Open Access

Cancer immunotherapy: are we there yet?

Experimental Hematology & Oncology20132:33

DOI: 10.1186/2162-3619-2-33

Received: 8 November 2013

Accepted: 4 December 2013

Published: 10 December 2013


The immune system is the built-in host defense mechanism against infectious agents as well as cancer. Protective immunity against cancer was convincingly demonstrated in the 1940s with syngeneic animal models (JNCI 18:769-778, 1976; Cancer Immun 1:6, 2001). Since then, the last century’s dream has been to effectively prevent and cure cancers by immunological means. This dream has slowly but surely become a reality (Nature 480:480-489, 2011). The successful examples of immunoprophylaxis and therapy against cancers include: (i) targeted therapy using monoclonal antibodies (Nat Rev Cancer 12:278-287, 2012); (ii) allogeneic hematopoietic stem cell transplantion to elicit graft-versus-cancer effect against a variety of hematopoietic malignancies (Blood 112:4371-4383, 2008); (iii) vaccination for preventing cancers with clear viral etiology such as hepatocellular carcinoma and cervical cancer (Cancer J Clin 57:7-28, 2007; NEJM 336:1855-1859, 1997); (iv) T cell checkpoint blockade against inhibitory pathways including targeting CTLA-4 and PD-1 inhibitory molecules for the treatment of melanoma and other solid tumors (NEJM 363:711-723, 2010; NEJM 366:2443-2454, 2012; NEJM 369:122-133, 2013; NEJM 366:2455-2465, 2012); (v) antigen-pulsed autologous dendritic cell vaccination against prostate cancer (NEJM 363:411-422, 2010); and (vi) the transfer of T cells including those genetically engineered with chimeric antigen receptors allowing targeting of B cell neoplasms (NEJM 365:725-733, 2011; NEJM 368:1509-1518, 2013; Blood 118:4817-4828, 2013; Sci Transl Med 5:177ra138, 2013).

This article provides an overview on the exciting and expanding immunological arsenals against cancer, and discusses critical remaining unanswered questions of cancer immunology. The inherent specificity and memory of the adaptive immune response towards cancer will undoubtedly propel cancer immunotherapy to the forefront of cancer treatment in the immediate near future. Study of the fundamental mechanisms of the immune evasion of cancer shall also advance the field of immunology towards the development of effective immunotherapeutics against a wide spectrum of human diseases.


Cancer immunotherapy has come a long way [116]. In the late 1800 s, William Coley was one of a growing number of investigators who noticed a correlation between regression of cancer and infection [1720]. Coley expanded on this observation and became the first person to treat substantial numbers of cancer patients with a mixture of killed bacteria (known as Coley’s toxin). Although not meeting the standards of today’s trials, Coley achieved tumor regression in a relatively high proportion of sarcoma patients. Despite much enthusiasm, the advent of immune-suppressing radiation therapy and chemotherapy which could directly impact cancer progression diverted much attention away from immune-based therapies [17, 18]. Furthermore, as the immune system was not well understood, there was much skepticism that tumor cells could be different from self and capable of eliciting immune-mediated eradiation. However, with growing understanding of how the immune system functioned, in 1957, Frank Macfarlane Burnet proposed a revolutionary concept that cancer cells may have antigenic differences allowing immune-mediated eradication [21]. This seed of great expectation raised hope that one day cancers might be routinely and effectively treated by immunological means. While there has been much optimism over the past 50 years, it is only during the last decade that this optimism has been met with true meaningful progress [22, 23]. There is now no question that cancer immunology has entered into a period of renaissance [24, 25], thanks largely to the affirmative and emphatic answer to several fundamental questions: (i) does cancer immunity exist? [2] (ii) can cancer-specific immunity lead to eradication of large established cancer? [16, 26] (iii) does host immune defense exert pressure to cancer during oncogenesis? [27, 28] (iv) are there tumor-specific and/or tumor-associated antigens? [2931] (v) can immune tolerance to cancer be broken to result in therapeutic benefit? [8, 10, 32] Therefore, it is not a question of “if” but for many cancers “when” immunotherapy will be the main treatment modality.

