. United Kingdom: Taylor & Francis; 2016. p. 377–89.

  48. Fleischer LC, Spencer HT, Raikar SS. Targeting T cell malignancies using CAR-based immunotherapy: challenges and potential solutions. J Hematol Oncol. 2019;12(1):1–21.

    Article  Google Scholar 

  49. Zhang J, Hu Y, Yang J, Li W, Zhang M, Wang Q, et al. Non-viral, specifically targeted CAR-T cells achieve high safety and efficacy in B-NHL. Nature. 2022;609(7926):369–74.

    Article  CAS  Google Scholar 

  50. Greco R, Oliveira G, Stanghellini MTL, Vago L, Bondanza A, Peccatori J, et al. Improving the safety of cell therapy with the TK-suicide gene. Front Pharmacol. 2015;6:95.

    Article  Google Scholar 

  51. Tey S-K, Dotti G, Rooney CM, Heslop HE, Brenner MK. Inducible caspase 9 suicide gene to improve the safety of allodepleted T cells after haploidentical stem cell transplantation. Biol Blood Marrow Transplant. 2007;13(8):913–24.

    Article  CAS  Google Scholar 

  52. Yu S, Yi M, Qin S, Wu K. Next generation chimeric antigen receptor T cells: safety strategies to overcome toxicity. Mol Cancer. 2019;18(1):1–13.

    Article  Google Scholar 

  53. Mamonkin M, Mukherjee M, Srinivasan M, Sharma S, Gomes-Silva D, Mo F, et al. Reversible transgene expression reduces fratricide and permits 4–1BB costimulation of CAR T cells directed to T-cell malignancies regulated CAR expression minimizes tonic signaling. Cancer Immunol Res. 2018;6(1):47–58.

    Article  CAS  Google Scholar 

  54. Gomes-Silva D, Srinivasan M, Sharma S, Lee CM, Wagner DL, Davis TH, et al. CD7-edited T cells expressing a CD7-specific CAR for the therapy of T-cell malignancies. Blood, J Am Soc Hematol. 2017;130(3):285–96.

    CAS  Google Scholar 

  55. Png YT, Vinanica N, Kamiya T, Shimasaki N, Coustan-Smith E, Campana D. Blockade of CD7 expression in T cells for effective chimeric antigen receptor targeting of T-cell malignancies. Blood Adv. 2017;1(25):2348–60.

    Article  CAS  Google Scholar 

  56. You F, Wang Y, Jiang L, Zhu X, Chen D, Yuan L, et al. A novel CD7 chimeric antigen receptor-modified NK-92MI cell line targeting T-cell acute lymphoblastic leukemia. Am J Cancer Res. 2019;9(1):64.

    CAS  Google Scholar 

  57. Coventry B, Heinzel S. CD1a in human cancers: a new role for an old molecule. Trends Immunol. 2004;25(5):242–8.

    Article  CAS  Google Scholar 

  58. Bechan GI, Lee DW, Zajonc DM, Heckel D, Xian R, Throsby M, et al. Phage display generation of a novel human anti-CD 1 A monoclonal antibody with potent cytolytic activity. Br J Haematol. 2012;159(3):299–310.

    Article  CAS  Google Scholar 

  59. Carrera Silva EA, Nowak W, Tessone L, Olexen CM, Ortiz Wilczyñski JM, Estecho IG, et al. CD207+ CD1a+ cells circulate in pediatric patients with active Langerhans cell histiocytosis. Blood, J Am Soc Hematol. 2017;130(17):1898–902.

    Google Scholar 

  60. Kim JH, Hu Y, Yongqing T, Kim J, Hughes VA, Le Nours J, et al. CD1a on Langerhans cells controls inflammatory skin disease. Nat Immunol. 2016;17(10):1159–66.

    Article  CAS  Google Scholar 

  61. Sánchez-Martínez D, Baroni ML, Gutierrez-Agüera F, Roca-Ho H, Blanch-Lombarte O, González-García S, et al. Fratricide-resistant CD1a-specific CAR T cells for the treatment of cortical T-cell acute lymphoblastic leukemia. Blood, J Am Soc Hematol. 2019;133(21):2291–304.

    Google Scholar 

  62. Chancellor A, Gadola SD, Mansour S. The versatility of the CD 1 lipid antigen presentation pathway. Immunology. 2018;154(2):196–203.

    Article  CAS  Google Scholar 

  63. Bechan GI, Lee DW, Zajonc DM, Heckel D, Xian R, Throsby M, et al. Phage display generation of a novel human anti-CD1A monoclonal antibody with potent cytolytic activity. Br J Haematol. 2012;159(3):299–310.

    Article  CAS  Google Scholar 

  64. Riillo C, Caracciolo D, Grillone K, Polerà N, Tuccillo FM, Bonelli P, et al. A novel bispecific T-cell engager (CD1a x CD3ε) BTCE is effective against cortical-derived T cell acute lymphoblastic leukemia (T-ALL) cells. Cancers (Basel). 2022;14(12):2886.

    Article  CAS  Google Scholar 

  65. Brodeur J-F, Li S, Damlaj O, Dave VP. Expression of fully assembled TCR–CD3 complex on double positive thymocytes: synergistic role for the PRS and ER retention motifs in the intra-cytoplasmic tail of CD3ε. Int Immunol. 2009;21(12):1317–27.

    Article  CAS  Google Scholar 

  66. Muromonab TG. Adverse events with biomedicines. Cham: Springer; 2014. p. 263–5.

    Google Scholar 

  67. Trinquand A, Dos Santos NR, Tran Quang C, Rocchetti F, Zaniboni B, Belhocine M, et al. Triggering the TCR developmental checkpoint activates a therapeutically targetable tumor suppressive pathway in T-cell leukemia TCR activation is tumor suppressive in T-cell leukemia. Cancer Discov. 2016;6(9):972–85.

