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

Nature Reviews Clinical Oncology

Volumn 13, Issue 5, 2016, Pages 273-290

  Khalil, Danny N ^a   Smith, Eric L ^a   Brentjens, Renier J ^a   Wolchok, Jedd D ^a  

^a MEMORIAL SLOAN KETTERING CANCER CENTER   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

C REACTIVE PROTEIN; CANCER VACCINE; CD19 ANTIGEN; CD40 ANTIGEN; CELL PROTEIN; CHIMERIC ANTIGEN RECEPTOR; CYTOTOXIC T LYMPHOCYTE ANTIGEN 4; FLUDARABINE; GLUCOCORTICOID INDUCED TUMOR NECROSIS FACTOR RECEPTOR; GLYCOPROTEIN GP 100; IPILIMUMAB; LYMPHOCYTE ACTIVATION GENE 3; MEMBRANE PROTEIN; MONOCLONAL ANTIBODY; NIVOLUMAB; OX40 LIGAND; PEMBROLIZUMAB; T CELL MEMBRANE PROTEIN 3; UNCLASSIFIED DRUG; HYBRID PROTEIN; LYMPHOCYTE ANTIGEN RECEPTOR;

ADOPTIVE TRANSFER; ADVANCED CANCER; CANCER IMMUNIZATION; CANCER IMMUNOTHERAPY; CANCER SURVIVAL; CELL STIMULATION; CELL THERAPY; DISEASE SEVERITY; DRUG APPROVAL; DRUG EFFECT; DRUG POTENCY; HEMATOLOGIC MALIGNANCY; HUMAN; IMMUNOCOMPETENT CELL; IMMUNOMODULATION; MELANOMA; METASTATIC MELANOMA; NONHODGKIN LYMPHOMA; NONHUMAN; OVERALL SURVIVAL; PRIORITY JOURNAL; REGULATORY T LYMPHOCYTE; REVIEW; SOLID TUMOR; T LYMPHOCYTE ACTIVATION; TREATMENT PLANNING; BIOLOGICAL MODEL; FORECASTING; GENETICS; IMMUNOLOGY; IMMUNOTHERAPY; METABOLISM; MULTIMODALITY CANCER THERAPY; NEOPLASMS; PROCEDURES; T LYMPHOCYTE; TRANSPLANTATION; TRENDS;

ANTIBODIES, MONOCLONAL; COMBINED MODALITY THERAPY; FORECASTING; HUMANS; IMMUNOTHERAPY; MODELS, IMMUNOLOGICAL; NEOPLASMS; RECEPTORS, ANTIGEN, T-CELL; RECOMBINANT FUSION PROTEINS; T-LYMPHOCYTES;

EID: 84961219372     PISSN: 17594774     EISSN: 17594782     Source Type: Journal    
DOI: 10.1038/nrclinonc.2016.25     Document Type: Review

References (221)