Established practice of immunotherapy of cancer

Cancer immunotherapy has already entered the mainstream of oncology [23]. Existing strategies focus on enhancing immune destruction of cancer cells by a variety of means (Table 1). One of the most successful and longstanding forms of cell-based immunotherapy is allogeneic stem cell transplant for the treatment of hematological malignancies. Although stem cell transplantation was initially thought to enhance cancer cure by allowing myeloablative therapy in the forms of high dose chemotherapy and total body irradiation [33], it has become clear that allogeneic immune response against tumor cells is a key mechanism of action [5]. The antibody-based strategy against cancer continues to make impact in cancer care, as antibodies can eliminate cancer cells via immunological means (through antibody or complement-dependent cytotoxicty) as well as via other biological means (e.g., blocking key oncogenic signals) [22, 34, 35]. In addition, immunomodulating cytokines remain important in the treatment of selected tumor types, such as the use of type I interferon as an adjuvant therapy for high-risk melanoma [36]. One significant milestone in the field of cancer immunology was the 2010 FDA-approval of sipuleucel-T (Sip-T), an autologous dendritic cell preparation, loaded with recombinant fusion protein between GM-CSF and prostate-specific acid phosphatase, for the treatment of metastatic prostate cancer [12]. Sip-T represents the first of its kind of therapeutic vaccine against cancer using dendritic cell-based platform [37]. In 2011, the FDA approved ipilimumab injection for the treatment of unresectable or metastatic melanoma. Ipilimumab represents a new class of cancer immunotherapeutics based on blockage of negative T cell check-point signal [3, 38]. Tumor-specific T cells can be activated by professional antigen presenting cells through engagement of T cell receptor and co-stimulatory molecules such as CD28. However, to maintain immune homeostasis, activated T cells have to be temporally turned off via engaging inhibitory receptors on T cells such as CTLA-4 [39, 40]. Ipilimumab is a fully human monoclonal antibody that binds and blocks CTLA-4 to sustain T cell activity, and it has been shown to improve overall survival of patients with advanced melanoma [8]. Importantly, maximizing T cell co-stimulation was demonstrated to be an effective anti-tumor strategy as early as 1992 when stable expression of the B7 molecule in tumor cells was shown to result in T-cell specific tumor eradication [41].
Table 1

Examples of FDA-approved cancer immunotherapeutic agents



Hematopoietic stem cell transplantion (e.g., leukemia and myeloma)

1. Reset the immune system

2. Allo-antigen response (graft versus tumor effect)

Antibody (e.g., retuximab, trastuzumab)

1. Eliminate cancer cells

2. Block key signaling pathways

Cytokines (e.g., type I interferon, interleukin-2)

Boost both innate and adaptive immunity

Dendritic cells (e.g., Sip-T for prostate cancer)

Enhance tumor-specific T cell priming

T cell checkpoint blockade (e.g., Ipilumimab for melanoma)

Block/reverse immune tolerance

Microbes (e.g., BCG for the transitional bladder cancer)

Enhance innate and adaptive immunity

What is hot in cancer immunotherapy in 2013?

Three kinds of cancer immunotherapeutics have emerged as key breakthroughs in clinical cancer care in 2013. These advances include T cell checkpoint blockers (Figure 1A), adoptive therapy with T cells genetically modified with chimeric antigen receptor (CAR) (Figure 1B), and targeted monoclonal antibody therapy (Figure 1C).
Figure 1

Emerging effective immunotherapies of cancer. A. T cell checkpoint blocker. B. Adoptive therapy with CAR-enforced T cells. C. Monoclonal antibody therapy.