    Article  CAS  Google Scholar 

  68. Tran Quang C, Zaniboni B, Humeau R, Lengliné E, Dourthe ME, Ganesan R, et al. Preclinical efficacy of humanized, non–FcγR-binding anti-CD3 antibodies in T-cell acute lymphoblastic leukemia. Blood. 2020;136(11):1298–302.

    Article  Google Scholar 

  69. Frankel A, Zuckero S, Mankin A, Grable M, Mitchell K, Lee Y, et al. Anti-CD3 recombinant diphtheria immunotoxin therapy of cutaneous T cell lymphoma. Curr Drug Targets. 2009;10(2):104–9.

    Article  CAS  Google Scholar 

  70. Chen KH, Wada M, Firor AE, Pinz KG, Jares A, Liu H, et al. Novel anti-CD3 chimeric antigen receptor targeting of aggressive T cell malignancies. Oncotarget. 2016;7(35):56219.

    Article  Google Scholar 

  71. Rasaiyaah J, Georgiadis C, Preece R, Mock U, Qasim W. TCRαβ/CD3 disruption enables CD3-specific antileukemic T cell immunotherapy. JCI Insight. 2018;3(13):e99442.

    Article  Google Scholar 

  72. Juillerat A, Tkach D, Yang M, Boyne A, Valton J, Poirot L, et al. Straightforward generation of ultrapure off-the-shelf allogeneic CAR-T cells. Front Bioeng Biotechnol. 2020;8:678.

    Article  Google Scholar 

  73. Pinz K, Liu H, Golightly M, Jares A, Lan F, Zieve GW, et al. Preclinical targeting of human T-cell malignancies using CD4-specific chimeric antigen receptor (CAR)-engineered T cells. Leukemia. 2016;30(3):701–7.

    Article  CAS  Google Scholar 

  74. Nguyen QP, Deng TZ, Witherden DA, Goldrath AW. Origins of CD 4+ circulating and tissue-resident memory T-cells. Immunology. 2019;157(1):3–12.

    Article  CAS  Google Scholar 

  75. Zhou L, Chong MM, Littman DR. Plasticity of CD4+ T cell lineage differentiation. Immunity. 2009;30(5):646–55.

    Article  CAS  Google Scholar 

  76. Glatzová D, Cebecauer M. Dual role of CD4 in peripheral T lymphocytes. Front Immunol. 2019;10:618.

    Article  Google Scholar 

  77. d’Amore F, Radford J, Relander T, Jerkeman M, Tilly H, Österborg A, et al. Phase II trial of zanolimumab (HuMax-CD4) in relapsed or refractory non-cutaneous peripheral T cell lymphoma. Br J Haematol. 2010;150(5):565–73.

    Article  Google Scholar 

  78. Hagberg H, Pettersson M, Bjerner T, Enblad G. Treatment of a patient with a nodal peripheral T-cell lymphoma (angioimmunoblastic T-Cell lymphoma) with a human monoclonal antibody against the CD4 antigen (HuMax-CD4). Med Oncol. 2005;22(2):191–4.

    Article  CAS  Google Scholar 

  79. Kim YH, Duvic M, Obitz E, Gniadecki R, Iversen L, Österborg A, et al. Clinical efficacy of zanolimumab (HuMax-CD4): two phase 2 studies in refractory cutaneous T-cell lymphoma. Blood, J Am Soc Hematol. 2007;109(11):4655–62.

    CAS  Google Scholar 

  80. Pinz KG, Yakaboski E, Jares A, Liu H, Firor AE, Chen KH, et al. Targeting T-cell malignancies using anti-CD4 CAR NK-92 cells. Oncotarget. 2017;8(68): 112783.

    Article  Google Scholar 

  81. Ma G, Shen J, Pinz K, Wada M, Park J, Kim S, et al. Targeting T cell malignancies using CD4CAR T-cells and implementing a natural safety switch. Stem Cell Rev Rep. 2019;15(3):443–7.

    Article  Google Scholar 

  82. Alotaibi F, Vincent M, Min W-P, Koropatnick J. Reduced CD5 on CD8+ T cells in tumors but not lymphoid organs is associated with increased activation and effector function. Front Immunol. 2021;11: 584937.

    Article  Google Scholar 

  83. Feng J, Xu H, Cinquina A, Wu Z, Chen Q, Zhang P, et al. Treatment of aggressive t cell lymphoblastic lymphoma/leukemia using anti-CD5 CAR T cells. Stem Cell Rev Rep. 2021;17(2):652–61.

    Article  CAS  Google Scholar 

  84. Huang H, Jones NH, Strominger JL, Herzenberg LA. Molecular cloning of Ly-1, a membrane glycoprotein of mouse T lymphocytes and a subset of B cells: molecular homology to its human counterpart Leu-1/T1 (CD5). Proc Natl Acad Sci. 1987;84(1):204–8.

    Article  CAS  Google Scholar 

  85. Burgueño-Bucio E, Mier-Aguilar CA, Soldevila G. The multiple faces of CD5. J Leukoc Biol. 2019;105(5):891–904.

    Article  Google Scholar 

  86. Li H, Burgueño-Bucio E, Xu S, Das S, Olguin-Alor R, Elmets CA, et al. CD5 on dendritic cells regulates CD4+ and CD8+ T cell activation and induction of immune responses. PLoS ONE. 2019;14(9): e0222301.

    Article  CAS  Google Scholar 

  87. Azzam HS, DeJarnette JB, Huang K, Emmons R, Park C-S, Sommers CL, et al. Fine tuning of TCR signaling by CD5. J Immunol. 2001;166(9):5464–72.

