Enhancing the efficacy of adoptive cellular therapy by targeting tumor-induced immunosuppression

Immunotherapy

Volumn 7, Issue 5, 2015, Pages 499-512

  Beavis, Paul A ^a,b   Slaney, Clare Y ^a,b   Kershaw, Michael H ^a,b,c   Neeson, Paul J ^a,b   Darcy, Phillip K ^a,b,c  

^a PETER MACCALLUM CANCER CENTRE   (Australia)

^b UNIVERSITY OF MELBOURNE   (Australia)

^c MONASH UNIVERSITY   (Australia)

Author keywords

adoptive cellular therapy; checkpoint blockade; chemotherapy; chimeric antigen receptor; cytokine; genetic modification; immunosuppression; radiotherapy; T cells; tumor

Indexed keywords

ANTINEOPLASTIC AGENT; CHIMERIC ANTIGEN RECEPTOR; CYTOKINE; NONSTEROID ANTIINFLAMMATORY AGENT; ONCOLYTIC VIRUS;

ADOPTIVE IMMUNOTHERAPY; ADOPTIVE TRANSFER; CANCER CHEMOTHERAPY; CANCER RADIOTHERAPY; CD4+ T LYMPHOCYTE; CELL SURVIVAL; CYTOKINE PRODUCTION; DNA MODIFICATION; GENETICS; HUMAN; IMMUNE DEFICIENCY; IMMUNE RESPONSE; IMMUNOMODULATION; INTRACELLULAR SIGNALING; LYMPHOCYTE; MOLECULARLY TARGETED THERAPY; NONHUMAN; PHASE 1 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; RADIATION RESPONSE; REVIEW; T LYMPHOCYTE; T LYMPHOCYTE ACTIVATION; THERAPY EFFECT; TREATMENT OUTCOME; TUMOR IMMUNITY; TUMOR INDUCED IMMUNOSUPPRESSION; ANIMAL; IMMUNOLOGICAL TOLERANCE; IMMUNOLOGY; NEOPLASMS; PATHOLOGY; PROCEDURES;

ANIMALS; HUMANS; IMMUNE TOLERANCE; IMMUNOTHERAPY, ADOPTIVE; NEOPLASMS;

EID: 84931046039     PISSN: 1750743X     EISSN: 17507448     Source Type: Journal    
DOI: 10.2217/imt.15.16     Document Type: Review

References (163)