Recent findings demonstrate that a variety of functionally non-overlapping co-inhibitory receptors can be expressed by T cells to turn off their effector function [3, 42]. These inhibitory receptors include CTLA-4, PD-1, TIM-3, BTLA, PD-1H (VISTA) and LAG-3. While in theory, blocking any of these inhibitory receptors could lead to increased activation of tumor-reactive T cells, systemic activation of T cells does not necessarily lead to more effective anti-tumor activity. Blockade of CTLA-4 with antibody led to tumor regression in 10-15% patients with advanced melanoma whereas severe autoimmune toxicity was evident in >30% of patients. Therefore, a strategy to selectively manipulate tumor microenvironment rather than systemic promotion of T cell immunity is desirable. It is particularly promising as many tumor cells express ligands for the co-inhibitory receptors, such as PD-L1 (also known as B7-H1), the ligand for PD-1 whereas there is minimal expression of this molecule in normal tissues [43]. Indeed, 9 of 25 patients (36%) with PD-L1-positive advanced tumors had an objective response to anti-PD-1 antibody therapy [9]. Surprisingly, when nivolumab (anti-PD-1 antibody) and ipilimumab were given to patients with advanced melanoma concurrently every 3 weeks for 4 doses, followed by nivolumab alone every 3 weeks for 4 doses, 53% of patients had an objective response, all with tumor reduction of 80% or more [10]. This study demonstrated the potential to combine multiple T cell checkpoint blockade to maximize anti-cancer immunity, with acceptable toxicity. Because this type of immunotherapy depends on a healthy immune system, conventional cancer treatments including chemotherapy and radiation therapy often impair immune system and could decrease the efficacy of this therapy. The field is waiting with anticipation of data of frontline therapy with T cell checkpoint blockade of cancer patients.

Several proof-of-principle studies have demonstrated the huge potential of utilizing synthetic immunology to engineer CAR-expressing or TCR-expressing T cells for the adoptive therapy of select cancers including lymphocytic leukemia [4446]. Building off work from Steven Rosenberg’s group [47], Carl June and his colleagues successfully engineered a CD19-reactive CAR composed of a fusion protein between extracellular single chain anti-CD19 antibody, the transmembrane domain, 4-1BB (CD137) survival signal, and the CD3ς chain signaling motif [48]. Autologous T cells transduced with the CD19-reactive CAR were shown to have potent clinical activity against CD19+ tumors after infusion in three of three patients with advanced chronic lymphocytic leukemia (CLL) [13]. In April 2013, it was reported that two children with relapsed and refractory pre-B-cell acute lymphocytic leukemia received infusions of T cells transduced with CD19-reactive CAR [14]. In both patients, these T cells expanded to a level that was more than 1000 times as high as the initial engraftment level, and the cells were identified in bone marrow. In addition, the CAR+ T cells were observed in the cerebrospinal fluid. More importantly, complete remission was observed in both patients and is ongoing in one patient at 11 months after treatment at the time of the report. The other patient had a relapse, with blast cells that no longer expressed CD19, approximately 2 months after treatment. Thus, CAR-modified T cells are capable of killing even aggressive, treatment-refractory acute leukemia cells in vivo. Indeed, Michel Sadelain’s group treated five relapsed acute B cell lymphocytic leukemia subjects with autologous T cells expressing a CD19-reactive CD28/CD3ζ second-generation dual-signaling CAR [16]. All patients with persistent disease upon T cell infusion demonstrated rapid tumor eradication and achieved complete molecular remissions as assessed by polymerase chain reaction, therefore, this therapy appears to be very promising in treating hematopoietic malignancies. It will be interesting to see whether the same approach could also be applied successfully for the treatment of solid tumors.
  1. 2013

    continues to witness the increasing application of monoclonal antibody for cancer immunotherapy [22]. Approved monoclonal antibodies by the FDA in 2013 include Ado-trastuzumab emtansine and pertuzumab for Her2+ breast cancer, denosumab for giant cell tumor of the bone, bevacizumab for both first and second line therapy for metastatic colorectal cancer in combination with chemotherapy. Ever since anti-CD3 antibody was approved in 1986 for the treatment of autoimmune diseases, more than 35 antibodies have been introduced to the market with a significant portion of them indicated for cancer therapy including rituximab (anti-CD20 antibody), Herceptin (anti-Her2 antibody), and Ipilimumab (anti-CTLA-4 antibody).