    Article  CAS  Google Scholar 

  88. Voisinne G, Gonzalez de Peredo A, Roncagalli R. CD5, an undercover regulator of TCR signaling. Front Immunol. 2018;9:2900.

    Article  CAS  Google Scholar 

  89. Bertram JH, Gill PS, Levine AM, Boquiren D, Hoffman FM, Meyer P, et al. Monoclonal antibody T101 in T cell malignancies: a clinical, pharmacokinetic, and immunologic correlation. Blood. 1986;68(3):752–61.

    Article  CAS  Google Scholar 

  90. Kernan N, Knowles R, Burns M, Broxmeyer H, Lu L, Lee H, et al. Specific inhibition of in vitro lymphocyte transformation by an anti-pan T cell (gp67) ricin A chain immunotoxin. J Immunol. 1984;133(1):137–46.

    Article  CAS  Google Scholar 

  91. LeMaistre C, Rosen S, Frankel A, Kornfeld S, Saria E, Meneghetti C, et al. Phase I trial of H65-RTA immunoconjugate in patients with cutaneous T-cell lymphoma. Blood. 1991;78(5):1173–82.

    Article  CAS  Google Scholar 

  92. Mamonkin M, Rouce RH, Tashiro H, Brenner MK. A T-cell–directed chimeric antigen receptor for the selective treatment of T-cell malignancies. Blood J Am Soc Hematol. 2015;126(8):983–92.

    CAS  Google Scholar 

  93. Chen K, Wada M, Pinz K, Liu H, Lin K, Jares A, et al. Preclinical targeting of aggressive T-cell malignancies using anti-CD5 chimeric antigen receptor. Leukemia. 2017;31(10):2151–60.

    Article  CAS  Google Scholar 

  94. Raikar SS, Fleischer LC, Moot R, Fedanov A, Paik NY, Knight KA, et al. Development of chimeric antigen receptors targeting T-cell malignancies using two structurally different anti-CD5 antigen binding domains in NK and CRISPR-edited T cell lines. Oncoimmunology. 2018;7(3): e1407898.

    Article  Google Scholar 

  95. Xu Y, Liu Q, Zhong M, Wang Z, Chen Z, Zhang Y, et al. 2B4 costimulatory domain enhancing cytotoxic ability of anti-CD5 chimeric antigen receptor engineered natural killer cells against T cell malignancies. J Hematol Oncol. 2019;12(1):1–13.

    Article  Google Scholar 

  96. Dai Z, Mu W, Zhao Y, Jia X, Liu J, Wei Q, et al. The rational development of CD5-targeting biepitopic CARs with fully human heavy-chain-only antigen recognition domains. Mol Ther. 2021;29(9):2707–22.

    Article  CAS  Google Scholar 

  97. Wada M, Zhang H, Fang L, Feng J, Tse CO, Zhang W, et al. Characterization of an anti-CD5 directed CAR T-cell against T-cell malignancies. Stem Cell Rev Rep. 2020;16(2):369–84.

    Article  CAS  Google Scholar 

  98. Murphy K, Weaver C. Janeway’s immunobiology. Routledge: Garland Science/Taylor & Francis Group, LLC; 2016.

    Book  Google Scholar 

  99. Scherer LD, Brenner MK, Mamonkin M. Chimeric antigen receptors for T-cell malignancies. Front Oncol. 2019;9:126.

    Article  Google Scholar 

  100. Lee DM, Staats HF, Sundy JS, Patel DD, Sempowski GD, Scearce RM, et al. Immunologic characterization of CD7-deficient mice. J Immunol. 1998;160(12):5749–56.

    Article  CAS  Google Scholar 

  101. Frankel AE, Laver JH, Willingham MC, Burns LJ, Kersey JH, Vallera DA. Therapy of patients with T-cell lymphomas and leukemias using an anti-CD7 monoclonal antibody-rich a chain immunotoxin. Leuk Lymphoma. 1997;26(3–4):287–98.

    Article  CAS  Google Scholar 

  102. Alcantara M, Tesio M, June CH, Houot R. CAR T-cells for T-cell malignancies: challenges in distinguishing between therapeutic, normal, and neoplastic T-cells. Leukemia. 2018;32(11):2307–15.

    Article  CAS  Google Scholar 

  103. Freiwan A, Zoine JT, Crawford JC, Vaidya A, Schattgen SA, Myers JA, et al. Engineering naturally occurring CD7 negative T cells for the immunotherapy of hematological malignancies. Blood. 2022;140(25):2684–96.

    Article  CAS  Google Scholar 

  104. Cooper ML, Choi J, Staser K, Ritchey JK, Devenport JM, Eckardt K, et al. An “off-the-shelf” fratricide-resistant CAR-T for the treatment of T cell hematologic malignancies. Leukemia. 2018;32(9):1970–83.

    Article  CAS  Google Scholar 

  105. Jackson MR, Nilsson T, Peterson PA. Identification of a consensus motif for retention of transmembrane proteins in the endoplasmic reticulum. EMBO J. 1990;9(10):3153–62.

    Article  CAS  Google Scholar 

  106. Kamiya T, Wong D, Png YT, Campana D. A novel method to generate T-cell receptor-deficient chimeric antigen receptor T cells. Blood Adv. 2018;2(5):517–28.

    Article  CAS  Google Scholar 

  107. Xie L, Gu R, Yang X, Qiu S, Xu Y, Mou J, et al. Universal anti-CD7 CAR-T cells targeting T-ALL and functional analysis of CD7 antigen on T/CAR-T Cells. Blood. 2022;140(Supplement 1):4535.

    Article  Google Scholar 

  108. Kimberland ML, Hou W, Alfonso-Pecchio A, Wilson S, Rao Y, Zhang S, et al. Strategies for controlling CRISPR/Cas9 off-target effects and biological variations in mammalian genome editing experiments. J Biotechnol. 2018;284:91–101.