1. Rosenberg SA, Yang JC, Sherry RM et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin. Cancer Res. 17(13), 4550-4557 (2011).
2. Zhou J, Shen X, Huang J, Hodes RJ, Rosenberg SA, Robbins PF. Telomere length of transferred lymphocytes correlates with in vivo persistence and tumor regression in melanoma patients receiving cell transfer therapy. J. Immunol. 175(10), 7046-7052 (2005).
3. Morgan RA, Dudley ME, Wunderlich JR et al. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 314(5796), 126-129 (2006).
4. Eshhar Z, Waks T, Gross G, Schindler DG. Specific activation and targeting of cytotoxic lymphocytes through chimeric single chains consisting of antibody-binding domains and the gamma or zeta subunits of the immunoglobulin and T-cell receptors. Proc. Natl Acad. Sci. USA 90(2), 720-724 (1993).
5. Finney HM, Lawson AD, Bebbington CR, Weir AN. Chimeric receptors providing both primary and costimulatory signaling in T cells from a single gene product. J. Immunol. 161(6), 2791-2797 (1998).
6. Carpenito C, Milone MC, Hassan R et al. Control of large, established tumor xenografts with genetically retargeted human T cells containing CD28 and CD137 domains. Proc. Natl Acad. Sci. USA 106(9), 3360-3365 (2009).
7. Zhong XS, Matsushita M, Plotkin J, Riviere I, Sadelain M. Chimeric antigen receptors combining 4-1BB and CD28 signaling domains augment PI3kinase/AKT/Bcl-XL activation and CD8+ T cell-mediated tumor eradication. Mol. Ther. 18(2), 413-420 (2010).
8. Tammana S, Huang X, Wong M et al. 4-1BB and CD28 signaling plays a synergistic role in redirecting umbilical cord blood T cells against B-cell malignancies. Hum. Gene Ther. 21(1), 75-86 (2010).
9. Bridgeman JS, Hawkins RE, Hombach AA, Abken H, Gilham DE. Building better chimeric antigen receptors for adoptive T cell therapy. Curr. Gene Ther. 10(2), 77-90 (2010).
10. Sadelain M, Brentjens R, Riviere I. The basic principles of chimeric antigen receptor design. Cancer Discov. 3(4), 388-398 (2013).
11. Grupp SA, Kalos M, Barrett D et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N. Engl. J. Med. 368(16), 1509-1518 (2013).
12. Brentjens RJ, Davila ML, Riviere I et al. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci. Transl. Med. 5(177), 177ra138 (2013).
13. Brentjens RJ, Riviere I, Park JH 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(18), 4817-4828 (2011).
14. Porter DL, Levine BL, Kalos M, Bagg A, June CH. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N. Engl. J. Med. 365(8), 725-733 (2011).
15. Kalos M, Levine BL, Porter DL et al. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci. Transl. Med. 3(95), 95ra73 (2011).
16. Kochenderfer JN, Wilson WH, Janik JE et al. Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19. Blood 116(20), 4099-4102 (2010).
17. Maus MV, Grupp SA, Porter DL, June CH. Antibody-modified T cells: CARs take the front seat for hematologic malignancies. Blood 123(17), 2625-2635 (2014).
18. Ritchie DS, Neeson PJ, Khot A et al. Persistence and efficacy of second generation CAR T cell against the LeY antigen in acute myeloid leukemia. Mol. Ther. 21(11), 2122-2129 (2013).
19. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12(4), 252-264 (2012).
20. Curran MA, Montalvo W, Yagita H, Allison JP. PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc. Natl Acad. Sci. USA 107(9), 4275-4280 (2010).
21. Sakuishi K, Apetoh L, Sullivan JM, Blazar BR, Kuchroo VK, Anderson AC. Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. J. Exp. Med. 207(10), 2187-2194 (2010).
22. Simpson TR, Li F, Montalvo-Ortiz W 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(9), 1695-1710 (2013).
23. Peggs KS, Quezada SA, Chambers CA, Korman AJ, Allison JP. Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti-CTLA-4 antibodies. J. Exp. Med. 206(8), 1717-1725 (2009).
24. Taube JM, Klein A, Brahmer JR et al. Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin. Cancer Res. 20(19), 5064-74 (2014).
25. Topalian SL, Sznol M, Mcdermott DF et al. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J. Clin. Oncol. 32(10), 1020-1030 (2014).
26. Wolchok JD, Hodi FS, Weber JS et al. Development of ipilimumab: a novel immunotherapeutic approach for the treatment of advanced melanoma. Ann. NY Acad. Sci. 1291, 1-13 (2013).
27. Wolchok JD, Kluger H, Callahan MK et al. Nivolumab plus ipilimumab in advanced melanoma. N. Engl. J. Med. 369(2), 122-133 (2013).