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).
2. Robert, C. et al. Nivolumab in previously untreated melanoma without BRAF mutation. N. Engl. J. Med. 372, 320-330 (2014).
3. Robert, C. et al. Pembrolizumab versus ipilimumab in advanced melanoma. N. Engl. J. Med. 372, 2521-2532 (2015).
4. Hodi, F. S. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711-723 (2010).
5. Kantoff, P. W. et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N. Engl. J. Med. 363, 411-422 (2010).
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).
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).
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).
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).
10. Postow, M. A. et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N. Engl. J. Med. 372, 2006-2017 (2015).
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).
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).
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).
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).
15. Snyder, A. et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N. Engl. J. Med. 371, 2189-2199 (2014).
16. Van Allen, E. M. et al. Genomic correlates of response to CTLA4 blockade in metastatic melanoma. Science 350, 207-211 (2015).
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).
18. Walunas, T. L. et al. CTLA-4 can function as a negative regulator of T cell activation. Immunity 1, 405-413 (1994).
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).
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).
21. Waterhouse, P. et al. Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science 270, 985-988 (1995).
22. Matheu, M. P. et al. Imaging regulatory T cell dynamics and CTLA4-mediated suppression of T cell priming. Nat. Commun. 6, 6219 (2015).
23. Wing, K. et al. CTLA-4 control over Foxp3+ regulatory T cell function. Science 322, 271-275 (2008).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
38. Zamarin, D. et al. Localized oncolytic virotherapy overcomes systemic tumor resistance to immune checkpoint blockade immunotherapy. Sci. Transl. Med. 6, 22632-22632 (2014).
39. Waitz, R., Fassò, M., Allison, J. P. CTLA-4 blockade synergizes with cryoablation to mediate tumor rejection. Oncoimmunology 1, 544-546 (2014).
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).
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).
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).
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).
44. Nishimura, H. et al. Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science 291, 319-322 (2001).
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).
46. Okazaki, T., Honjo, T. PD-1 and PD-1 ligands: from discovery to clinical application. Int. Immunol. 19, 813-824 (2007).
47. Larkin, J. et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N. Engl. J. Med. 373, 23-34 (2015).
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).
49. U.S. Food and Drug Administation. FDA expands approved use of Opdivo in advanced lung cancer. [online], http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm466413.htm (2014).
50. U.S. Food and Drug Administation. FDA approves Keytruda for advanced non-small cell lung cancer. [online], http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm465444.htm (2015).
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).
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).
53. Powles, T. et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature 515, 558-562 (2014).
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).
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).
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).
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).
58. Huang, C.-T. et al. Role of LAG-3 in regulatory T cells. Immunity 21, 503-513 (2004).
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).
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).
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).
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).
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).
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).
65. US National Library of Science. ClinicalTrials.gov [online], https://www.clinicaltrials.gov/ct2/show/NCT01968109 (2016).
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).
67. Zhu, C. et al. The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. Nat. Immunol. 6, 1245-1252 (2005).
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).
69. Nakayama, M. et al. Tim-3 mediates phagocytosis of apoptotic cells and cross-presentation. Blood 113, 3821-3830 (2009).
70. Huang, Y.-H. et al. CEACAM1 regulates TIM-3-mediated tolerance and exhaustion. Nature 517, 386-390 (2015).
71. Ngiow, S. F. et al. Anti-TIM3 antibody promotes T cell IFN-mediated antitumor immunity and suppresses established tumors. Cancer Res. 71, 3540-3551 (2011).
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).
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).
74. Johnston, R. J. et al. The immunoreceptor TIGIT regulates antitumor and antiviral CD8+ T cell effector function. Cancer Cell 26, 923-937 (2014).
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).
76. Kurtulus, S. et al. Mechanisms of TIGIT-driven immune suppression in cancer. J. Immunother. Cancer 2, O13 (2014).
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).
78. Bartkowiak, T., Curran, M. A. 4-1BB agonists: multi-potent potentiators of tumor immunity. Front. Oncol. 5, 117 (2015).
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).
80. Strck, L., Scholz, C., Drken, 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).
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).
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).
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).
84. Uno, T. et al. Eradication of established tumors in mice by a combination antibody-based therapy. Nat. Med. 12, 693-698 (2006).
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).
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).
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).
88. Garber, K. Beyond ipilimumab: new approaches target the immunological synapse. J. Natl Cancer Inst. 103, 1079-1082 (2011).
89. US National Library of Science. ClinicalTrials.gov [online], https://clinicaltrials.gov/ct2/show/NCT02253992 (2016).
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).
91. Kohrt, H. E. et al. Targeting CD137 enhances the efficacy of cetuximab. J. Clin. Invest. 124, 2668-2682 (2014).
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).
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).
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).
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).
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).
97. Bulliard, Y. et al. Activating Fc receptors contribute to the antitumor activities of immunoregulatory receptor-targeting antibodies. J. Exp. Med. 210, 1685-1693 (2013).
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).
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).
100. US National Library of Science. ClinicalTrials.gov [online], https://clinicaltrials.gov/ct2/show/NCT02583165 (2015).
101. US National Library of Science. ClinicalTrials.gov [online], https://clinicaltrials.gov/ct2/show/NCT02628574 (2015).
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).
103. Van Kooten, C., Banchereau, J. CD40-CD40 ligand. J. Leukoc. Biol. 67, 2-17 (2000).
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).
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).
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).
107. Baumann, R. et al. Functional expression of CD134 by neutrophils. Eur. J. Immunol. 34, 2268-2275 (2004).
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).
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).
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).
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).
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).
113. Curti, B. D. et al. OX40 is a potent immune-stimulating target in late-stage cancer patients. Cancer Res. 73, 7189-7198 (2013).
114. US National Library of Science. ClinicalTrials.gov [online], https://clinicaltrials.gov/ct2/show/NCT01862900 (2015).
115. US National Library of Science. ClinicalTrials.gov [online], https://clinicaltrials.gov/ct2/show/NCT01303705 (2015).