    Article  CAS  Google Scholar 

  109. Ye J, Jia Y, Tuhin IJ, Tan J, Monty MA, Xu N, et al. Feasibility study of a novel preparation strategy for anti-CD7 CAR-T cells with a recombinant anti-CD7 blocking antibody. Mol Therapy-Oncolytics. 2022;24:719–28.

    Article  CAS  Google Scholar 

  110. Pan J, Tan Y, Wang G, Deng B, Ling Z, Song W, et al. Donor-derived CD7 chimeric antigen receptor T cells for T-cell acute lymphoblastic leukemia: first-in-human, Phase I trial. J Clin Oncol. 2021;39(30):3340–51.

    Article  CAS  Google Scholar 

  111. Kozani PS, Kozani PS, Rahbarizadeh F. Novel antigens of CAR T cell therapy: new roads; old destination. Transl Oncol. 2021;14(7): 101079.

    Article  Google Scholar 

  112. SafarzadehKozani P, SafarzadehKozani P, Rahbarizadeh F, Khoshtinat NS. Strategies for dodging the obstacles in CAR T cell therapy. Front Oncol. 2021;11: 627549.

    Article  Google Scholar 

  113. Wang D, Starr R, Chang W-C, Aguilar B, Alizadeh D, Wright SL, et al. Chlorotoxin-directed CAR T cells for specific and effective targeting of glioblastoma. Sci Transl Med. 2020;12(533):eaaw2672.

    Article  CAS  Google Scholar 

  114. Wang Y, Xu Y, Li S, Liu J, Xing Y, Xing H, et al. Targeting FLT3 in acute myeloid leukemia using ligand-based chimeric antigen receptor-engineered T cells. J Hematol Oncol. 2018;11(1):1–12.

    Article  Google Scholar 

  115. Xie YJ, Dougan M, Jailkhani N, Ingram J, Fang T, Kummer L, et al. Nanobody-based CAR T cells that target the tumor microenvironment inhibit the growth of solid tumors in immunocompetent mice. Proc Natl Acad Sci. 2019;116(16):7624–31.

    Article  CAS  Google Scholar 

  116. SafarzadehKozani P, Naseri A, Mirarefin SMJ, Salem F, Nikbakht M, EvaziBakhshi S, et al. Nanobody-based CAR-T cells for cancer immunotherapy. Biomark Res. 2022;10(1):1–18.

    Google Scholar 

  117. Zhang M, Chen D, Fu X, Meng H, Nan F, Sun Z, et al. Autologous nanobody-derived fratricide-resistant CD7-CAR T-cell therapy for patients with relapsed and refractory T-cell acute lymphoblastic leukemia/lymphoma. Clin Cancer Res. 2022;28(13):2830–43.

    Article  CAS  Google Scholar 

  118. Dai H-P, Cui W, Cui Q-Y, Zhu W-J, Meng H-M, Zhu M-Q, et al. Haploidentical CD7 CAR T-cells induced remission in a patient with TP53 mutated relapsed and refractory early T-cell precursor lymphoblastic leukemia/lymphoma. Biomark Res. 2022;10(1):1–5.

    Article  Google Scholar 

  119. Lu P, Liu Y, Yang J, Zhang X, Yang X, Wang H, et al. Naturally selected CD7 CAR-T therapy without genetic manipulations for T-ALL/LBL: first-in-human phase I clinical trial. Blood. 2022;140(4):321–34.

    CAS  Google Scholar 

  120. Geng H, Brennan S, Milne TA, Chen W-Y, Li Y, Hurtz C, et al. Integrative epigenomic analysis identifies biomarkers and therapeutic targets in adult B-acute lymphoblastic leukemia. Cancer Discov. 2012;2(11):1004–23.

    Article  CAS  Google Scholar 

  121. Lee J-W, Chen Z, Geng H, Xiao G, Eugene P, Parekh S, et al. CD25 (IL2RA) orchestrates negative feedback control and stabilizes oncogenic signaling strength in acute lymphoblastic leukemia. Blood. 2015;126(23):1434.

    Article  Google Scholar 

  122. Orenstein LA, Coughlin CC, Flynn AT, Pillai V, Boos MD, Wertheim GB, et al. Severe Mucha–Habermann-like ulceronecrotic skin disease in T-cell acute lymphoblastic leukemia responsive to basiliximab and stem cell transplant. Pediatr Dermatol. 2017;34(5):e265–70.

    Article  Google Scholar 

  123. Nikolaenko L, Zain J, Rosen ST, Querfeld C. CD30-positive lymphoproliferative disorders. T-Cell and NK-Cell Lymphomas. Springer, Cham; 2019. p. 249–68.

  124. Gopal AK, Bartlett NL, Forero-Torres A, Younes A, Chen R, Friedberg JW, et al. Brentuximab vedotin in patients aged 60 years or older with relapsed or refractory CD30-positive lymphomas: a retrospective evaluation of safety and efficacy. Leuk Lymphoma. 2014;55(10):2328–34.

    Article  CAS  Google Scholar 

  125. Oka S, Ono K, Nohgawa M. Successful treatment with brentuximab vedotin for relapsed and refractory adult T cell leukemia. Anticancer Drugs. 2020;31(5):536–9.

    Article  CAS  Google Scholar 

  126. Horwitz S, O’Connor OA, Pro B, Illidge T, Fanale M, Advani R, et al. Brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma (ECHELON-2): a global, double-blind, randomised, phase 3 trial. Lancet. 2019;393(10168):229–40.

    Article  CAS  Google Scholar 

  127. Shea L, Mehta-Shah N. Brentuximab vedotin in the treatment of peripheral T cell lymphoma and cutaneous T cell lymphoma. Curr Hematol Malig Rep. 2020;15(1):9–19.