28. Hodi FS, Oday SJ, Mcdermott DF et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363(8), 711-723 (2010).
29. Croft M. Co-stimulatory members of the TNFR family: keys to effective T-cell immunity? Nat. Rev. Immunol. 3(8), 609-620 (2003).
30. Diaz-Montero CM, Finke J, Montero AJ. Myeloid-derived suppressor cells in cancer: therapeutic, predictive, and prognostic implications. Semin. Oncol. 41(2), 174-184 (2014).
31. Gabrilovich DI, Ostrand-Rosenberg S, Bronte V. Coordinated regulation of myeloid cells by tumours. Nat. Rev. Immunol. 12(4), 253-268 (2012).
32. Nishikawa H, Sakaguchi S. Regulatory T cells in tumor immunity. Int. J. Cancer 127(4), 759-767 (2010).
33. Curiel TJ, Coukos G, Zou L et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat. Med. 10(9), 942-949 (2004).
34. Ishida T, Ishii T, Inagaki A et al. Specific recruitment of CC chemokine receptor 4-positive regulatory T cells in Hodgkin lymphoma fosters immune privilege. Cancer Res. 66(11), 5716-5722 (2006).
35. Liu VC, Wong LY, Jang T et al. Tumor evasion of the immune system by converting CD4+CD25- T cells into CD4+CD25+ T regulatory cells: role of tumor-derived TGF-beta. J. Immunol. 178(5), 2883-2892 (2007).
36. Valzasina B, Piconese S, Guiducci C, Colombo MP. Tumor-induced expansion of regulatory T cells by conversion of CD4+CD25-lymphocytes is thymus and proliferation independent. Cancer Res. 66(8), 4488-4495 (2006).
37. Ladoire S, Martin F, Ghiringhelli F. Prognostic role of FOXP3+ regulatory T cells infiltrating human carcinomas: the paradox of colorectal cancer. Cancer Immunol Immunother 60(7), 909-918 (2011).
38. Nauta AJ, Fibbe WE. Immunomodulatory properties of mesenchymal stromal cells. Blood 110(10), 3499-3506 (2007).
39. Spaggiari GM, Capobianco A, Abdelrazik H, Becchetti F, Mingari MC, Moretta L. Mesenchymal stem cells inhibit natural killer-cell proliferation, cytotoxicity, and cytokine production: role of indoleamine 2,3-dioxygenase and prostaglandin E2. Blood 111(3), 1327-1333 (2008).
40. Le Blanc K, Rasmusson I, Sundberg B et al. Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet 363(9419), 1439-1441 (2004).
41. Klages K, Mayer CT, Lahl K et al. Selective depletion of Foxp3+ regulatory T cells improves effective therapeutic vaccination against established melanoma. Cancer Res. 70(20), 7788-7799 (2010).
42. Li X, Kostareli E, Suffner J, Garbi N, Hammerling GJ. Efficient Treg depletion induces T-cell infiltration and rejection of large tumors. Eur J. Immunol. 40(12), 3325-3335 (2010).
43. Zhou Q, Bucher C, Munger ME et al. Depletion of endogenous tumor-associated regulatory T cells improves the efficacy of adoptive cytotoxic T-cell immunotherapy in murine acute myeloid leukemia. Blood 114(18), 3793-3802 (2009).
44. Baba J, Watanabe S, Saida Y et al. Depletion of radio-resistant regulatory T cells enhances antitumor immunity during recovery from lymphopenia. Blood 120(12), 2417-2427 (2012).
45. Lesokhin AM, Hohl TM, Kitano S et al. Monocytic CCR2(+) myeloid-derived suppressor cells promote immune escape by limiting activated CD8 T-cell infiltration into the tumor microenvironment. Cancer Res. 72(4), 876-886 (2012).
46. Mok S, Koya RC, Tsui C et al. Inhibition of CSF-1 receptor improves the antitumor efficacy of adoptive cell transfer immunotherapy. Cancer Res. 74(1), 153-161 (2014).
47. Highfill SL, Long AH, Orentas RJ, Mackall CL. Neutralization of murine myeloid-derived suppressor cells enhances the efficacy of a chimeric antigen receptor T-cells directed against pediatric solid tumors. J. Immunother. Cancer 1, 265 (2013).
48. Greenberg PD, Cheever MA. Treatment of disseminated leukemia with cyclophosphamide and immune cells: tumor immunity reflects long-term persistence of tumor-specific donor T cells. J. Immunol. 133(6), 3401-3407 (1984).
49. Bracci L, Moschella F, Sestili P et al. Cyclophosphamide enhances the antitumor efficacy of adoptively transferred immune cells through the induction of cytokine expression, B-cell and T-cell homeostatic proliferation, and specific tumor infiltration. Clin. Cancer Res. 13(2 Pt 1), 644-653 (2007).
50. Wallen H, Thompson JA, Reilly JZ, Rodmyre RM, Cao J, Yee C. Fludarabine modulates immune response and extends in vivo survival of adoptively transferred CD8 T cells in patients with metastatic melanoma. PLoS ONE 4(3), e4749 (2009).
51. Dudley ME, Yang JC, Sherry R et al. Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens. J. Clin. Oncol. 26(32), 5233-5239 (2008).
