The future of cancer treatment: immunomodulation, CARs and combination immunotherapy

A Corrigendum to this article was published on 26 April 2016

This article has been updated

Key Points

  • Cancer immunotherapies have the potential to generate robust antitumour responses; this can be achieved through several methods, such as modulatory antibodies or adoptive cellular therapy

  • Since 2010, clinical trials using different immunotherapeutic approaches to treat patients with several tumour types have yielded unprecedented results

  • In contrast with therapies that act on the tumour itself, immunotherapy-dependent antitumour responses can be sustained after the treatment has finished

  • The optimal efficacy of immunotherapy will likely be achieved with designs that include combinations of different immunotherapeutic approaches, or immunotherapy combined with other cancer treatments

Abstract

In the past decade, advances in the use of monoclonal antibodies (mAbs) and adoptive cellular therapy to treat cancer by modulating the immune response have led to unprecedented responses in patients with advanced-stage tumours that would otherwise have been fatal. To date, three immune-checkpoint-blocking mAbs have been approved in the USA for the treatment of patients with several types of cancer, and more patients will benefit from immunomodulatory mAb therapy in the months and years ahead. Concurrently, the adoptive transfer of genetically modified lymphocytes to treat patients with haematological malignancies has yielded dramatic results, and we anticipate that this approach will rapidly become the standard of care for an increasing number of patients. In this Review, we highlight the latest advances in immunotherapy and discuss the role that it will have in the future of cancer treatment, including settings for which testing combination strategies and 'armoured' CAR T cells are recommended.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Immunomodulatory monoclonal antibodies and armoured chimeric antigen receptor (CAR) T cells overcome immune suppression.
Figure 2: Neoantigen presentation in the tumour microenvironment.

Change history

  • 26 April 2016

    In the sentence "Results of a phase I trial113 demonstrated that an agonist mAb targeting CD40 given as monotherapy has antitumour activity in patients with melanoma or RCC", CD40 should have read OX40. This error has been corrected in the online HTML and PDF versions of the article.

References

  1. 1

    Coley, W. B. The treatment of inoperable sarcoma by bacterial toxins (the mixed toxins of the Streptococcus erysipelas and the Bacillus prodigiosus). Proc. R. Soc. Med. 3, 1–48 (1910).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. 2

    Robert, C. et al. Nivolumab in previously untreated melanoma without BRAF mutation. N. Engl. J. Med. 372, 320–330 (2014).

    PubMed  Google Scholar 

  3. 3

    Robert, C. et al. Pembrolizumab versus ipilimumab in advanced melanoma. N. Engl. J. Med. 372, 2521–2532 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4

    Hodi, F. S. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711–723 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5

    Kantoff, P. W. et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N. Engl. J. Med. 363, 411–422 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6

    Rizvi, N. A. et al. Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet. Oncol. 16, 257–265 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7

    Pedicord, V. A., Montalvo, W., Leiner, I. M. & Allison, J. P. Single dose of anti-CTLA-4 enhances CD8+ T-cell memory formation, function, and maintenance. Proc. Natl Acad. Sci. USA 108, 266–271 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8

    Schadendorf, D. et al. Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma. J. Clin. Oncol. 33, 1889–1894 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9

    Chapman, P. B., D'Angelo, S. P. & Wolchok, J. D. Rapid eradication of a bulky melanoma mass with one dose of immunotherapy. N. Engl. J. Med. 372, 2073–2074 (2015).

    PubMed  PubMed Central  Google Scholar 

  10. 10

    Postow, M. A. et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N. Engl. J. Med. 372, 2006–2017 (2015).

    PubMed  PubMed Central  Google Scholar 

  11. 11

    Wilgenhof, S. et al. Single-center experience with ipilimumab in an expanded access program for patients with pretreated advanced melanoma. J. Immunother. 36, 215–222 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12

    Kitano, S. et al. Computational algorithm-driven evaluation of monocytic myeloid-derived suppressor cell frequency for prediction of clinical outcomes. Cancer Immunol. Res. 2, 812–821 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13

    Hannani, D. et al. Anticancer immunotherapy by CTLA-4 blockade: obligatory contribution of IL-2 receptors and negative prognostic impact of soluble CD25. Cell Res. 25, 208–224 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14

    Rizvi, N. A. et al. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348, 124–128 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15

    Snyder, A. et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N. Engl. J. Med. 371, 2189–2199 (2014).

    PubMed  PubMed Central  Google Scholar 

  16. 16

    Van Allen, E. M. et al. Genomic correlates of response to CTLA4 blockade in metastatic melanoma. Science 350, 207–211 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17

    Bonifaz, L. et al. Efficient targeting of protein antigen to the dendritic cell receptor DEC-205 in the steady state leads to antigen presentation on major histocompatibility complex class I products and peripheral CD8+ T cell tolerance. J. Exp. Med. 196, 1627–1638 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

    Walunas, T. L. et al. CTLA-4 can function as a negative regulator of T cell activation. Immunity 1, 405–413 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

    Krummel, M. F. & Allison, J. P. CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. J. Exp. Med. 182, 459–465 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20

    Tivol, E. A. et al. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 3, 541–547 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21

    Waterhouse, P. et al. Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science 270, 985–988 (1995).