    Article  Google Scholar 

  128. Ramos CA, Ballard B, Zhang H, Dakhova O, Gee AP, Mei Z, et al. Clinical and immunological responses after CD30-specific chimeric antigen receptor-redirected lymphocytes. J Clin Investig. 2017;127(9):3462–71.

    Article  Google Scholar 

  129. Wang C-M, Wu Z-Q, Wang Y, Guo Y-L, Dai H-R, Wang X-H, et al. Autologous T cells expressing CD30 chimeric antigen receptors for relapsed or refractory Hodgkin lymphoma: an open-label phase I TrialCART-30 cell therapy for relapsed or refractory hodgkin lymphoma. Clin Cancer Res. 2017;23(5):1156–66.

    Article  CAS  Google Scholar 

  130. Zheng W, Medeiros LJ, Young KH, Goswami M, Powers L, Kantarjian HH, et al. CD30 expression in acute lymphoblastic leukemia as assessed by flow cytometry analysis. Leuk Lymphoma. 2014;55(3):624–7.

    Article  CAS  Google Scholar 

  131. Malavasi F, Deaglio S, Funaro A, Ferrero E, Horenstein AL, Ortolan E, et al. Evolution and function of the ADP ribosyl cyclase/CD38 gene family in physiology and pathology. Physiol Rev. 2008;88(3):841–86.

    Article  CAS  Google Scholar 

  132. Vale AM, Schroeder HW Jr. Clinical consequences of defects in B-cell development. J Allergy Clin Immunol. 2010;125(4):778–87.

    Article  CAS  Google Scholar 

  133. Partida-Sanchez S, Cockayne DA, Monard S, Jacobson EL, Oppenheimer N, Garvy B, et al. Cyclic ADP-ribose production by CD38 regulates intracellular calcium release, extracellular calcium influx and chemotaxis in neutrophils and is required for bacterial clearance in vivo. Nat Med. 2001;7(11):1209–16.

    Article  CAS  Google Scholar 

  134. Zubiaur M, Fernández O, Ferrero E, Salmerón J, Malissen B, Malavasi F, et al. CD38 is associated with lipid rafts and upon receptor stimulation leads to Akt/protein kinase B and Erk activation in the absence of the CD3-ζ immune receptor tyrosine-based activation motifs. J Biol Chem. 2002;277(1):13–22.

    Article  CAS  Google Scholar 

  135. Jiao Y, Yi M, Xu L, Chu Q, Yan Y, Luo S, et al. CD38: targeted therapy in multiple myeloma and therapeutic potential for solid cancers. Expert Opin Investig Drugs. 2020;29(11):1295–308.

    Article  CAS  Google Scholar 

  136. Morandi F, Horenstein AL, Costa F, Giuliani N, Pistoia V, Malavasi F. CD38: a target for immunotherapeutic approaches in multiple myeloma. Front Immunol. 2018;9:2722.

    Article  Google Scholar 

  137. Tembhare PR, Sriram H, Khanka T, Chatterjee G, Panda D, Ghogale S, et al. Flow cytometric evaluation of CD38 expression levels in the newly diagnosed T-cell acute lymphoblastic leukemia and the effect of chemotherapy on its expression in measurable residual disease, refractory disease and relapsed disease: an implication for anti-CD38 immunotherapy. J Immunother Cancer. 2020;8(1):e000630.

  138. Mihara K, Yoshida T, Ishida S, Takei Y, Kitanaka A, Shimoda K, et al. All-trans retinoic acid and interferon-alpha increase CD38 expression on adult T-cell leukemia cells and sensitize them to T cells bearing anti-CD38 chimeric antigen receptors. Blood. 2015;126(23):591.

    Article  Google Scholar 

  139. Bride KL, Vincent TL, Im S-Y, Aplenc R, Barrett DM, Carroll WL, et al. Preclinical efficacy of daratumumab in T-cell acute lymphoblastic leukemia. Blood, J Am Soc Hematol. 2018;131(9):995–9.

    CAS  Google Scholar 

  140. Gurunathan A, Emberesh M, Norris R. A case report of using daratumumab in refractory T-cell acute lymphoblastic leukemia. In: Newburger PE, editor. Pediatr Blood Cancer. NJ USA: Wiley; 2019. p. S38–s39.

  141. Ofran Y, Ringelstein-Harlev S, Slouzkey I, Zuckerman T, Yehudai-Ofir D, Henig I, et al. Daratumumab for eradication of minimal residual disease in high-risk advanced relapse of T-cell/CD19/CD22-negative acute lymphoblastic leukemia. Leukemia. 2020;34(1):293–5.

    Article  Google Scholar 

  142. Wang X, Yu X, Li W, Neeli P, Liu M, Li L, et al. Expanding anti-CD38 immunotherapy for lymphoid malignancies. J Exp Clin Cancer Res. 2022;41(1):1–18.

    Article  CAS  Google Scholar 

  143. Muller K, Vogiatzi F, Winterberg D, Rosner T, Lenk L, Bastian L, et al. Combining daratumumab with CD47 blockade prolongs survival in preclinical models of pediatric T-ALL. Blood. 2022;140(1):45–57.

    Article  Google Scholar 

  144. Stefano S, Grandclement C, Labanca V, De Angelis S, Estoppey C, Chimen M, et al. Preclinical evaluation of ISB 1442, a first-in-class CD38 and CD47 bispecific antibody innate cell modulator for the treatment of AML and T-ALL. Blood. 2022;140(Supplement 1):6237–8.

    Article  Google Scholar 

  145. Frerichs KA, Minnema MC, Levin M-D, Broijl A, Bos GM, Kersten MJ, et al. Efficacy and safety of daratumumab combined with all-trans retinoic acid in relapsed/refractory multiple myeloma. Blood Adv. 2021;5(23):5128–39.