52. North RJ. Cyclophosphamide-facilitated adoptive immunotherapy of an established tumor depends on elimination of tumor-induced suppressor T cells. J. Exp. Med. 155(4), 1063-1074 (1982).
53. Ercolini AM, Ladle BH, Manning EA et al. Recruitment of latent pools of high-avidity CD8(+) T cells to the antitumor immune response. J. Exp. Med. 201(10), 1591-1602 (2005).
54. Lutsiak ME, Semnani RT, De Pascalis R, Kashmiri SV, Schlom J, Sabzevari H. Inhibition of CD4(+)25+ T regulatory cell function implicated in enhanced immune response by low-dose cyclophosphamide. Blood 105(7), 2862-2868 (2005).
55. Medina-Echeverz J, Fioravanti J, Zabala M, Ardaiz N, Prieto J, Berraondo P. Successful colon cancer eradication after chemoimmunotherapy is associated with profound phenotypic change of intratumoral myeloid cells. J. Immunol. 186(2), 807-815 (2011).
56. Medina-Echeverz J, Berraondo P. Colon cancer eradication after chemoimmunotherapy is associated with intratumoral emergence of proinflammatory myeloid cells. Oncoimmunology 1(1), 118-120 (2012).
57. Ghiringhelli F, Apetoh L, Tesniere A et al. Activation of the NLRP3 inflammasome in dendritic cells induces IL-1beta-dependent adaptive immunity against tumors. Nat. Med. 15(10), 1170-1178 (2009).
58. Ma Y, Adjemian S, Mattarollo SR et al. Anticancer chemotherapy-induced intratumoral recruitment and differentiation of antigen-presenting cells. Immunity 38(4), 729-741 (2013).
59. Kroemer G, Galluzzi L, Kepp O, Zitvogel L. Immunogenic cell death in cancer therapy. Annu. Rev. Immunol. 31, 51-72 (2013).
60. Vacchelli E, Senovilla L, Eggermont A et al. Trial watch: chemotherapy with immunogenic cell death inducers. Oncoimmunology 2(3), e23510 (2013).
61. Tesniere A, Schlemmer F, Boige V et al. Immunogenic death of colon cancer cells treated with oxaliplatin. Oncogene 29(4), 482-491 (2010).
62. Alizadeh D, Trad M, Hanke NT et al. Doxorubicin eliminates myeloid-derived suppressor cells and enhances the efficacy of adoptive T-cell transfer in breast cancer. Cancer Res. 74(1), 104-118 (2014).
63. Guo ZS, Hong JA, Irvine KR et al. De novo induction of a cancer/testis antigen by 5-aza-2-deoxycytidine augments adoptive immunotherapy in a murine tumor model. Cancer Res. 66(2), 1105-1113 (2006).
64. Bruchard M, Mignot G, Derangere V et al. Chemotherapy-triggered cathepsin B release in myeloid-derived suppressor cells activates the Nlrp3 inflammasome and promotes tumor growth. Nat. Med. 19(1), 57-64 (2013).
65. Spisek R, Charalambous A, Mazumder A, Vesole DH, Jagannath S, Dhodapkar MV. Bortezomib enhances dendritic cell (DC)-mediated induction of immunity to human myeloma via exposure of cell surface heat shock protein 90 on dying tumor cells: therapeutic implications. Blood 109(11), 4839-4845 (2007).
66. Blanco B, Perez-Simon JA, Sanchez-Abarca LI et al. Bortezomib induces selective depletion of alloreactive T lymphocytes and decreases the production of Th1 cytokines. Blood 107(9), 3575-3583 (2006).
67. Huye LE, Nakazawa Y, Patel MP et al. Combining mTor inhibitors with rapamycin-resistant T cells: a two-pronged approach to tumor elimination. Mol. Ther. 19(12), 2239-2248 (2011).
68. Ko HJ, Kim YJ, Kim YS et al. A combination of chemoimmunotherapies can efficiently break self-tolerance and induce antitumor immunity in a tolerogenic murine tumor model. Cancer Res. 67(15), 7477-7486 (2007).
69. Fridlender ZG, Sun J, Singhal S et al. Chemotherapy delivered after viral immunogene therapy augments antitumor efficacy via multiple immune-mediated mechanisms. Mol. Ther. 18(11), 1947-1959 (2010).
70. Suzuki E, Kapoor V, Jassar AS, Kaiser LR, Albelda SM. Gemcitabine selectively eliminates splenic Gr-1+/CD11b+ myeloid suppressor cells in tumor-bearing animals and enhances antitumor immune activity. Clin. Cancer Res. 11(18), 6713-6721 (2005).
71. Ding ZC, Lu X, Yu M et al. Immunosuppressive myeloid cells induced by chemotherapy attenuate antitumor CD4+ T-cell responses through the PD-1-PD-L1 axis. Cancer Res. 74(13), 3441-3453 (2014).
72. Kang TH, Mao CP, Lee SY et al. Chemotherapy acts as an adjuvant to convert the tumor microenvironment into a highly permissive state for vaccination-induced antitumor immunity. Cancer Res. 73(8), 2493-2504 (2013).
73. Ramakrishnan R, Assudani D, Nagaraj S et al. Chemotherapy enhances tumor cell susceptibility to CTL-mediated killing during cancer immunotherapy in mice. J. Clin. Invest. 120(4), 1111-1124 (2010).