    CAS  PubMed  Google Scholar 

  22. 22

    Matheu, M. P. et al. Imaging regulatory T cell dynamics and CTLA4-mediated suppression of T cell priming. Nat. Commun. 6, 6219 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    Wing, K. et al. CTLA-4 control over Foxp3+ regulatory T cell function. Science 322, 271–275 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24

    Takahashi, T. et al. Immunologic self-tolerance maintained by CD25+CD4+ regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J. Exp. Med. 192, 303–310 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

    Read, S., Malmström, V. & Powrie, F. Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25+CD4+ regulatory cells that control intestinal inflammation. J. Exp. Med. 192, 295–302 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

    Simpson, T. R. et al. Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma. J. Exp. Med. 210, 1695–1710 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27

    Selby, M. J. et al. Anti-CTLA-4 antibodies of IgG2a isotype enhance antitumor activity through reduction of intratumoral regulatory T cells. Cancer Immunol. Res. 1, 32–42 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28

    Phan, G. Q. et al. Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc. Natl Acad. Sci. USA 100, 8372–8377 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29

    Gregor, P. D. et al. CTLA-4 blockade in combination with xenogeneic DNA vaccines enhances T-cell responses, tumor immunity and autoimmunity to self antigens in animal and cellular model systems. Vaccine 22, 1700–1708 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30

    Quezada, S. A. CTLA4 blockade and GM-CSF combination immunotherapy alters the intratumor balance of effector and regulatory T cells. J. Clin. Invest. 116, 1935–1945 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31

    Weber, J. S., Kähler, K. C. & Hauschild, A. Management of immune-related adverse events and kinetics of response with ipilimumab. J. Clin. Oncol. 30, 2691–2697 (2012).

    CAS  Google Scholar 

  32. 32

    Wolchok, J. D. et al. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet. Oncol. 11, 155–164 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33

    Wolchok, J. D. et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin. Cancer Res. 15, 7412–7420 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34

    Eisenhauer, E. A. et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur. J. Cancer 45, 228–247 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    Yang, J. C. et al. Ipilimumab (anti-CTLA4 antibody) causes regression of metastatic renal cell cancer associated with enteritis and hypophysitis. J. Immunother. 30, 825–830 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    Royal, R. E. et al. Phase 2 trial of single agent Ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J. Immunother. 33, 828–833 (2010).

    CAS  PubMed  Google Scholar 

  37. 37

    Postow, M. A. et al. Immunologic correlates of the abscopal effect in a patient with melanoma. N. Engl. J. Med. 366, 925–931 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Zamarin, D. et al. Localized oncolytic virotherapy overcomes systemic tumor resistance to immune checkpoint blockade immunotherapy. Sci. Transl. Med. 6, 226ra32–226ra32 (2014).

    PubMed  PubMed Central  Google Scholar 

  39. 39

    Waitz, R., Fassò, M. & Allison, J. P. CTLA-4 blockade synergizes with cryoablation to mediate tumor rejection. Oncoimmunology 1, 544–546 (2014).

    Google Scholar 

  40. 40

    Chemnitz, J. M. et al. SHP-1 and SHP-2 associate with immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary human T cell stimulation, but only receptor ligation prevents T cell activation. J. Immunol. 173, 945–954 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41

    Parry, R. V. et al. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol. Cell. Biol. 25, 9543–9553 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    Park, J.-J. et al. B7-H1/CD80 interaction is required for the induction and maintenance of peripheral T-cell tolerance. Blood 116, 1291–1298 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43

    Paterson, A. M. et al. The programmed death-1 ligand 1:B7-1 pathway restrains diabetogenic effector T cells in vivo. J. Immunol. 187, 1097–1105 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    Nishimura, H. et al. Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science 291, 319–322 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45

    Nishimura, H. et al. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity 11, 141–151 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46

    Okazaki, T. & Honjo, T. PD-1 and PD-1 ligands: from discovery to clinical application. Int. Immunol. 19, 813–824 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47

    Larkin, J. et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N. Engl. J. Med. 373, 23–34 (2015).

    PubMed  PubMed Central  Google Scholar 

  48. 48

    Brahmer, J. et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N. Engl. J. Med. 373, 123–134 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49

    U.S. Food and Drug Administation. FDA expands approved use of Opdivo in advanced lung cancer. [online], (2014).

  50. 50

    U.S. Food and Drug Administation. FDA approves Keytruda for advanced non-small cell lung cancer. [online], (2015).

  51. 51

    Topalian, S. L. et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 366, 2443–2454 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

    Brahmer, J. R. et al. Nivolumab (anti-PD-1, BMS-936558, ONO-4538) in patients (pts) with advanced non-small-cell lung cancer (NSCLC): survival and clinical activity by subgroup analysis [abstract]. J. Clin. Oncol. 32 (Suppl.), 8112 (2014).

    Google Scholar 

  53. 53

    Powles, T. et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature 515, 558–562 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54

    Ansell, S. M. et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. N. Engl. J. Med. 372, 311–319 (2014).

    PubMed  PubMed Central  Google Scholar 

  55. 55

    Brahmer, J. R. et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 366, 2455–2465 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56

    Huard, B. et al. Cellular expression and tissue distribution of the human LAG-3-encoded protein, an MHC class II ligand. Immunogenetics 39, 213–217 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57

    Huard, B. et al. CD4/major histocompatibility complex class II interaction analyzed with CD4- and lymphocyte activation gene-3 (LAG-3)–Ig fusion proteins. Eur. J. Immunol. 25, 2718–2721 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58

    Huang, C.-T. et al. Role of LAG-3 in regulatory T cells. Immunity 21, 503–513 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59

    Okamura, T. et al. CD4+CD25LAG3+ regulatory T cells controlled by the transcription factor Egr-2. Proc. Natl Acad. Sci. USA 106, 13974–13979 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60

    Blackburn, S. D. et al. Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat. Immunol. 10, 29–37 (2009).