    Article  CAS  Google Scholar 

  146. Guru Murthy GS, Kearl T, Cui W, Johnson B, Hoffmeister K, Harrington A, et al. A phase 1 study of CD38-bispecific antibody (XmAb18968) for patients with CD38 expressing relapsed/refractory acute myeloid leukemia and T-cell acute lymphoblastic leukemia. Am Soc Clin Oncol. 2022;40(16):TPS7070.

  147. De Laurentiis A, Gaspari M, Palmieri C, Falcone C, Iaccino E, Fiume G, et al. Mass spectrometry-based identification of the tumor antigen UN1 as the transmembrane CD43 sialoglycoprotein. Mol Cell Proteomics. 2011;10(5):M111.007898.

  148. Tuccillo FM, De Laurentiis A, Palmieri C, Fiume G, Bonelli P, Borrelli A, et al. Aberrant glycosylation as biomarker for cancer: focus on CD43. BioMed Res Int. 2014;2014:742831.

  149. Caracciolo D, Riillo C, Ballerini A, Gaipa G, Lhermitte L, Rossi M, et al. Therapeutic afucosylated monoclonal antibody and bispecific T-cell engagers for T-cell acute lymphoblastic leukemia. J Immunother Cancer. 2021;9(2).

  150. Tassone P, Bond H, Bonelli P, Tuccillo F, Cecco L, Lamberti A, et al. UN-1, a murine monoclonal antibody recognizing a human thymocyte undescribed antigen. Pharmacol Res. 1992;26(Supplement 2):128–9.

    Article  Google Scholar 

  151. Tassone P, Bond H, Bonelli P, Tuccillo F, Valerio G, Petrella A, et al. UN1, a murine monoclonal antibody recognizing a novel human thymic antigen. Tissue Antigens. 1994;44(2):73–82.

    Article  CAS  Google Scholar 

  152. Tassone P, Tuccillo F, Bonelli P, D’Armiento FP, Bond HM, Palmieri C, et al. Fetal ontogeny and tumor expression of the early thymic antigen UN1. Int J Oncol. 2002;20(4):707–11.

    CAS  Google Scholar 

  153. Gökbuget N, Dombret H, Bonifacio M, Reichle A, Graux C, Faul C, et al. Blinatumomab for minimal residual disease in adults with B-cell precursor acute lymphoblastic leukemia. Blood, J Am Soc Hematol. 2018;131(14):1522–31.

    Google Scholar 

  154. Orian-Rousseau V. CD44, a therapeutic target for metastasising tumours. Eur J Cancer. 2010;46(7):1271–7.

    Article  CAS  Google Scholar 

  155. Chen C, Zhao S, Karnad A, Freeman JW. The biology and role of CD44 in cancer progression: therapeutic implications. J Hematol Oncol. 2018;11(1):1–23.

    Article  Google Scholar 

  156. Stoop R, Gál I, Glant TT, McNeish JD, Mikecz K. Trafficking of CD44-deficient murine lymphocytes under normal and inflammatory conditions. Eur J Immunol. 2002;32(9):2532–42.

    Article  CAS  Google Scholar 

  157. Lee-Sayer SS, Dougan MN, Cooper J, Sanderson L, Dosanjh M, Maxwell CA, et al. CD44-mediated hyaluronan binding marks proliferating hematopoietic progenitor cells and promotes bone marrow engraftment. PLoS ONE. 2018;13(4): e0196011.

    Article  Google Scholar 

  158. Krause DS, Lazarides K, von Andrian UH, Van Etten RA. Requirement for CD44 in homing and engraftment of BCR-ABL-expressing leukemic stem cells. Nat Med. 2006;12(10):1175–80.

    Article  CAS  Google Scholar 

  159. Canté-Barrett K, Mendes RD, Li Y, Vroegindeweij E, Pike-Overzet K, Wabeke T, et al. Loss of CD44dim expression from early progenitor cells marks T-cell lineage commitment in the human thymus. Front Immunol. 2017;8:32.

    Article  Google Scholar 

  160. Zöller M. CD44: can a cancer-initiating cell profit from an abundantly expressed molecule? Nat Rev Cancer. 2011;11(4):254–67.

    Article  Google Scholar 

  161. García-Peydró M, Fuentes P, Mosquera M, García-León MJ, Alcain J, Rodríguez A, et al. The NOTCH1/CD44 axis drives pathogenesis in a T cell acute lymphoblastic leukemia model. J Clin Investig. 2018;128(7):2802–18.

    Article  Google Scholar 

  162. Marques LVC, Noronha EP, Andrade FG, Santos-Bueno FVd, Mansur MB, Terra-Granado E, et al. CD44 expression profile varies according to maturational subtypes and molecular profiles of pediatric T-cell lymphoblastic leukemia. Front Oncol. 2018;8:488.

    Article  Google Scholar 

  163. Hoofd C, Wang X, Lam S, Jenkins C, Wood B, Giambra V, et al. CD44 promotes chemoresistance in T-ALL by increased drug efflux. Exp Hematol. 2016;44(3):166-71.e17.

    Article  CAS  Google Scholar 

  164. Oehler VG, Walter RB, Cummings C, Sala-Torra O, Stirewalt DL, Fang M, et al. CD52 expression in leukemic stem/progenitor cells. Blood. 2010;116(21):2743.

    Article  Google Scholar 

  165. Lozanski G, Sanford B, Yu D, Pearson R, Edwards C, Byrd JC, et al. CD52 expression in adult acute lymphoblastic leukemia (ALL): quantitative flow cytometry provides new insights. Blood. 2006;108(11):2293.