74. Casares N, Pequignot MO, Tesniere A et al. Caspase-dependent immunogenicity of doxorubicin-induced tumor cell death. J. Exp. Med. 202(12), 1691-1701 (2005).
75. Schiavoni G, Sistigu A, Valentini M et al. Cyclophosphamide synergizes with type I interferons through systemic dendritic cell reactivation and induction of immunogenic tumor apoptosis. Cancer Res. 71(3), 768-778 (2011).
76. Ghiringhelli F, Larmonier N, Schmitt E et al. CD4+CD25+ regulatory T cells suppress tumor immunity but are sensitive to cyclophosphamide which allows immunotherapy of established tumors to be curative. Eur J. Immunol. 34(2), 336-344 (2004).
77. Xu W, Cai J, Li S et al. Improving the in vivo persistence, distribution and function of cytotoxic T lymphocytes by inhibiting the tumor immunosuppressive microenvironment. Scand. J. Immunol. 78(1), 50-60 (2013).
78. Seeger JM, Schmidt P, Brinkmann K et al. The proteasome inhibitor bortezomib sensitizes melanoma cells toward adoptive CTL attack. Cancer Res. 70(5), 1825-1834 (2010).
79. Mikyskova R, Indrova M, Vlkova V et al. DNA demethylating agent 5-azacytidine inhibits myeloid-derived suppressor cells induced by tumor growth and cyclophosphamide treatment. J. Leukoc. Biol. doi:10.1189/ jlb.0813435 (2014) (Epub ahead of print).
80. Umansky V, Sevko A. Overcoming immunosuppression in the melanoma microenvironment induced by chronic inflammation. Cancer Immunol. Immunother. 61(2), 275-282 (2012).
81. Zhu Y, Liu N, Xiong SD, Zheng YJ, Chu YW. CD4+Foxp3+ regulatory T-cell impairment by paclitaxel is independent of toll-like receptor 4. Scand. J. Immunol. 73(4), 301-308 (2011).
82. Zhang L, Dermawan K, Jin M et al. Differential impairment of regulatory T cells rather than effector T cells by paclitaxel-based chemotherapy. Clin. Immunol. 129(2), 219-229 (2008).
83. Kodumudi KN, Weber A, Sarnaik AA, Pilon-Thomas S. Blockade of myeloid-derived suppressor cells after induction of lymphopenia improves adoptive T cell therapy in a murine model of melanoma. J. Immunol. 189(11), 5147-5154 (2012).
84. Formenti SC, Demaria S. Combining radiotherapy and cancer immunotherapy: a paradigm shift. J. Natl Cancer Inst. 105(4), 256-265 (2013).
85. Ma Y, Kepp O, Ghiringhelli F et al. Chemotherapy and radiotherapy: cryptic anticancer vaccines. Semin Immunol. 22(3), 113-124 (2010).
86. Vereecque R, Buffenoir G, Gonzalez R et al. gamma-ray irradiation induces B7.1 expression in myeloid leukaemic cells. Br. J. Haematol. 108(4), 825-831 (2000).
87. Zamai L, Rana R, Mazzotti G, Centurione L, Di Pietro R, Vitale M. Lymphocyte binding to K562 cells: effect of target cell irradiation and correlation with ICAM-1 and LFA-3 expression. Eur. J. Histochem. 38(Suppl. 1), 53-60 (1994).
88. Gaugler MH, Squiban C, Van Der Meeren A, Bertho JM, Vandamme M, Mouthon MA. Late and persistent up-regulation of intercellular adhesion molecule-1 (ICAM-1) expression by ionizing radiation in human endothelial cells in vitro. Int. J. Radiat. Biol. 72(2), 201-209 (1997).
89. Kim JY, Son YO, Park SW et al. Increase of NKG2D ligands and sensitivity to NK cell-mediated cytotoxicity of tumor cells by heat shock and ionizing radiation. Exp. Mol. Med. 38(5), 474-484 (2006).
90. Chakraborty M, Abrams SI, Camphausen K et al. Irradiation of tumor cells up-regulates Fas and enhances CTL lytic activity and CTL adoptive immunotherapy. J. Immunol. 170(12), 6338-6347 (2003).
91. Chakraborty M, Abrams SI, Coleman CN, Camphausen K, Schlom J, Hodge JW. External beam radiation of tumors alters phenotype of tumor cells to render them susceptible to vaccine-mediated T-cell killing. Cancer Res. 64(12), 4328-4337 (2004).
92. Hodge JW, Sharp HJ, Gameiro SR. Abscopal regression of antigen disparate tumors by antigen cascade after systemic tumor vaccination in combination with local tumor radiation. Cancer Biother. Radiopharm. 27(1), 12-22 (2012).
93. Ganss R, Ryschich E, Klar E, Arnold B, Hammerling GJ. Combination of T-cell therapy and trigger of inflammation induces remodeling of the vasculature and tumor eradication. Cancer Res. 62(5), 1462-1470 (2002).
94. Klug F, Prakash H, Huber PE et al. Low-dose irradiation programs macrophage differentiation to an iNOS(+)/M1 phenotype that orchestrates effective T cell immunotherapy. Cancer Cell 24(5), 589-602 (2013).