    CAS  Google Scholar 

  61. 61

    Butler, N. S. et al. Therapeutic blockade of PD-L1 and LAG-3 rapidly clears established blood-stage Plasmodium infection. Nat. Immunol. 13, 188–195 (2012).

    CAS  Google Scholar 

  62. 62

    Woo, S.-R. et al. Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape. Cancer Res. 72, 917–927 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63

    Triebel, F., Hacene, K. & Pichon, M.-F. A soluble lymphocyte activation gene-3 (sLAG-3) protein as a prognostic factor in human breast cancer expressing estrogen or progesterone receptors. Cancer Lett. 235, 147–153 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64

    Brignone, C. et al. A phase I pharmacokinetic and biological correlative study of IMP321, a novel MHC class II agonist, in patients with advanced renal cell carcinoma. Clin. Cancer Res. 15, 6225–6231 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65

    US National Library of Science. ClinicalTrials.gov [online], (2016).

  66. 66

    Jin, H.-T. et al. Cooperation of Tim-3 and PD-1 in CD8 T-cell exhaustion during chronic viral infection. Proc. Natl Acad. Sci. USA 107, 14733–14738 (2010).

    CAS  PubMed  Google Scholar 

  67. 67

    Zhu, C. et al. The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. Nat. Immunol. 6, 1245–1252 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68

    Chiba, S. et al. Tumor-infiltrating DCs suppress nucleic acid-mediated innate immune responses through interactions between the receptor TIM-3 and the alarmin HMGB1. Nat. Immunol. 13, 832–842 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69

    Nakayama, M. et al. Tim-3 mediates phagocytosis of apoptotic cells and cross-presentation. Blood 113, 3821–3830 (2009).

    CAS  PubMed  Google Scholar 

  70. 70

    Huang, Y.-H. et al. CEACAM1 regulates TIM-3-mediated tolerance and exhaustion. Nature 517, 386–390 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71

    Ngiow, S. F. et al. Anti-TIM3 antibody promotes T cell IFN-γ-mediated antitumor immunity and suppresses established tumors. Cancer Res. 71, 3540–3551 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72

    Sakuishi, K. et al. Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. J. Exp. Med. 207, 2187–2194 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73

    Fourcade, J. et al. Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen-specific CD8+ T cell dysfunction in melanoma patients. J. Exp. Med. 207, 2175–2186 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74

    Johnston, R. J. et al. The immunoreceptor TIGIT regulates antitumor and antiviral CD8+ T cell effector function. Cancer Cell 26, 923–937 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75

    Lozano, E., Dominguez-Villar, M., Kuchroo, V. & Hafler, D. A. The TIGIT/CD226 axis regulates human T cell function. J. Immunol. 188, 3869–3875 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76

    Kurtulus, S. et al. Mechanisms of TIGIT-driven immune suppression in cancer. J. Immunother. Cancer 2, O13 (2014).

    Google Scholar 

  77. 77

    Khalil, D. N. et al. The new era of cancer immunotherapy: manipulating T-cell activity to overcome malignancy. Adv. Cancer Res. 128, 1–68 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78

    Bartkowiak, T. & Curran, M. A. 4-1BB agonists: multi-potent potentiators of tumor immunity. Front. Oncol. 5, 117 (2015).

    PubMed  PubMed Central  Google Scholar 

  79. 79

    Lee, H.-W. et al. 4-1BB promotes the survival of CD8+ T lymphocytes by increasing expression of Bcl-xL and Bfl-1. J. Immunol. 169, 4882–4888 (2002).

    PubMed  PubMed Central  Google Scholar 

  80. 80

    Stärck, L., Scholz, C., Dörken, B. & Daniel, P. T. Costimulation by CD137/4-1BB inhibits T cell apoptosis and induces Bcl-xL and c-FLIPshort via phosphatidylinositol 3-kinase and AKT/protein kinase B. Eur. J. Immunol. 35, 1257–1266 (2005).

    PubMed  PubMed Central  Google Scholar 

  81. 81

    Shuford, W. W. et al. 4-1BB costimulatory signals preferentially induce CD8+ T cell proliferation and lead to the amplification in vivo of cytotoxic T cell responses. J. Exp. Med. 186, 47–55 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82

    Vinay, D. S. & Kwon, B. S. 4-1BB (CD137), an inducible costimulatory receptor, as a specific target for cancer therapy. BMB Rep. 47, 122–129 (2014).

    PubMed  PubMed Central  Google Scholar 

  83. 83

    Curran, M. A. et al. Combination CTLA-4 blockade and 4-1BB activation enhances tumor rejection by increasing T-cell infiltration, proliferation, and cytokine production. PLoS ONE 6, e19499 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84

    Uno, T. et al. Eradication of established tumors in mice by a combination antibody-based therapy. Nat. Med. 12, 693–698 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85

    Tirapu, I. et al. Improving efficacy of interleukin-12-transfected dendritic cells injected into murine colon cancer with anti-CD137 monoclonal antibodies and alloantigens. Int. J. Cancer 110, 51–60 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86

    Shi, W. & Siemann, D. W. Augmented antitumor effects of radiation therapy by 4-1BB antibody (BMS-469492) treatment. Anticancer Res. 26, 3445–3453 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87

    Molckovsky, A. & Siu, L. L. First-in-class, first-in-human phase I results of targeted agents: highlights of the 2008 American Society of Clinical Oncology meeting. J. Hematol. Oncol. 1, 20 (2008).