116. US National Library of Science. ClinicalTrials.gov [online], https://clinicaltrials.gov/ct2/show/NCT02205333 (2015).
117. US National Library of Science. ClinicalTrials.gov [online], https://clinicaltrials.gov/ct2/show/NCT02221960 (2015).
118. Naidoo, J., Page, D. B., Wolchok, J. D. Immune modulation for cancer therapy. Br. J. Cancer 111, 2214-2219 (2014).
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).
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).
121. Brentjens, R. J. et al. Genetically targeted T cells eradicate systemic acute lymphoblastic leukemia xenografts. Clin. Cancer Res. 13, 5426-5435 (2007).
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, 224-25 (2014).
123. Imai, C. et al. Chimeric receptors with 4-1BB signaling capacity provoke potent cytotoxicity against acute lymphoblastic leukemia. Leukemia 18, 676-684 (2004).
124. Maude, S. L. et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N. Engl. J. Med. 371, 1507-1517 (2014).
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).
126. Guedan, S. et al. ICOS-based chimeric antigen receptors program bipolar TH17/TH1 cells. Blood 124, 1070-1080 (2014).
127. US National Library of Science. ClinicalTrials.gov [online], http://www.clinicaltrials.gov/ct2/show/NCT02498912 (2015).
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).
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).
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).
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).
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).
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).
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).
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).
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).
137. Grupp, S. A. Immunotherapy for childhood leukemia. Presented at the 2015 ASCO Annual Meeting (2015).
138. Lee, D. W. et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood 124, 188-195 (2014).
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).
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).
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).
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).
143. Howlader, N. et al. SEER Cancer Statistics Review, 1975-2012. National Cancer Institute [online], http://seer.cancer.gov/crs/1975-2012/(2015).
144. Aspinall, R., Andrew, D. Thymic involution in aging. J. Clin. Immunol. 20, 250-256 (2000).
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).
146. Croft, M. Co-stimulatory members of the TNFR family: keys to effective T-cell immunity Nat. Rev. Immunol. 3, 609-620 (2003).
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).
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).
149. Ramos, C. et al. Clinical responses in patients infused with T lymphocytes redirected to target-light immunoglobulin chain. Blood 122, 506 (2013).
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).
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).
152. Porter, D. L. et al. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N. Engl. J. Med. 365, 725-733 (2011).
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).
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).
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).
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 E-TCL1 CLL mouse model. Blood 126, 212-221 (2015).
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).
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).
159. Boissard, F. et al. Nurse like cells: chronic lymphocytic leukemia associated macrophages. Leuk. Lymphoma 56, 1570-1572 (2015).
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).
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).
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).
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).
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).
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).
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).
167. Frey, N. V. et al. Refractory cytokine release syndrome in recipients of chimeric antigen receptor (CAR) T cells. Blood 124, 2296 (2014).
168. Haso, W. et al. Anti-CD22-chimeric antigen receptors targeting B-cell precursor acute lymphoblastic leukemia. Blood 121, 1165-1174 (2013).
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).
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).
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. 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).
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).
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).
175. Drent, E. et al. CD38 chimeric antigen receptor engineered T cells as therapeutic tools for multiple myeloma. Blood 124, 4759 (2014).
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. 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).
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).
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).
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).
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. Marusyk, A., Polyak, K. Tumor heterogeneity: causes and consequences. Biochim. Biophys. Acta 1805, 105-117 (2010).
183. Fidler, I. J., Hart, I. R. Biological diversity in metastatic neoplasms: origins and implications. Science 217, 998-1003 (1982).
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, 261-151 (2014).
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).
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.), 105 (2015).
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).
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).
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).
190. Koneru, M. et al. IL-12 secreting tumor-targeted chimeric antigen receptor T cells eradicate ovarian tumors in vivo. Oncoimmunology 4, e994446 (2015).
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).
192. Grupp, S. A. et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N. Engl. J. Med. 368, 1509-1518 (2013).
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).
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).
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, 146 (2015).
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).
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).
198. Leonard, J. P. et al. Effects of single-dose interleukin-12 exposure on interleukin-12-associated toxicity and interferon-production. Blood 90, 2541-2548 (1997).
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).
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).
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).
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).
203. Dunn, G. P. et al. Cancer immunoediting: from immunosurveillance to tumor escape. Nat. Immunol. 3, 991-998 (2002).
204. Koebel, C. M. et al. Adaptive immunity maintains occult cancer in an equilibrium state. Nature 450, 903-907 (2007).
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).
206. Shankaran, V. et al. IFN and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature 410, 1107-1111 (2001).
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).
208. Matsushita, H. et al. Cancer exome analysis reveals a T-cell-dependent mechanism of cancer immunoediting. Nature 482, 400-404 (2012).
209. Alexandrov, L. B. et al. Signatures of mutational processes in human cancer. Nature 500, 415-421 (2013).
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).
211. Garon, E. B. et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N. Engl. J. Med. 372, 2018-2028 (2015).
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).
213. US National Library of Science. ClinicalTrials.gov [online], http://www.clinicaltrials.gov/ct2/show/NCT00586391 (2015).
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).
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).
216. Dudley, M. E. et al. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 298, 850-854 (2002).
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).
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. 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).
220. DiLillo, D. J., Ravetch, J. V. Differential Fc-receptor engagement drives an anti-tumor vaccinal effect. Cell 161, 1035-1045 (2015).
221. Kraman, M. et al. Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-. Science 330, 827-830 (2010).