95. Lugade AA, Sorensen EW, Gerber SA, Moran JP, Frelinger JG, Lord EM. Radiation-induced IFN-gamma production within the tumor microenvironment influences antitumor immunity. J. Immunol. 180(5), 3132-3139 (2008).
96. Matsumura S, Wang B, Kawashima N et al. Radiation-induced CXCL16 release by breast cancer cells attracts effector T cells. J. Immunol. 181(5), 3099-3107 (2008).
97. Hallahan DE, Spriggs DR, Beckett MA, Kufe DW, Weichselbaum RR. Increased tumor necrosis factor alpha mRNA after cellular exposure to ionizing radiation. Proc. Natl Acad. Sci. USA 86(24), 10104-10107 (1989).
98. Zhang B, Bowerman NA, Salama JK et al. Induced sensitization of tumor stroma leads to eradication of established cancer by T cells. J. Exp. Med. 204(1), 49-55 (2007).
99. Reits EA, Hodge JW, Herberts CA et al. Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy. J. Exp. Med. 203(5), 1259-1271 (2006).
100. Kachikwu EL, Iwamoto KS, Liao YP et al. Radiation enhances regulatory T cell representation. Int. J. Radiat. Oncol. Biol. Phys. 81(4), 1128-1135 (2011).
101. Tsai CS, Chen FH, Wang CC et al. Macrophages from irradiated tumors express higher levels of iNOS, arginase-I and COX-2, and promote tumor growth. Int. J. Radiat. Oncol. Biol. Phys. 68(2), 499-507 (2007).
102. Abate-Daga D, Hanada K, Davis JL, Yang JC, Rosenberg SA, Morgan RA. Expression profiling of TCR-engineered T cells demonstrates overexpression of multiple inhibitory receptors in persisting lymphocytes. Blood 122(8), 1399-1410 (2013).
103. Moon EK, Wang LC, Dolfi DV 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(16), 4262-4273 (2014).
104. John LB, Devaud C, Duong CP et al. Anti-PD-1 antibody therapy potently enhances the eradication of established tumors by gene-modified T cells. Clin. Cancer Res. 19(20), 5636-5646 (2013).
105. Peng W, Liu C, Xu C et al. PD-1 blockade enhances T-cell migration to tumors by elevating IFN-gamma inducible chemokines. Cancer Res. 72(20), 5209-5218 (2012).
106. Berrien-Elliott MM, Jackson SR, Meyer JM et al. Durable adoptive immunotherapy for leukemia produced by manipulation of multiple regulatory pathways of CD8+ T-cell tolerance. Cancer Res. 73(2), 605-616 (2013).
107. Flavell RA, Sanjabi S, Wrzesinski SH, Licona-Limon P. The polarization of immune cells in the tumour environment by TGFbeta. Nat. Rev. Immunol. 10(8), 554-567 (2010).
108. Sato T, Terai M, Tamura Y, Alexeev V, Mastrangelo MJ, Selvan SR. Interleukin 10 in the tumor microenvironment: a target for anticancer immunotherapy. Immunol. Res. 51(2-3), 170-182 (2011).
109. Wallace A, Kapoor V, Sun J et al. Transforming growth factor-beta receptor blockade augments the effectiveness of adoptive T-cell therapy of established solid cancers. Clin. Cancer Res. 14(12), 3966-3974 (2008).
110. Beavis PA, Stagg J, Darcy PK, Smyth MJ. CD73: a potent suppressor of antitumor immune responses. Trends Immunol. 33(5), 231-237 (2012).
111. Ohta A, Gorelik E, Prasad SJ et al. A2A adenosine receptor protects tumors from antitumor T cells. Proc. Natl Acad. Sci. USA 103(35), 13132-13137 (2006).
112. Jin D, Fan J, Wang L et al. CD73 on tumor cells impairs antitumor T-cell responses: a novel mechanism of tumor-induced immune suppression. Cancer Res. 70(6), 2245-2255 (2010).
113. Beavis PA, Divisekera U, Paget C et al. Blockade of A2A receptors potently suppresses the metastasis of CD73+ tumors. Proc. Natl Acad. Sci. USA 110(36), 14711-14716 (2013).
114. Kaidi A, Qualtrough D, Williams AC, Paraskeva C. Direct transcriptional up-regulation of cyclooxygenase-2 by hypoxia-inducible factor (HIF)-1 promotes colorectal tumor cell survival and enhances HIF-1 transcriptional activity during hypoxia. Cancer Res. 66(13), 6683-6691 (2006).
115. Tsujii M, Kawano S, Dubois RN. Cyclooxygenase-2 expression in human colon cancer cells increases metastatic potential. Proc. Natl Acad. Sci. USA 94(7), 3336-3340 (1997).
116. Gobel C, Breitenbuecher F, Kalkavan H et al. Functional expression cloning identifies COX-2 as a suppressor of antigen-specific cancer immunity. Cell Death Dis. 5, e1568 (2014).
117. Sobolewski C, Cerella C, Dicato M, Ghibelli L, Diederich M. The role of cyclooxygenase-2 in cell proliferation and cell death in human malignancies. Int. J. Cell Biol. 2010, 215158 (2010).
118. Nishio N, Diaconu I, Liu H et al. Armed oncolytic virus enhances immune functions of chimeric antigen receptor-modified T cells in solid tumors. Cancer Res. 74(18), 5195-5205 (2014).