Key unanswered questions in cancer immunology

The current enthusiasm in cancer immunology raises the question of whether all cancers may be amenable by immune intervention. As a basis for addressing this question and making existing therapies more effective, there are four critical unanswered questions (Table 2). First, what is the molecular entity in cancer that triggers the initial immune response particularly during advanced disease? If we understand the antigens the immune system targets successfully in cancers known to be immune amenable, we may be able to better identify such antigens in patients with other types of cancer. Second, what determines the outcome of tumor immunity? We need to be mindful that tumors are not bacteria, virus or parasites. The quality of immune response to cancer cannot simply be viewed through the conventional immunological prisms we use to predict the immune response against infectious agents. Third, what is the mechanism of tumor evasion? In this case, the answer might have to come from the study of the tumor microenvironment rather than systemic suppression. Finally, as much as we all hope to have a universal cancer vaccine on a population basis [49], immunotherapy of established (clinically detectable) cancer may often need to be individualized. Figuring out how to combine various arsenals in the immune system in a tailored fashion to individual patients is a challenge as well as a wonderful opportunity for future research.
Table 2

A few key research themes in cancer immunology


Research question

Immune recognition of cancer

What are characteristics of antigens critical for immune recognition of cancer cells? Do these antigens exist for all cancers?

Fate determination of tumor immunity

Tumors are not bacteria, not viruses, and not parasites. How do differences in antigen presentation and innate immunity signals impact the ability to initiate and mediate effective anti-tumor immunity?

Mechanism of immune evasion

Are immune evasion and oncogenesis closely coupled? What is the molecular definition of oncoinflammation in the tumor environment and its impact on cancer immunity?


It is time to redefine the goals of conventional therapy to convert non-immunogenic signals to immunogenic ones. What is the best strategy to combine immunotherapy with radiation therapy, chemotherapy or targeted therapy? More innovative immunotherapeutic strategies are needed including novel targets (e.g., cancer stem cells), novel sources of antigens (subdominant antigens), novel adjuvants, novel cytokines and new ways to reset the immune system from tolerogenic status to immunogenic one.

Goals of cancer immunotherapy and perspective: are we there yet?

Slowly but surely there has been a growing paradigm shift in the understanding of biology and immunology of cancer. This is evident from the essay by Douglas Hanahan and Robert Weinberg on the Hallmarks of Cancer (The Next Generation) in 2011 which added “avoiding immune destruction” and “tumor-promoting inflammation” as another two hallmarks of cancer to their original perspective [50]. Given that the immune system has a remarkable ability to detect, “remember” and eliminate cancer cells, it is becoming clear that immunotherapy is not simply a means of cancer treatment. Rather, establishing long-lasting, cancer-specific immunity can be a goal to allow for curative therapy. In addition, development of effective immunotherapeutic cancer strategies requires our attention to deal with both of the immunological hallmarks of cancer: “avoiding immune destruction” and “tumor-promoting inflammation”. Presently, most of the approved cancer immunotherapeutics (Table 1) focus on maximizing immune destruction of cancers. No specific modalities are available clinically to silence “tumor-promoting inflammation”, other than antibiotics and vaccines to eliminate microbes-associated cancer. We are just starting to understand how cancer cells “avoiding immune destruction”. Defining and blunting oncoinflammation will likely prove critical in the future for achieving effective anti-cancer immune responses (Table 2).

Immunotherapy of cancer is no longer a dream. Gone is the time when elimination of cancer by immunological means was anecdotal or achievable only in animal studies. Immune-based therapies have now demonstrated efficacy in a range of clinical studies and types of cancer. Adoptive transfer of tumor-reactive T cells can cure select patients with advanced metastatic disease that have exhausted all other options. Other reagents, such as selective manipulation of T cell checkpoint blockers in cancer microenvironment, offer the possibility of off-the-shelf dosing or novel combinatorial therapies. More than ever before, the field of cancer immunology is permeated with a sense of optimism [23]. The key question today is not whether immune-based therapies will transform cancer therapy, but how will these approaches transform cancer medicine in the future.



This article was presented in part recently in a lecture (by Z.L) given to the 2013 Joint Conference on Immunotherapy of Cancer by the Society of Immunotherapy of Cancer (SITC), Chinese America Hematologist and Oncologist Network (CAHON), and the Chinese Society of Clinical Oncology (CSCO) in Xiamen, China.