    PubMed  PubMed Central  Google Scholar 

  88. 88

    Garber, K. Beyond ipilimumab: new approaches target the immunological synapse. J. Natl Cancer Inst. 103, 1079–1082 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89

    US National Library of Science. ClinicalTrials.gov [online], (2016).

  90. 90

    James, A. M., Cohen, A. D. & Campbell, K. S. Combination immune therapies to enhance anti-tumor responses by NK cells. Front. Immunol. 4, 481 (2013).

    Google Scholar 

  91. 91

    Kohrt, H. E. et al. Targeting CD137 enhances the efficacy of cetuximab. J. Clin. Invest. 124, 2668–2682 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92

    Schaer, D. A., Cohen, A. D. & Wolchok, J. D. Anti-GITR antibodies — potential clinical applications for tumor immunotherapy. Curr. Opin. Investig. Drugs 11, 1378–1386 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93

    Kanamaru, F. et al. Costimulation via glucocorticoid-induced TNF receptor in both conventional and CD25+ regulatory CD4+ T cells. J. Immunol. 172, 7306–7314 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 94

    Ronchetti, S. et al. Glucocorticoid-induced TNFR-related protein lowers the threshold of CD28 costimulation in CD8+ T cells. J. Immunol. 179, 5916–5926 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 95

    Valzasina, B. et al. Triggering of OX40 (CD134) on CD4+CD25+ T cells blocks their inhibitory activity: a novel regulatory role for OX40 and its comparison with GITR. Blood 105, 2845–2851 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96

    Mitsui, J. et al. Two distinct mechanisms of augmented antitumor activity by modulation of immunostimulatory/inhibitory signals. Clin. Cancer Res. 16, 2781–2791 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97

    Bulliard, Y. et al. Activating Fc γ receptors contribute to the antitumor activities of immunoregulatory receptor-targeting antibodies. J. Exp. Med. 210, 1685–1693 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98

    Cohen, A. D. et al. Agonist anti-GITR monoclonal antibody induces melanoma tumor immunity in mice by altering regulatory T cell stability and intra-tumor accumulation. PLoS ONE 5, e10436 (2010).

    PubMed  PubMed Central  Google Scholar 

  99. 99

    Schaer, D. A. et al. GITR pathway activation abrogates tumor immune suppression through loss of regulatory T cell lineage stability. Cancer Immunol. Res. 1, 320–331 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100

    US National Library of Science. ClinicalTrials.gov[online], (2015).

  101. 101

    US National Library of Science. ClinicalTrials.gov[online],(2015).

  102. 102

    Eliopoulos, A. G. & Young, L. S. The role of the CD40 pathway in the pathogenesis and treatment of cancer. Curr. Opin. Pharmacol. 4, 360–367 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. 103

    Van Kooten, C. & Banchereau, J. CD40–CD40 ligand. J. Leukoc. Biol. 67, 2–17 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. 104

    Kawabe, T. et al. The immune responses in CD40-deficient mice: impaired immunoglobulin class switching and germinal center formation. Immunity 1, 167–178 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 105

    Burington, B. et al. CD40 pathway activation status predicts response to CD40 therapy in diffuse large B cell lymphoma. Sci. Transl. Med. 3, 74ra22 (2011).

    PubMed  PubMed Central  Google Scholar 

  106. 106

    Beatty, G. L. et al. CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science 331, 1612–1616 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107

    Baumann, R. et al. Functional expression of CD134 by neutrophils. Eur. J. Immunol. 34, 2268–2275 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. 108

    Rogers, P. R. et al. OX40 promotes Bcl-xL and Bcl-2 expression and is essential for long-term survival of CD4 T cells. Immunity 15, 445–455 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 109

    Arestides, R. S. S. et al. Costimulatory molecule OX40L is critical for both Th1 and Th2 responses in allergic inflammation. Eur. J. Immunol. 32, 2874–2880 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. 110

    Griseri, T., Asquith, M., Thompson, C. & Powrie, F. OX40 is required for regulatory T cell-mediated control of colitis. J. Exp. Med. 207, 699–709 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. 111

    Hirschhorn-Cymerman, D. et al. OX40 engagement and chemotherapy combination provides potent antitumor immunity with concomitant regulatory T cell apoptosis. J. Exp. Med. 206, 1103–1116 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. 112

    Pan, P.-Y. et al. OX40 ligation enhances primary and memory cytotoxic T lymphocyte responses in an immunotherapy for hepatic colon metastases. Mol. Ther. 6, 528–536 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113

    Curti, B. D. et al. OX40 is a potent immune-stimulating target in late-stage cancer patients. Cancer Res. 73, 7189–7198 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. 114

    US National Library of Science. ClinicalTrials.gov[online], (2015).

  115. 115

    US National Library of Science. ClinicalTrials.gov[online], (2015).

  116. 116

    US National Library of Science. ClinicalTrials.gov[online], (2015).

  117. 117

    US National Library of Science. ClinicalTrials.gov[online], (2015).

  118. 118

    Naidoo, J., Page, D. B. & Wolchok, J. D. Immune modulation for cancer therapy. Br. J. Cancer 111, 2214–2219 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. 119

    Gross, G., Waks, T. & Eshhar, Z. Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity. Proc. Natl Acad. Sci. USA 86, 10024–10028 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. 120

    Brentjens, R. J. et al. Eradication of systemic B-cell tumors by genetically targeted human T lymphocytes co-stimulated by CD80 and interleukin-15. Nat. Med. 9, 279–286 (2003).