119. John LB, Howland LJ, Flynn JK et al. Oncolytic virus and anti-4-1BB combination therapy elicits strong antitumor immunity against established cancer. Cancer Res. 72(7), 1651-1660 (2012).
120. Engeland CE, Grossardt C, Veinalde R et al. CTLA-4 and PD-L1 checkpoint blockade enhances oncolytic measles virus therapy. Mol. Ther. 22(11), 1949-1959 (2014).
121. Moeller M, Haynes NM, Kershaw MH et al. Adoptive transfer of gene-engineered CD4+ helper T cells induces potent primary and secondary tumor rejection. Blood 106(9), 2995-3003 (2005).
122. Moeller M, Kershaw MH, Cameron R et al. Sustained antigen-specific antitumor recall response mediated by gene-modified CD4+ T helper-1 and CD8+ T cells. Cancer Res. 67(23), 11428-11437 (2007).
123. Dudley ME, Gross CA, Somerville RP et al. Randomized selection design trial evaluating CD8+-enriched versus unselected tumor-infiltrating lymphocytes for adoptive cell therapy for patients with melanoma. J. Clin. Oncol. 31(17), 2152-2159 (2013).
124. Guedan S, Chen X, Madar A et al. ICOS-based chimeric antigen receptors program bipolar TH17/TH1 cells. Blood 124(7), 1070-1080 (2014).
125. Haynes NM, Trapani JA, Teng MW et al. Rejection of syngeneic colon carcinoma by CTLs expressing single-chain antibody receptors codelivering CD28 costimulation. J. Immunol. 169(10), 5780-5786 (2002).
126. Kowolik CM, Topp MS, Gonzalez S et al. CD28 costimulation provided through a CD19-specific chimeric antigen receptor enhances in vivo persistence and antitumor efficacy of adoptively transferred T cells. Cancer Res. 66(22), 10995-11004 (2006).
127. Savoldo B, Ramos CA, Liu E et al. CD28 costimulation improves expansion and persistence of chimeric antigen receptor-modified T cells in lymphoma patients. J. Clin. Invest. 121(5), 1822-1826 (2011).
128. Milone MC, Fish JD, Carpenito C et al. Chimeric receptors containing CD137 signal transduction domains mediate enhanced survival of T cells and increased antileukemic efficacy in vivo. Mol. Ther. 17(8), 1453-1464 (2009).
129. Hombach AA, Abken H. Costimulation by chimeric antigen receptors revisited the T cell antitumor response benefits from combined CD28-OX40 signaling. Int. J. Cancer 129(12), 2935-2944 (2011).
130. Till BG, Jensen MC, Wang J et al. CD20-specific adoptive immunotherapy for lymphoma using a chimeric antigen receptor with both CD28 and 4-1BB domains: pilot clinical trial results. Blood 119(17), 3940-3950 (2012).
131. Daniel-Meshulam I, Horovitz-Fried M, Cohen CJ. Enhanced antitumor activity mediated by human 4-1BB-engineered T cells. Int. J. Cancer 133(12), 2903-2913 (2013).
132. Stephan MT, Ponomarev V, Brentjens RJ et al. T cell-encoded CD80 and 4-1BBL induce auto- and transcostimulation, resulting in potent tumor rejection. Nat. Med. 13(12), 1440-1449 (2007).
133. Ankri C, Shamalov K, Horovitz-Fried M, Mauer S, Cohen CJ. Human T cells engineered to express a programmed death 1/28 costimulatory retargeting molecule display enhanced antitumor activity. J. Immunol. 191(8), 4121-4129 (2013).
134. Shin JH, Park HB, Oh YM et al. Positive conversion of negative signaling of CTLA4 potentiates antitumor efficacy of adoptive T-cell therapy in murine tumor models. Blood 119(24), 5678-5687 (2012).
135. Chou CK, Schietinger A, Liggitt HD et al. Cell-intrinsic abrogation of TGF-beta signaling delays but does not prevent dysfunction of self/tumor-specific CD8 T cells in a murine model of autochthonous prostate cancer. J. Immunol. 189(8), 3936-3946 (2012).
136. Zurkova K, Chlanda P, Samkova Z et al. Expression of soluble TGF-beta receptor II by recombinant Vaccinia virus enhances E7 specific immunotherapy of HPV16 tumors. Neoplasma 58(3), 181-188 (2011).
137. Yang B, Liu H, Shi W et al. Blocking transforming growth factor-beta signaling pathway augments antitumor effect of adoptive NK-92 cell therapy. Int. Immunopharmacol. 17(2), 198-204 (2013).
138. Quatromoni JG, Wang Y, Vo DD et al. T cell receptor (TCR)-transgenic CD8 lymphocytes rendered insensitive to transforming growth factor beta (TGFbeta) signaling mediate superior tumor regression in an animal model of adoptive cell therapy. J. Transl. Med. 10, 127 (2012).
139. Bollard CM, Rossig C, Calonge MJ et al. Adapting a transforming growth factor beta-related tumor protection strategy to enhance antitumor immunity. Blood 99(9), 3179-3187 (2002).
140. Bendle GM, Linnemann C, Bies L, Song JY, Schumacher TN. Blockade of TGF-beta signaling greatly enhances the efficacy of TCR gene therapy of cancer. J. Immunol. 191(6), 3232-3239 (2013).