Authors’ Affiliations

Hollings Cancer Center, Medical University of South Carolina
Yale Cancer Center, Yale University School of Medicine


  1. Prehn RT, Main JM: Immunity to methylcholanthrene-induced sarcomas. J Natl Cancer Inst 1957, 18: 769–778.PubMedGoogle Scholar
  2. Klein G: The strange road to the tumor-specific transplantation antigens (TSTAs). Cancer Immun 2001, 1: 6.PubMedGoogle Scholar
  3. Mellman I, Coukos G, Dranoff G: Cancer immunotherapy comes of age. Nature 2011,480(7378):480–489. 10.1038/nature10673PubMed CentralPubMedView ArticleGoogle Scholar
  4. Scott AM, Wolchok JD, Old LJ: Antibody therapy of cancer. Nat Rev Cancer 2012,12(4):278–287. 10.1038/nrc3236PubMedView ArticleGoogle Scholar
  5. Kolb HJ: Graft-versus-leukemia effects of transplantation and donor lymphocytes. Blood 2008,112(12):4371–4383. 10.1182/blood-2008-03-077974PubMedView ArticleGoogle Scholar
  6. Saslow D, Castle PE, Cox JT, Davey DD, Einstein MH, Ferris DG, Goldie SJ, Harper DM, Kinney W, Moscicki AB, et al.: American cancer society guideline for human papillomavirus (HPV) vaccine use to prevent cervical cancer and its precursors. CA Cancer J Clin 2007,57(1):7–28. 10.3322/canjclin.57.1.7PubMedView ArticleGoogle Scholar
  7. Chang MH, Chen CJ, Lai MS, Hsu HM, Wu TC, Kong MS, Liang DC, Shau WY, Chen DS: Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children: Taiwan childhood hepatoma study group. N Engl J Med 1997,336(26):1855–1859. 10.1056/NEJM199706263362602PubMedView ArticleGoogle Scholar
  8. Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, et al.: Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010,363(8):711–723. 10.1056/NEJMoa1003466PubMed CentralPubMedView ArticleGoogle Scholar
  9. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, et al.: Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012,366(26):2443–2454. 10.1056/NEJMoa1200690PubMed CentralPubMedView ArticleGoogle Scholar
  10. Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, Segal NH, Ariyan CE, Gordon RA, Reed K, et al.: Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 2013,369(2):122–133. 10.1056/NEJMoa1302369PubMedView ArticleGoogle Scholar
  11. Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, Drake CG, Camacho LH, Kauh J, Odunsi K, et al.: Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 2012,366(26):2455–2465. 10.1056/NEJMoa1200694PubMed CentralPubMedView ArticleGoogle Scholar
  12. Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, Redfern CH, Ferrari AC, Dreicer R, Sims RB, et al.: Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 2010,363(5):411–422. 10.1056/NEJMoa1001294PubMedView ArticleGoogle Scholar
  13. Porter DL, Levine BL, Kalos M, Bagg A, June CH: Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med 2011,365(8):725–733. 10.1056/NEJMoa1103849PubMed CentralPubMedView ArticleGoogle Scholar
  14. Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR, Teachey DT, Chew A, Hauck B, Wright JF, et al.: Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med 2013,368(16):1509–1518. 10.1056/NEJMoa1215134PubMed CentralPubMedView ArticleGoogle Scholar
  15. Brentjens RJ, Riviere I, Park JH, Davila ML, Wang X, Stefanski J, Taylor C, Yeh R, Bartido S, Borquez-Ojeda O, et al.: Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias. Blood 2013,118(18):4817–4828.View ArticleGoogle Scholar
  16. Brentjens RJ, Davila ML, Riviere I, Park J, Wang X, Cowell LG, Bartido S, Stefanski J, Taylor C, Olszewska M, et al.: CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med 2013,5(177):177ra138.View ArticleGoogle Scholar