    CAS  PubMed  Google Scholar 

  121. 121

    Brentjens, R. J. et al. Genetically targeted T cells eradicate systemic acute lymphoblastic leukemia xenografts. Clin. Cancer Res. 13, 5426–5435 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. 122

    Davila, M. L. et al. Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci. Transl. Med. 6, 224ra25 (2014).

    PubMed  PubMed Central  Google Scholar 

  123. 123

    Imai, C. et al. Chimeric receptors with 4-1BB signaling capacity provoke potent cytotoxicity against acute lymphoblastic leukemia. Leukemia 18, 676–684 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. 124

    Maude, S. L. et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N. Engl. J. Med. 371, 1507–1517 (2014).

    PubMed  PubMed Central  Google Scholar 

  125. 125

    Hombach, A. A. et al. OX40 costimulation by a chimeric antigen receptor abrogates CD28 and IL-2 induced IL-10 secretion by redirected CD4+ T cells. Oncoimmunology 1, 458–466 (2012).

    PubMed  PubMed Central  Google Scholar 

  126. 126

    Guedan, S. et al. ICOS-based chimeric antigen receptors program bipolar TH17/TH1 cells. Blood 124, 1070–1080 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. 127

    US National Library of Science. ClinicalTrials.gov[online], (2015).

  128. 128

    Pegram, H. J. et al. Tumor-targeted T cells modified tosecrete IL-12 eradicate systemic tumors without need for prior conditioning. Blood 119, 4133–4141 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. 129

    Zhao, Z. et al. Structural design of engineered costimulation determines tumor rejection kinetics and persistence of CAR T cells. Cancer Cell 28, 415–428 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. 130

    Curran, K. J. et al. Enhancing antitumor efficacy of chimeric antigen receptor T cells through constitutive CD40L expression. Mol. Ther. 23, 769–778 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. 131

    Lee, D. W. et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet 385, 517–528 (2014).

    PubMed  PubMed Central  Google Scholar 

  132. 132

    Fielding, A. K. et al. Outcome of 609 adults after relapse of acute lymphoblastic leukemia (ALL); an MRC UKALL12/ECOG 2993 study. Blood 109, 944–950 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. 133

    Pegram, H. J., Smith, E. L., Rafiq, S. & Brentjens, R. J. CAR therapy for hematological cancers: can success seen in the treatment of B-cell acute lymphoblastic leukemia be applied to other hematological malignancies? Immunotherapy 7, 545–561 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. 134

    Park, J. H. et al. CD19-Targeted 19-28z CAR modified autologous T cells induce high rates of complete remission and durable responses in adult patients with relapsed, refractory B-cell ALL. Blood 124, 382 (2014).

    Google Scholar 

  135. 135

    Park, J. H. et al. Efficacy and safety of CD19-targeted 19-28z CAR modified T cells in adult patients with relapsed or refractory B-ALL. J. Clin. Oncol. 33, 7010 (2015).

    Google Scholar 

  136. 136

    Grupp, S. A. et al. T cells engineered with a chimeric antigen receptor (CAR) targeting CD19 (CTL019) have long term persistence and induce durable remissions in children with relapsed, refractory ALL. Blood 124, 380 (2014).

    Google Scholar 

  137. 137

    Grupp, S. A. Immunotherapy for childhood leukemia. Presented at the 2015 ASCO Annual Meeting (2015).

  138. 138

    Lee, D. W. et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood 124, 188–195 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. 139

    Turtle, C. et al. Immunotherapy with CD19-specific chimeric antigen receptor (CAR)-modified T cells of defined subset composition. J. Clin. Oncol. 33, 3006 (2015).

    Google Scholar 

  140. 140

    Kebriaei, P. et al. Adoptive therapy using sleeping beauty gene transfer system and artificial antigen presenting cells to manufacture T cells expressing CD19-specific chimeric antigen receptor. Blood 124, 311 (2014).

    Google Scholar 

  141. 141

    Porter, D. L. et al. Randomized, phase II dose optimization study of chimeric antigen receptor modified T cells directed against CD19 (CTL019) in patients with relapsed, refractory CLL. Blood 124, 1982 (2014).

    Google Scholar 

  142. 142

    Beatty, G. L. et al. Safety and antitumor activity of chimeric antigen receptor modified T cells in patients with chemotherapy refractory metastatic pancreatic cancer [abstract]. J. Clin. Oncol. 33 (Suppl.), 3007 (2015).

    Google Scholar 

  143. 143

    Howlader, N. et al. SEER Cancer Statistics Review, 1975–2012. National Cancer Institute [online], (2015).

  144. 144

    Aspinall, R. & Andrew, D. Thymic involution in aging. J. Clin. Immunol. 20, 250–256 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. 145

    Goronzy, J. J., Li, G., Yu, M. & Weyand, C. M. Signaling pathways in aged T cells — a reflection of T cell differentiation, cell senescence and host environment. Semin. Immunol. 24, 365–372 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. 146

    Croft, M. Co-stimulatory members of the TNFR family: keys to effective T-cell immunity? Nat. Rev. Immunol. 3, 609–620 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. 147

    Brentjens, R. J. et al. Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias. Blood 118, 4817–4828 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. 148

    Park, J. H. et al. Impact of the conditioning chemotherapy on outcomes in adoptive T cell therapy: results from a phase I clinical trial of autologous CD19-targeted T cells for patients with relapsed CLL. Blood 120, 1797 (2012).