    Article  Google Scholar 

  166. Tibes R, Keating MJ, Ferrajoli A, Wierda W, Ravandi F, Garcia-Manero G, et al. Activity of alemtuzumab in patients with CD52-positive acute leukemia. Cancer Interdiscip Int J Am Cancer Soc. 2006;106(12):2645–51.

    CAS  Google Scholar 

  167. Bandala-Sanchez E, Zhang Y, Reinwald S, Dromey JA, Lee B-H, Qian J, et al. T cell regulation mediated by interaction of soluble CD52 with the inhibitory receptor Siglec-10. Nat Immunol. 2013;14(7):741–8.

    Article  CAS  Google Scholar 

  168. Watanabe T, Masuyama J-I, Sohma Y, Inazawa H, Horie K, Kojima K, et al. CD52 is a novel costimulatory molecule for induction of CD4+ regulatory T cells. Clin Immunol. 2006;120(3):247–59.

    Article  CAS  Google Scholar 

  169. Angiolillo AL, Yu AL, Reaman G, Ingle AM, Secola R, Adamson PC. A phase II study of Campath-1H in children with relapsed or refractory acute lymphoblastic leukemia: a Children’s Oncology Group report. Pediatr Blood Cancer. 2009;53(6):978–83.

    Article  Google Scholar 

  170. Ravandi F, Estey E, Jones D, Faderl S, O’Brien S, Fiorentino J, et al. Effective treatment of acute promyelocytic leukemia with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab ozogamicin. J Clin Oncol. 2009;27(4):504.

    Article  CAS  Google Scholar 

  171. Stock W, Sanford B, Lozanski G, Vij R, Byrd JC, Powell BL, et al. Alemtuzumab can be incorporated into front-line therapy of adult acute lymphoblastic leukemia (ALL): final phase I results of a cancer and leukemia group B study (CALGB 10102). Blood. 2009;114(22):838.

    Article  Google Scholar 

  172. Poirot L, Philip B, Schiffer-Mannioui C, Le Clerre D, Chion-Sotinel I, Derniame S, et al. Multiplex genome-edited T-cell manufacturing platform for “off-the-shelf” adoptive T-cell immunotherapies genome editing for allogenic adoptive T-cell immunotherapy. Cancer Res. 2015;75(18):3853–64.

    Article  CAS  Google Scholar 

  173. Qasim W, Amrolia PJ, Samarasinghe S, Ghorashian S, Zhan H, Stafford S, et al. First clinical application of talen engineered universal CAR19 T cells in B-ALL. Blood. 2015;126(23):2046.

    Article  Google Scholar 

  174. Imbert A-M, Belaaloui G, Bardin F, Tonnelle C, Lopez M, Chabannon C. CD99 expressed on human mobilized peripheral blood CD34+ cells is involved in transendothelial migration. Blood. 2006;108(8):2578–86.

    Article  CAS  Google Scholar 

  175. Vaikari VP, Du Y, Wu S, Zhang T, Metzeler K, Batcha AM, et al. Clinical and preclinical characterization of CD99 isoforms in acute myeloid leukemia. Haematologica. 2020;105(4):999.

    Article  CAS  Google Scholar 

  176. Pettersen RD, Bernard G, Olafsen MK, Pourtein M, Lie SO. CD99 signals caspase-independent T cell death. J Immunol. 2001;166(8):4931–42.

    Article  CAS  Google Scholar 

  177. Husak Z, Printz D, Schumich A, Pötschger U, Dworzak MN. Death induction by CD99 ligation in TEL/AML1-positive acute lymphoblastic leukemia and normal B cell precursors. J Leukoc Biol. 2010;88(2):405–12.

    Article  CAS  Google Scholar 

  178. Enein AAA, Rahman HAA, Sharkawy NE, Elhamid SA, Abbas S, Abdelfaatah R, et al. Significance of CD99 expression in T-lineage acute lymphoblastic leukemia. Cancer Biomark. 2016;17(2):117–23.

    Article  Google Scholar 

  179. Dworzak M, Fröschl G, Printz D, De Zen L, Gaipa G, Ratei R, et al. CD99 expression in T-lineage ALL: implications for flow cytometric detection of minimal residual disease. Leukemia. 2004;18(4):703–8.

    Article  CAS  Google Scholar 

  180. Husak Z, Dworzak M. CD99 ligation upregulates HSP70 on acute lymphoblastic leukemia cells and concomitantly increases NK cytotoxicity. Cell Death Dis. 2012;3(11): e425-e.

    Article  Google Scholar 

  181. Shi J, Zhang Z, Cen H, Wu H, Zhang S, Liu J, et al. CAR T cells targeting CD99 as an approach to eradicate T-cell acute lymphoblastic leukemia without normal blood cells toxicity. J Hematol Oncol. 2021;14(1):1–5.

    Article  Google Scholar 

  182. Baer C, Kimura S, Rana MS, Kleist AB, Flerlage T, Feith DJ, et al. CCL22 mutations drive natural killer cell lymphoproliferative disease by deregulating microenvironmental crosstalk. Nat Genet. 2022;54(5):637–48.

    Article  CAS  Google Scholar 

  183. Shichijo T, Nosaka K, Tatetsu H, Higuchi Y, Endo S, Inoue Y, et al. Beneficial impact of first-line mogamulizumab-containing chemotherapy in adult T-cell leukaemia-lymphoma. Br J Haematol. 2022; 198:983–87.

    Article  CAS  Google Scholar 

  184. Perera LP, Zhang M, Nakagawa M, Petrus MN, Maeda M, Kadin ME, et al. Chimeric antigen receptor modified T cells that target chemokine receptor CCR4 as a therapeutic modality for T-cell malignancies. Am J Hematol. 2017;92(9):892–901.