  17. McCarthy EF: The toxins of William B Coley and the treatment of bone and soft-tissue sarcomas. Iowa Orthop J 2006, 26: 154–158.PubMed CentralPubMedGoogle Scholar
  18. Hoption Cann SA, Van Netten JP, Van Netten C, Glover DW: Spontaneous regression: a hidden treasure buried in time. Med Hypotheses 2002,58(2):115–119. 10.1054/mehy.2001.1469PubMedView ArticleGoogle Scholar
  19. Hobohm U: Fever and cancer in perspective. Cancer Immunol Immunother 2001,50(8):391–396.PubMedGoogle Scholar
  20. Goldstein MG, Li Z: Heat-shock proteins in infection-mediated inflammation-induced tumorigenesis. J Hematol Oncol 2009, 2: 5. 10.1186/1756-8722-2-5PubMed CentralPubMedView ArticleGoogle Scholar
  21. Burnet M: Cancer; a biological approach: I: the processes of control. Br Med J 1957,1(5022):779–786. 10.1136/bmj.1.5022.779PubMed CentralPubMedView ArticleGoogle Scholar
  22. Sliwkowski MX, Mellman I: Antibody therapeutics in cancer. Science 2013,341(6151):1192–1198. 10.1126/science.1241145PubMedView ArticleGoogle Scholar
  23. DeVita VT Jr, Rosenberg SA: Two hundred years of cancer research. N Engl J Med 2012,366(23):2207–2214. 10.1056/NEJMra1204479PubMedView ArticleGoogle Scholar
  24. Sawyers CL, Abate-Shen C, Anderson KC, Barker A, Baselga J, Berger NA, Foti M, Jemal A, Lawrence TS, Li CI, et al.: Cancer progress report 2013. Clin Cancer Res 2013,19(20 Suppl):S4–98.PubMedGoogle Scholar
  25. Eggermont AM, Kroemer G, Zitvogel L: Immunotherapy and the concept of a clinical cure. Eur J Cancer 2013,49(14):2965–2967. 10.1016/j.ejca.2013.06.019PubMedView ArticleGoogle Scholar
  26. Morgan RA, Dudley ME, Wunderlich JR, Hughes MS, Yang JC, Sherry RM, Royal RE, Topalian SL, Kammula US, Restifo NP, et al.: Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 2006,314(5796):126–129. 10.1126/science.1129003PubMed CentralPubMedView ArticleGoogle Scholar
  27. Smyth MJ, Godfrey DI, Trapani JA: A fresh look at tumor immunosurveillance and immunotherapy. Nat Immunol 2001,2(4):293–299. 10.1038/86297PubMedView ArticleGoogle Scholar
  28. Schreiber RD, Old LJ, Smyth MJ: Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science 2011,331(6024):1565–1570. 10.1126/science.1203486PubMedView ArticleGoogle Scholar
  29. Boon T, Coulie PG, Van den Eynde BJ, van der Bruggen P: Human T cell responses against melanoma. Annu Rev Immunol 2006, 24: 175–208. 10.1146/annurev.immunol.24.021605.090733PubMedView ArticleGoogle Scholar
  30. Vigneron N, Stroobant V, Van den Eynde BJ, van der Bruggen P: Database of T cell-defined human tumor antigens: the 2013 update. Cancer Immun 2013, 13: 15.PubMed CentralPubMedGoogle Scholar
  31. Liu B, Nash J, Runowicz C, Swede H, Stevens R, Li Z: Ovarian cancer immunotherapy: opportunities, progresses and challenges. J Hematol Oncol 2010, 3: 7. 10.1186/1756-8722-3-7PubMed CentralPubMedView ArticleGoogle Scholar
  32. Overwijk WW, Theoret MR, Finkelstein SE, Surman DR, De Jong LA, Vyth-Dreese FA, Dellemijn TA, Antony PA, Spiess PJ, Palmer DC, et al.: Tumor regression and autoimmunity after reversal of a functionally tolerant state of self-reactive CD8+ T cells. J Exp Med 2003,198(4):569–580. 10.1084/jem.20030590PubMed CentralPubMedView ArticleGoogle Scholar
  33. Thomas ED: Bone marrow transplantation: a review. Semin Hematol 1999,36(4 Suppl 7):95–103.PubMedGoogle Scholar
  34. Ferris RL, Jaffee EM, Ferrone S: Tumor antigen-targeted, monoclonal antibody-based immunotherapy: clinical response, cellular immunity, and immunoescape. J Clin Oncol 2010,28(28):4390–4399. 10.1200/JCO.2009.27.6360PubMed CentralPubMedView ArticleGoogle Scholar
  35. Pandey JP, Li Z: The forgotten tale of immunoglobulin allotypes in cancer risk and treatment. Exp Hematol Oncol 2013,2(1):6. 10.1186/2162-3619-2-6PubMed CentralPubMedView ArticleGoogle Scholar
  36. Agarwala SS: An update on pegylated IFN-alpha2b for the adjuvant treatment of melanoma. Expert Rev Anticancer Ther 2012,12(11):1449–1459. 10.1586/era.12.120PubMedView ArticleGoogle Scholar
  37. Steinman RM, Mellman I: Immunotherapy: bewitched, bothered, and bewildered no more. Science 2004,305(5681):197–200. 10.1126/science.1099688PubMedView ArticleGoogle Scholar
  38. Zou W, Chen L: Inhibitory B7-family molecules in the tumour microenvironment. Nat Rev Immunol 2008,8(6):467–477. 10.1038/nri2326PubMedView ArticleGoogle Scholar
  39. Krummel MF, Allison JP: CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. J Exp Med 1995,182(2):459–465. 10.1084/jem.182.2.459PubMedView ArticleGoogle Scholar
  40. Leach DR, Krummel MF, Allison JP: Enhancement of antitumor immunity by CTLA-4 blockade. Science 1996,271(5256):1734–1736. 10.1126/science.271.5256.1734PubMedView ArticleGoogle Scholar
  41. Chen L, Ashe S, Brady WA, Hellstrom I, Hellstrom KE, Ledbetter JA, McGowan P, Linsley PS: Costimulation of antitumor immunity by the B7 counterreceptor for the T lymphocyte molecules CD28 and CTLA-4. Cell 1992,71(7):1093–1102. 10.1016/S0092-8674(05)80059-5PubMedView ArticleGoogle Scholar
  42. Pardoll DM: The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012,12(4):252–264. 10.1038/nrc3239PubMedView ArticleGoogle Scholar
  43. Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, Roche PC, Lu J, Zhu G, Tamada K, et al.: Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med 2002,8(8):793–800.PubMedGoogle Scholar
  44. Restifo NP, Dudley ME, Rosenberg SA: Adoptive immunotherapy for cancer: harnessing the T cell response. Nat Rev Immunol 2012,12(4):269–281. 10.1038/nri3191PubMedView ArticleGoogle Scholar
  45. Riddell SR, Jensen MC, June CH: Chimeric antigen receptor–modified T cells: clinical translation in stem cell transplantation and beyond. Biol Blood Marrow Transplant 2013,19(1 Suppl):S2-S5.PubMed CentralPubMedView ArticleGoogle Scholar
  46. Kershaw MH, Westwood JA, Darcy PK: Gene-engineered T cells for cancer therapy. Nat Rev Cancer 2013,13(8):525–541. 10.1038/nrc3565PubMedView ArticleGoogle Scholar
  47. Kochenderfer JN, Wilson WH, Janik JE, Dudley ME, Stetler-Stevenson M, Feldman SA, Maric I, Raffeld M, Nathan DA, Lanier BJ, et al.: Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19. Blood 2010,116(20):4099–4102. 10.1182/blood-2010-04-281931PubMed CentralPubMedView ArticleGoogle Scholar
  48. Kalos M, June CH: Adoptive T cell transfer for cancer immunotherapy in the era of synthetic biology. Immunity 2013,39(1):49–60. 10.1016/j.immuni.2013.07.002PubMedView ArticleGoogle Scholar
  49. Li Y, Zeng H, Xu RH, Liu B, Li Z: Vaccination with human pluripotent stem cells generates a broad spectrum of immunological and clinical responses against colon cancer. Stem Cells 2009,27(12):3103–3111.PubMedGoogle Scholar
  50. Hanahan D, Weinberg RA: Hallmarks of cancer: the next generation. Cell 2011,144(5):646–674. 10.1016/j.cell.2011.02.013PubMedView ArticleGoogle Scholar


© Li et al.; licensee BioMed Central Ltd. 2013

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.