    Google Scholar 

  149. 149

    Ramos, C. et al. Clinical responses in patients infused with T lymphocytes redirected to target κ-light immunoglobulin chain. Blood 122, 506 (2013).

    Google Scholar 

  150. 150

    Hahn, T. et al. The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of acute lymphoblastic leukemia in adults: an evidence-based review. Biol. Blood Marrow Transplant. 12, 1–30 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. 151

    Eapen, M. et al. Outcomes after HLA-matched sibling transplantation or chemotherapy in children with B-precursor acute lymphoblastic leukemia in a second remission: a collaborative study of the Children's Oncology Group and the Center for International Blood and Marrow Transplant Research. Blood 107, 4961–4967 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. 152

    Porter, D. L. et al. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N. Engl. J. Med. 365, 725–733 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. 153

    Porter, D. L. et al. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci. Transl. Med. 7, 303ra139 (2015).

    PubMed  PubMed Central  Google Scholar 

  154. 154

    Christopoulos, P. et al. Definition and characterization of the systemic T-cell dysregulation in untreated indolent B-cell lymphoma and very early CLL. Blood 117, 3836–3846 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. 155

    Riches, J. C. et al. T cells from CLL patients exhibit features of T-cell exhaustion but retain capacity for cytokine production. Blood 121, 1612–1621 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. 156

    McClanahan, F. et al. Mechanisms of PD-L1/PD-1 mediated CD8 T-cell dysfunction in the context of aging-related immune defects in the Eμ-TCL1 CLL mouse model. Blood 126, 212–221 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. 157

    D'Arena, G. et al. Regulatory T-cell number is increased in chronic lymphocytic leukemia patients and correlates with progressive disease. Leuk. Res. 35, 363–368 (2011).

    PubMed  PubMed Central  Google Scholar 

  158. 158

    Jitschin, R. et al. CLL-cells induce IDOhi CD14+HLA-DRlo myeloid-derived suppressor cells that inhibit T-cell responses and promote TRegs . Blood 124, 750–760 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. 159

    Boissard, F. et al. Nurse like cells: chronic lymphocytic leukemia associated macrophages. Leuk. Lymphoma 56, 1570–1572 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. 160

    Burger, J. A. et al. Blood-derived nurse-like cells protect chronic lymphocytic leukemia B cells from spontaneous apoptosis through stromal cell-derived factor-1. Blood 96, 2655–2663 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. 161

    Saulep-Easton, D. et al. The BAFF receptor TACI controls IL-10 production by regulatory B cells and CLL B cells. Leukemia 30, 163–172 (2015).

    PubMed  PubMed Central  Google Scholar 

  162. 162

    Kochenderfer, J. N. et al. Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. J. Clin. Oncol. 33, 540–549 (2014).

    PubMed  PubMed Central  Google Scholar 

  163. 163

    Schuster, S. J. et al. Phase IIa trial of chimeric antigen receptor modified T cells directed against CD19 (CTL019) in patients with relapsed or refractory CD19+ lymphomas. J. Clin. Oncol. 33, 8516 (2015).

    Google Scholar 

  164. 164

    Sauter, C. S. et al. Phase I trial of 19-28z chimeric antigen receptor modified T cells (19-28z CAR-T) post-high dose therapy and autologous stem cell transplant (HDT-ASCT) for relapsed and refractory (rel/ref) aggressive B-cell non-Hodgkin lymphoma (B-NHL). J. Clin. Oncol. 33, 8515 (2015).

    Google Scholar 

  165. 165

    Savoldo, B. et al. CD28 costimulation improves expansion and persistence of chimeric antigen receptor-modified T cells in lymphoma patients. J. Clin. Invest. 121, 1822–1826 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. 166

    Maude, S. L., Barrett, D., Teachey, D. T. & Grupp, S. A. Managing cytokine release syndrome associated with novel T cell-engaging therapies. Cancer J. 20, 119–122 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. 167

    Frey, N. V. et al. Refractory cytokine release syndrome in recipients of chimeric antigen receptor (CAR) T cells. Blood 124, 2296 (2014).

    Google Scholar 

  168. 168

    Haso, W. et al. Anti-CD22-chimeric antigen receptors targeting B-cell precursor acute lymphoblastic leukemia. Blood 121, 1165–1174 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  169. 169

    Berger, C. et al. Safety of targeting ROR1 in primates with chimeric antigen receptor-modified T cells. Cancer Immunol. Res. 3, 206–216 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  170. 170

    Hudecek, M. et al. The B-cell tumor-associated antigen ROR1 can be targeted with T cells modified to express a ROR1-specific chimeric antigen receptor. Blood 116, 4532–4541 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. 171

    Ying, Z.-T. et al. First-in-patient proof of safety and efficacy of a 4th generation chimeric antigen receptor-modified T cells for the treatment of relapsed or refractory CD30 positive lymphomas [poster]. Presented at the 13th International Conference on Malignant Lymphoma (2015).

  172. 172

    Carpenter, R. O. et al. B-cell maturation antigen is a promising target for adoptive T-cell therapy of multiple myeloma. Clin. Cancer Res. 19, 2048–2060 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  173. 173

    Chu, J. et al. CS1-specific chimeric antigen receptor (CAR)-engineered natural killer cells enhance in vitro and in vivo antitumor activity against human multiple myeloma. Leukemia 28, 917–927 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. 174

    Mihara, K. et al. T-cell immunotherapy with a chimeric receptor against CD38 is effective in eliminating myeloma cells. Leukemia 26, 365–367 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  175. 175

    Drent, E. et al. CD38 chimeric antigen receptor engineered T cells as therapeutic tools for multiple myeloma. Blood 124, 4759 (2014).