141. Terai M, Tamura Y, Alexeev V et al. Human interleukin 10 receptor 1/IgG1-Fc fusion proteins: immunoadhesins for human IL-10 with therapeutic potential. Cancer Immunol. Immunother. 58(8), 1307-1317 (2009).
142. Brunda MJ, Luistro L, Warrier RR et al. Antitumor and antimetastatic activity of interleukin 12 against murine tumors. J. Exp. Med. 178(4), 1223-1230 (1993).
143. Wang LX, Westwood JA, Moeller M et al. Tumor ablation by gene-modified T cells in the absence of autoimmunity. Cancer Res. 70(23), 9591-9598 (2010).
144. Leonard JP, Sherman ML, Fisher GL et al. Effects of single-dose interleukin-12 exposure on interleukin-12-associated toxicity and interferon-gamma production. Blood 90(7), 2541-2548 (1997).
145. Rosenberg SA, Lotze MT, Yang JC et al. Experience with the use of high-dose interleukin-2 in the treatment of 652 cancer patients. Ann. Surg. 210(4), 474-484; discussion 484-475 (1989).
146. Zhang L, Kerkar SP, Yu Z et al. Improving adoptive T cell therapy by targeting and controlling IL-12 expression to the tumor environment. Mol. Ther. 19(4), 751-759 (2011).
147. Pegram HJ, Purdon TJ, Van Leeuwen DG et al. IL-12- secreting CD19-targeted cord blood-derived T cells for the immunotherapy of B-cell acute lymphoblastic leukemia. Leukemia 29(2), 415-422 (2014).
148. Chmielewski M, Kopecky C, Hombach AA, Abken H. IL-12 release by engineered T cells expressing chimeric antigen receptors can effectively Muster an antigen-independent macrophage response on tumor cells that have shut down tumor antigen expression. Cancer Res. 71(17), 5697-5706 (2011).
149. Hoyos V, Savoldo B, Quintarelli C 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(6), 1160-1170 (2010).
150. Klebanoff CA, Finkelstein SE, Surman DR et al. IL-15 enhances the in vivo antitumor activity of tumor-reactive CD8+ T cells. Proc. Natl Acad. Sci. USA 101(7), 1969-1974 (2004).
151. Klebanoff CA, Gattinoni L, Torabi-Parizi P et al. Central memory self/tumor-reactive CD8+ T cells confer superior antitumor immunity compared with effector memory T cells. Proc. Natl Acad. Sci. USA 102(27), 9571-9576 (2005).
152. Berger C, Jensen MC, Lansdorp PM, Gough M, Elliott C, Riddell SR. Adoptive transfer of effector CD8+ T cells derived from central memory cells establishes persistent T cell memory in primates. J. Clin. Invest. 118(1), 294-305 (2008).
153. Xu Y, Zhang M, Ramos CA et al. Closely related T-memory stem cells correlate with in vivo expansion of CAR. CD19-T cells and are preserved by IL-7 and IL-15. Blood 123(24), 3750-3759 (2014).
154. Sun J, Dotti G, Huye LE et al. T cells expressing constitutively active Akt resist multiple tumor-associated inhibitory mechanisms. Mol. Ther. 18(11), 2006-2017 (2010).
155. Riese MJ, Wang LC, Moon EK et al. Enhanced effector responses in activated CD8+ T cells deficient in diacylglycerol kinases. Cancer Res. 73(12), 3566-3577 (2013).
156. Hinterleitner R, Gruber T, Pfeifhofer-Obermair C et al. Adoptive transfer of siRNA Cblb-silenced CD8+ T lymphocytes augments tumor vaccine efficacy in a B16 melanoma model. PLoS ONE 7(9), e44295 (2012).
157. Waldmann TA. The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine design. Nat. Rev. Immunol. 6(8), 595-601 (2006).
158. Strand S, Hofmann WJ, Hug H et al. Lymphocyte apoptosis induced by CD95 (APO-1/Fas) ligand-expressing tumor cells - a mechanism of immune evasion? Nat. Med. 2(12), 1361-1366 (1996).
159. Dotti G, Savoldo B, Pule M et al. Human cytotoxic T lymphocytes with reduced sensitivity to Fas-induced apoptosis. Blood 105(12), 4677-4684 (2005).
160. Kalbasi A, Shrimali RK, Chinnasamy D, Rosenberg SA. Prevention of interleukin-2 withdrawal-induced apoptosis in lymphocytes retrovirally cotransduced with genes encoding an antitumor T-cell receptor and an antiapoptotic protein. J. Immunother. 33(7), 672-683 (2010).
161. Di Stasi A, Tey SK, Dotti G et al. Inducible apoptosis as a safety switch for adoptive cell therapy. N. Engl. J. Med. 365(18), 1673-1683 (2011).
162. Davila ML, Riviere I, Wang X et al. Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci. Transl. Med. 6(224), 224ra225 (2014).
163. Leen AM, Bollard CM, Mendizabal AM et al. Multicenter study of banked third-party virus-specific T cells to treat severe viral infections after hematopoietic stem cell transplantation. Blood 121(26), 5113-5123 (2013).