    Article  CAS  Google Scholar 

  185. Maciocia PM, Wawrzyniecka PA, Maciocia NC, Burley A, Karpanasamy T, Devereaux S, et al. Anti-CCR9 chimeric antigen receptor T cells for T-cell acute lymphoblastic leukemia. Blood. 2022;140(1):25–37.

    Article  CAS  Google Scholar 

  186. Busillo JM, Benovic JL. Regulation of CXCR4 signaling. Biochim Biophys Acta (BBA) Biomembr. 2007;1768(4):952–63.

    Article  CAS  Google Scholar 

  187. de Lourdes PA, Amarante MK, Guembarovski RL, de Oliveira CEC, Watanabe MAE. CXCL12/CXCR4 axis in the pathogenesis of acute lymphoblastic leukemia (ALL): a possible therapeutic target. Cell Mol Life Sci. 2015;72(9):1715–23.

    Article  Google Scholar 

  188. Pitt LA, Tikhonova AN, Hu H, Trimarchi T, King B, Gong Y, et al. CXCL12-producing vascular endothelial niches control acute T cell leukemia maintenance. Cancer Cell. 2015;27(6):755–68.

    Article  CAS  Google Scholar 

  189. Bertolini F, Dell’Agnola C, Mancuso P, Rabascio C, Burlini A, Monestiroli S, et al. CXCR4 neutralization, a novel therapeutic approach for non-Hodgkin’s lymphoma. Cancer Res. 2002;62(11):3106–12.

    CAS  Google Scholar 

  190. Uy GL, Kadia TM, Stock W, Brammer JE, Bohana-Kashtan O, Vainstein A, et al. CXCR4 inhibition with BL-8040 in combination with nelarabine in patients with relapsed or refractory T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma. Blood. 2019;134:2630.

    Article  Google Scholar 

  191. Hong Z, Wei Z, Xie T, Fu L, Sun J, Zhou F, et al. Targeting chemokines for acute lymphoblastic leukemia therapy. J Hematol Oncol. 2021;14(1):1–14.

    Article  Google Scholar 

  192. Passaro D, Irigoyen M, Catherinet C, Gachet S, De Jesus CDC, Lasgi C, et al. CXCR4 is required for leukemia-initiating cell activity in T cell acute lymphoblastic leukemia. Cancer Cell. 2015;27(6):769–79.

    Article  CAS  Google Scholar 

  193. Sasson SC, Zaunders JJ, Kelleher AD. The IL-7/IL-7 receptor axis: understanding its central role in T-cell homeostasis and the challenges facing its utilization as a novel therapy. Curr Drug Targets. 2006;7(12):1571–82.

    Article  CAS  Google Scholar 

  194. Barata JT, Durum SK, Seddon B. Flip the coin: IL-7 and IL-7R in health and disease. Nat Immunol. 2019;20(12):1584–93.

    Article  CAS  Google Scholar 

  195. Maki K, Sunaga S, Komagata Y, Kodaira Y, Mabuchi A, Karasuyama H, et al. Interleukin 7 receptor-deficient mice lack gammadelta T cells. Proc Natl Acad Sci. 1996;93(14):7172–7.

    Article  CAS  Google Scholar 

  196. Sprent J, Surh CD. Normal T cell homeostasis: the conversion of naive cells into memory-phenotype cells. Nat Immunol. 2011;12(6):478–84.

    Article  CAS  Google Scholar 

  197. González-García S, García-Peydró M, Martín-Gayo E, Ballestar E, Esteller M, Bornstein R, et al. CSL–MAML-dependent Notch1 signaling controls T lineage-specific IL-7Rα gene expression in early human thymopoiesis and leukemia. J Exp Med. 2009;206(4):779–91.

    Article  Google Scholar 

  198. Cramer SD, Aplan PD, Durum SK. Therapeutic targeting of IL-7Rα signaling pathways in ALL treatment. Blood, J Am Soc Hematol. 2016;128(4):473–8.

    CAS  Google Scholar 

  199. González-García S, Mosquera M, Fuentes P, Palumbo T, Escudero A, Pérez-Martínez A, et al. IL-7R is essential for leukemia-initiating cell activity of T-cell acute lymphoblastic leukemia. Blood. 2019;134(24):2171–82.

    Article  Google Scholar 

  200. Akkapeddi P, Fragoso R, Hixon JA, Ramalho AS, Oliveira ML, Carvalho T, et al. A fully human anti-IL-7Rα antibody promotes antitumor activity against T-cell acute lymphoblastic leukemia. Leukemia. 2019;33(9):2155–68.

    Article  CAS  Google Scholar 

  201. Hixon JA, Andrews C, Kashi L, Kohnhorst CL, Senkevitch E, Czarra K, et al. New anti-IL-7Rα monoclonal antibodies show efficacy against T cell acute lymphoblastic leukemia in pre-clinical models. Leukemia. 2020;34(1):35–49.

    Article  CAS  Google Scholar 

  202. Li F, Zhang H, Wang W, Yang P, Huang Y, Zhang J, et al. T cell receptor β-chain-targeting chimeric antigen receptor T cells against T cell malignancies. Nat Commun. 2022;13(1):1–13.

    Google Scholar 

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This manuscript has been supported by BiovelocITA grant. PT has been supported by Multi-Unit Regional No. 16695 (co-financed by AIRC and the CARICAL Foundation), 2015/18.

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P.T. and D.C. conceptualized the manuscript. D.C., A.M., N.P., C.F., G.D’A. and C.R. wrote sections of the manuscript. A.M. and N.P. designed the figures and tables. P.T. and P.T. supervised the manuscript by providing critical feedback and revision. All the authors read and approved the final manuscript.

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Caracciolo, D., Mancuso, A., Polerà, N. et al. The emerging scenario of immunotherapy for T-cell Acute Lymphoblastic Leukemia: advances, challenges and future perspectives. Exp Hematol Oncol 12, 5 (2023).

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