    Google Scholar 

  176. 176

    Guo, B. et al. CD138-directed adoptive immunotherapy of chimeric antigen receptor (CAR)-modified T cells for multiple myeloma. J. Cell. Immunother. http://dx.doi.org/10.1016/j.jocit.2014.11.001, (2015).

  177. 177

    Kenderian, S. S. et al. CD33 specific chimeric antigen receptor T cells exhibit potent preclinical activity against human acute myeloid leukemia. Leukemia 29, 1637–1647 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  178. 178

    Gill, S. et al. Preclinical targeting of human acute myeloid leukemia and myeloablation using chimeric antigen receptor-modified T cells. Blood 123, 2343–2354 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  179. 179

    Tettamanti, S. et al. Targeting of acute myeloid leukaemia by cytokine-induced killer cells redirected with a novel CD123-specific chimeric antigen receptor. Br. J. Haematol. 161, 389–401 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. 180

    Mardiros, A. et al. T cells expressing CD123-specific chimeric antigen receptors exhibit specific cytolytic effector functions and antitumor effects against human acute myeloid leukemia. Blood 122, 3138–3148 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  181. 181

    Jackson, H. J., Rafiq, S. & Brentjens, R. J. Driving CAR T cells forward. Nat. Rev. Clin. Oncol. http://dx.doi.org/10.1038/nrclinonc.2016.36, (2016).

  182. 182

    Marusyk, A. & Polyak, K. Tumor heterogeneity: causes and consequences. Biochim. Biophys. Acta 1805, 105–117 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  183. 183

    Fidler, I. J. & Hart, I. R. Biological diversity in metastatic neoplasms: origins and implications. Science 217, 998–1003 (1982).

    CAS  PubMed  PubMed Central  Google Scholar 

  184. 184

    Adusumilli, P. S. et al. Regional delivery of mesothelin-targeted CAR T cell therapy generates potent and long-lasting CD4-dependent tumor immunity. Sci. Transl. Med. 6, 261ra151 (2014).

    PubMed  PubMed Central  Google Scholar 

  185. 185

    Beatty, G. L. et al. Mesothelin-specific chimeric antigen receptor mRNA-engineered T cells induce anti-tumor activity in solid malignancies. Cancer Immunol. Res. 2, 112–120 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  186. 186

    Tanyi, J. et al. Safety and feasibility of chimeric antigen receptor modified T cells directed against mesothelin (CART-meso) in patients with mesothelin expressing cancers [abstract]. Cancer Res. 75 (Suppl.), CT105 (2015).

    Google Scholar 

  187. 187

    Louis, C. U. et al. Antitumor activity and long-term fate of chimeric antigen receptor-positive T cells in patients with neuroblastoma. Blood 118, 6050–6056 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  188. 188

    Singh, N. et al. Nature of tumor control by permanently and transiently modified GD2 chimeric antigen receptor T cells in xenograft models of neuroblastoma. Cancer Immunol. Res. 2, 1059–1070 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  189. 189

    Johnson, L. A. et al. Rational development and characterization of humanized anti-EGFR variant III chimeric antigen receptor T cells for glioblastoma. Sci. Transl. Med. 7, 275ra22 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  190. 190

    Koneru, M. et al. IL-12 secreting tumor-targeted chimeric antigen receptor T cells eradicate ovarian tumors in vivo. Oncoimmunology 4, e994446 (2015).

    PubMed  PubMed Central  Google Scholar 

  191. 191

    Koneru, M. et al. A phase I clinical trial of adoptive T cell therapy using IL-12 secreting MUC-16ecto directed chimeric antigen receptors for recurrent ovarian cancer. J. Transl. Med. 13, 102 (2015).

    PubMed  PubMed Central  Google Scholar 

  192. 192

    Grupp, S. A. et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N. Engl. J. Med. 368, 1509–1518 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  193. 193

    Moon, E. K. et al. Multifactorial T-cell hypofunction that is reversible can limit the efficacy of chimeric antigen receptor-transduced human T cells in solid tumors. Clin. Cancer Res. 20, 4262–4273 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  194. 194

    Ankri, C. et al. Human T cells engineered to express a programmed death 1/28 costimulatory retargeting molecule display enhanced antitumor activity. J. Immunol. 191, 4121–4129 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  195. 195

    Kobold, S. et al. Impact of a new fusion receptor on PD-1-mediated immunosuppression in adoptive T cell therapy. J. Natl. Cancer Inst. 107, djv146 (2015).

    PubMed  PubMed Central  Google Scholar 

  196. 196

    Heemskerk, B. et al. Adoptive cell therapy for patients with melanoma, using tumor-infiltrating lymphocytes genetically engineered to secrete interleukin-2. Hum. Gene Ther. 19, 496–510 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  197. 197

    Hoyos, V. et al. Engineering CD19-specific T lymphocytes with interleukin-15 and a suicide gene to enhance their anti-lymphoma/leukemia effects and safety. Leukemia 24, 1160–1170 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  198. 198

    Leonard, J. P. et al. Effects of single-dose interleukin-12 exposure on interleukin-12-associated toxicity and interferon-γ production. Blood 90, 2541–2548 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  199. 199

    Chinnasamy, D. et al. Local delivery of interleukin-12 using T cells targeting VEGF receptor-2 eradicates multiple vascularized tumors in mice. Clin. Cancer Res. 18, 1672–1683 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  200. 200

    Kerkar, S. P. et al. IL-12 triggers a programmatic change in dysfunctional myeloid-derived cells within mouse tumors. J. Clin. Invest. 121, 4746–4757 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  201. 201

    Kerkar, S. P. et al. Collapse of the tumor stroma is triggered by IL-12 induction of Fas. Mol. Ther. 21, 1369–1377 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  202. 202

    Pegram, H. J. et al. IL-12-secreting CD19-targeted cord blood-derived T cells for the immunotherapy of B-cell acute lymphoblastic leukemia. Leukemia 29, 415–422 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  203. 203

    Dunn, G. P. et al. Cancer immunoediting: from immunosurveillance to tumor escape. Nat. Immunol. 3, 991–998 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  204. 204

    Koebel, C. M. et al. Adaptive immunity maintains occult cancer in an equilibrium state. Nature 450, 903–907 (2007).

    CAS  PubMed  Google Scholar 

  205. 205

    Schreiber, R. D., Old, L. J. & Smyth, M. J. Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science 331, 1565–1570 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  206. 206

    Shankaran, V. et al. IFNγ and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature 410, 1107–1111 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  207. 207

    Vesely, M. D., Kershaw, M. H., Schreiber, R. D. & Smyth, M. J. Natural innate and adaptive immunity to cancer. Annu. Rev. Immunol. 29, 235–271 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  208. 208

    Matsushita, H. et al. Cancer exome analysis reveals a T-cell-dependent mechanism of cancer immunoediting. Nature 482, 400–404 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  209. 209

    Alexandrov, L. B. et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  210. 210

    John, L. B. et al. Anti-PD-1 antibody therapy potently enhances the eradication of established tumors by gene-modified T cells. Clin. Cancer Res. 19, 5636–5646 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  211. 211

    Garon, E. B. et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N. Engl. J. Med. 372, 2018–2028 (2015).

    PubMed  PubMed Central  Google Scholar 

  212. 212

    Skoulidis, F. et al. Co-occurring genomic alterations define major subsets of KRAS-mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities. Cancer Discov. 5, 860–877 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  213. 213

    US National Library of Science. ClinicalTrials.gov[online], (2015).

  214. 214

    Robbins, P. F. et al. Mining exomic sequencing data to identify mutated antigens recognized by adoptively transferred tumor-reactive T cells. Nat. Med. 19, 747–752 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  215. 215

    Rosenberg, S. A. et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin. Cancer Res. 17, 4550–4557 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  216. 216

    Dudley, M. E. et al. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 298, 850–854 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  217. 217

    Tran, E. et al. Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer. Science 344, 641–645 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  218. 218

    Stafford, J. H. et al. Colony stimulating factor 1 receptor inhibition delays recurrence of glioblastoma after radiation by altering myeloid cell recruitment and polarization. Neuro Oncol. http://dx.doi.org/10.1093/neuonc/nov272, (2015).

  219. 219

    Lipson, E. J. et al. Safety and immunologic correlates of melanoma GVAX, a GM-CSF secreting allogeneic melanoma cell vaccine administered in the adjuvant setting. J. Transl. Med. 13, 214 (2015).

    PubMed  PubMed Central  Google Scholar 

  220. 220

    DiLillo, D. J. & Ravetch, J. V. Differential Fc-receptor engagement drives an anti-tumor vaccinal effect. Cell 161, 1035–1045 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  221. 221

    Kraman, M. et al. Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-α. Science 330, 827–830 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors would like to thank their funders. D.N.K. receives support through the American Association for Cancer Research Amgen fellowship in Clinical/Translational Cancer Research and the American Philosophical Society Daland Fellowship in Clinical Investigation. E.L.S. receives support from the Conquer Cancer Foundation of ASCO, Lymphoma Research Foundation, MSKCC Technology Development Fund, and the Multiple Myeloma Research Foundation. R.B.J. receives support from the Annual Terry Fox Run for Cancer Research (New York, NY) organized by the Canada Club of New York, Carson Family Charitable Trust, Emerald Foundation, the Experimental Therapeutics Center of Memorial Sloan Kettering Cancer Center (Innovations in the structures, functions and targets of monoclonal antibody-based drugs for cancer), Kate's Team, National Institutes of Health Grants (R01CA138738-05, PO1CA059350, PO1CA190174-01), and the William Lawrence and Blanche Hughes Foundation. J.D.W. receives funding support from Bristol-Myers Squibb, Emerald Foundation, Genentech, the Ludwig Center for Cancer Immunotherapy, Medimmune, Merck Pharmaceuticals, Polynoma Pharmaceuticals and Swim Across America.

Author information

Affiliations

Authors

Contributions

All authors researched data for article, contributed to discussion of the content, wrote the manuscript and reviewed/edited the article before submission.

Corresponding author

Correspondence to Jedd D. Wolchok.

Ethics declarations

Competing interests

D.N.K. and E.L.S. and declare no competing interests. R.J.B. is a co.founder, stockholder, and consultant for Juno Therapeutics Inc. J.D.W. is a consultant for Bristol Myers Squibb, Genentech, Medimmune, Merck Pharmaceuticals and Polynoma Pharmaceuticals.

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Khalil, D., Smith, E., Brentjens, R. et al. The future of cancer treatment: immunomodulation, CARs and combination immunotherapy. Nat Rev Clin Oncol 13, 273–290 (2016). https://doi.org/10.1038/nrclinonc.2016.25

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing