Preclinical development of ipilimumab and nivolumab combination immunotherapy: Mouse tumor models, In vitro functional studies, and cynomolgus macaque toxicology

PLoS ONE

Volumn 11, Issue 9, 2016, Pages

  Selby, Mark J ^a   Engelhardt, John J ^a   Johnston, Robert J ^a   Lu, Li Sheng ^a   Han, Minhua ^a   Thudium, Kent ^a   Yao, Dapeng ^a   Quigley, Michael ^a   Valle, Jose ^a   Wang, Changyu ^a   Chen, Bing ^a   Cardarelli, Pina M ^a   Blanset, Diann ^a   Korman, Alan J ^a  

^a Bristol Myers Squibb   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CYTOTOXIC T LYMPHOCYTE ANTIGEN 4; GAMMA INTERFERON; GAMMA INTERFERON INDUCIBLE PROTEIN 10; GRANULOCYTE MACROPHAGE COLONY STIMULATING FACTOR; INTERLEUKIN 10; INTERLEUKIN 13; INTERLEUKIN 17; INTERLEUKIN 1ALPHA; INTERLEUKIN 2; INTERLEUKIN 21; INTERLEUKIN 22; INTERLEUKIN 27; INTERLEUKIN 4; INTERLEUKIN 5; INTERLEUKIN 6; IPILIMUMAB; NIVOLUMAB; PROGRAMMED DEATH 1 RECEPTOR; TUMOR NECROSIS FACTOR; ANTINEOPLASTIC AGENT; MONOCLONAL ANTIBODY;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTINEOPLASTIC ACTIVITY; ARTICLE; CANCER COMBINATION CHEMOTHERAPY; CANCER IMMUNOTHERAPY; CD3+ T LYMPHOCYTE; COLORECTAL CANCER; COLORECTAL CANCER CELL LINE; CONTROLLED STUDY; CT26 CELL LINE; CYTOKINE RELEASE; DIGESTIVE SYSTEM INFLAMMATION; DOSE RESPONSE; DRUG DOSE REDUCTION; DRUG POTENTIATION; DRUG SAFETY; EFFECTOR CELL; FLOW CYTOMETRY; HUMAN; HUMAN CELL; IMMUNOASSAY; IMMUNOHISTOCHEMISTRY; IMMUNOSTIMULATION; IN VITRO STUDY; IN VIVO STUDY; LYMPHOCYTIC INFILTRATION; MACACA FASCICULARIS; MC38 CELL LINE; MIXED LYMPHOCYTE RESPONSE ASSAY; MONOTHERAPY; MOUSE; MOUSE MODEL; NONHUMAN; PERIPHERAL BLOOD MONONUCLEAR CELL; PRECLINICAL STUDY; REGULATORY T LYMPHOCYTE; T LYMPHOCYTE ACTIVATION; TUMOR MODEL; TUMOR VOLUME; ANIMAL; ANTAGONISTS AND INHIBITORS; C57BL MOUSE; CELL CULTURE; COLORECTAL NEOPLASMS; DISEASE MODEL; FEMALE; IMMUNOLOGY; IMMUNOTHERAPY; LYMPHOCYTE; MELANOMA; METABOLISM; MULTIMODALITY CANCER THERAPY; TUMOR CELL LINE;

ANIMALS; ANTIBODIES, MONOCLONAL; ANTINEOPLASTIC COMBINED CHEMOTHERAPY PROTOCOLS; CELL LINE, TUMOR; CELLS, CULTURED; COLORECTAL NEOPLASMS; COMBINED MODALITY THERAPY; CTLA-4 ANTIGEN; DISEASE MODELS, ANIMAL; FEMALE; HUMANS; IMMUNOTHERAPY; LYMPHOCYTES; MACACA FASCICULARIS; MELANOMA; MICE; MICE, INBRED C57BL; PROGRAMMED CELL DEATH 1 RECEPTOR; T-LYMPHOCYTES, REGULATORY;

EID: 84991246476     PISSN: None     EISSN: 19326203     Source Type: Journal    
DOI: 10.1371/journal.pone.0161779     Document Type: Article

References (57)

1. Chen L, Flies DB. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat Rev Immunol. 2013; 13:227-42. doi: 10.1038/nri3405 PMID: 23470321
2. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012; 12:252-64. doi: 10.1038/nrc3239 PMID: 22437870
3. Wolchok JD, Hodi FS, Weber JS, Allison JP, Urba WJ, Robert C, et al. Development of ipilimumab: a novel immunotherapeutic approach for the treatment of advanced melanoma. Ann N Y Acad Sci. 2013; 1291:1-13. doi: 10.1111/nyas.12180 PMID: 23772560
4. Brahmer JR, Hammers H, Lipson EJ. Nivolumab: targeting PD-1 to bolster antitumor immunity. Future Oncol. 2015; 11:1307-26. doi: 10.2217/fon.15.52 PMID: 25798726
5. Melero I, Berman DM, Aznar MA, Korman AJ, Gracia JL, Haanen J. Evolving synergistic combinations of targeted immunotherapies to combat cancer. Nat Rev Cancer. 2015; 15:457-72. doi: 10.1038/ nrc3973 PMID: 26205340
6. Wang CJ, Kenefeck R, Wardzinski L, Attridge K, Manzotti C, Schmidt EM, et al. Cutting edge: cellextrinsic immune regulation by CTLA-4 expressed on conventional T cells. J Immunol. 2012; 189:1118-22. doi: 10.4049/jimmunol.1200972 PMID: 22753931
7. Corse E, Allison JP. Cutting edge: CTLA-4 on effector T cells inhibits in trans. J Immunol. 2012; 189:1123-7. doi: 10.4049/jimmunol.1200695 PMID: 22753941
8. Qureshi OS, Zheng Y, Nakamura K, Attridge K, Manzotti C, Schmidt EM, et al. Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4. Science. 2011; 332:600-3. doi: 10.1126/science.1202947 PMID: 21474713
9. Peggs KS, Quezada SA, Allison JP. Cell intrinsic mechanisms of T-cell inhibition and application to cancer therapy. Immunol Rev. 2008; 224:141-65. doi: 10.1111/j.1600-065X.2008.00649.x PMID: 18759925
10. Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T, Miyara M, Fehervari Z, et al. CTLA-4 control over Foxp3+ regulatory T cell function. Science. 2008; 322:271-5. doi: 10.1126/science.1160062 PMID: 18845758
11. Walker LS, Sansom DM. Confusing signals: recent progress in CTLA-4 biology. Trends Immunol. 2015; 36:63-70. doi: 10.1016/j.it.2014.12.001 PMID: 25582039
12. Grosso JF, Jure-Kunkel MN. CTLA-4 blockade in tumor models: an overview of preclinical and translational research. Cancer Immun. 2013; 13:5. PMID: 23390376
13. Selby MJ, Engelhardt JJ, Quigley M, Henning KA, Chen T, Srinivasan M, et al. Anti-CTLA-4 antibodies of IgG2a isotype enhance antitumor activity through reduction of intratumoral regulatoryT cells. Cancer Immunol Res. 2013; 1:32-42. doi: 10.1158/2326-6066.CIR-13-0013 PMID: 24777248
14. Simpson TR, Li F, Montalvo-Ortiz W, Sepulveda MA, Bergerhoff K, Arce F, 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. 2013; 210:1695-710. doi: 10.1084/jem.20130579 PMID: 23897981
15. Bulliard Y, Jolicoeur R, Windman M, Rue SM, Ettenberg S, Knee DA, et al. Activating Fc ã receptors contribute to the antitumor activities of immunoregulatory receptor-targeting antibodies. J Exp Med. 2013; 210:1685-93. doi: 10.1084/jem.20130573 PMID: 23897982
16. Chemnitz JM, Parry RV, Nichols KE, June CH, Riley JL. SHP-1 and SHP-2 associate with immunoreceptor tyrosine-based switch motif of programmed death 1 upon primaryhuman T cell stimulation, but only receptor ligation prevents T cell activation. J Immunol. 2004; 173:945-54. PMID: 15240681
17. Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002; 8:793-800. PMID: 12091876
18. Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. Immunol Rev. 2010; 236:219-42. doi: 10.1111/j.1600-065X.2010.00923.x PMID: 20636820
19. Day CL, Kaufmann DE, Kiepiela P, Brown JA, Moodley ES, Reddy S, et al. PD-1 expression on HIVspecific T cells is associated with T-cell exhaustion and disease progression. Nature. 2006; 443:350-4. PMID: 16921384
20. Wherry EJ, Kurachi M. Molecular and cellular insights into T cell exhaustion. Nat Rev Immunol. 2015; 15:486-99. doi: 10.1038/nri3862 PMID: 26205583
21. Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015; 373:23-34. doi: 10.1056/ NEJMoa1504030 PMID: 26027431
22. Li B, VanRoey M, Wang C, Chen TH, Korman A, Jooss K. Anti-programmed death-1 synergizes with granulocyte macrophage colony-stimulating factor-secreting tumor cell immunotherapy providing therapeutic benefit to mice with established tumors. Clin Cancer Res. 2009; 15:1623-34. doi: 10.1158/ 1078-0432.CCR-08-1825 PMID: 19208793
23. Nimmerjahn F, Ravetch JV. Fcgamma receptors as regulators of immune responses. Nat Rev Immunol. 2008; 8:34-47. PMID: 18064051
24. 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 U S A. 2010; 107:4275-80. doi: 10.1073/pnas.0915174107 PMID: 20160101
25. Duraiswamy J, Kaluza KM, Freeman GJ, Coukos G. Dual blockade of PD-1 and CTLA-4 combined with tumor vaccine effectively restores T-cell rejection function in tumors. Cancer Res. 2013; 73:3591-603. doi: 10.1158/0008-5472.CAN-12-4100 PMID: 23633484
26. Sivan A, Corrales L, Hubert N, Williams JB, Aquino-Michaels K, Earley ZM, et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science. 2015; 350:1084-9. doi: 10.1126/science.aac4255 PMID: 26541606
27. Vétizou M, Pitt JM, Daillère R, Lepage P, Waldschmitt N, Flament C, et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science. 2015; 350:1079-84. doi: 10.1126/science. aad1329 PMID: 26541610
28. Gubin MM, Zhang X, Schuster H, Caron E, Ward JP, Noguchi T, et al. Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature. 2014; 515:577-81. doi: 10.1038/ nature13988 PMID: 25428507
29. Llosa NJ, Cruise M, Tam A, Wicks EC, Hechenbleikner EM, Taube JM, et al. The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints. Cancer Discov. 2015: 5:43-51. doi: 10.1158/2159-8290.CD-14-0863 PMID: 25358689
30. Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med. 2015 Jun 25; 372(26):2509-20. doi: 10.1056/ NEJMoa1500596 PMID: 26028255
31. Ueha S, Yokochi S, Ishiwata Y, Ogiwara H, Chand K, Nakajima T, et al. Robust antitumor effects of combined anti-CD4-depleting antibody and anti-PD-1/PD-L1 immune checkpoint antibody treatment in mice. Cancer Immunol Res. 2015; 3:631-40. doi: 10.1158/2326-6066.CIR-14-0190 PMID: 25711759
32. Spranger S, Spaapen RM, Zha Y, Williams J, Meng Y, Ha T, et al. Up-regulation of PD-L1, IDO, and T (regs) in the melanoma tumor microenvironment Is driven by CD8+ (T) Cells. Sci Transl Med. 2013; 5 (200):ra116.
33. Zou W, Chen L. Inhibitory B7-family molecules in the tumour microenvironment. Nat Rev Immunol. 2008; 8:467-77. doi: 10.1038/nri2326 PMID: 18500231
34. Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, Robert L, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 2014; 515:568-71. doi: 10.1038/ nature13954 PMID: 25428505
35. Quezada SA, Peggs KS, Curran MA, Allison JP. CTLA4 blockade and GM-CSF combination immunotherapy alters the intratumor balance of effector and regulatory T cells. J Clin Invest. 2006; 116:1935-45. PMID: 16778987
36. Keler T, Halk E, Vitale L, O'Neill T, Blanset D, Lee S, et al. Activity and safety of CTLA-4 blockade combined with vaccines in cynomolgus macaques. J Immunol. 2003; 171:6251-9. PMID: 14634142
37. Wang C, Thudium KB, Han M, Wang XT, Huang H, Feingersh D, et al. In vitro characterization of the anti-PD-1 antibody nivolumab, BMS-936558, and in vivo toxicology in non-human primates. Cancer Immunol Res. 2014; 2:846-56. doi: 10.1158/2326-6066.CIR-14-0040 PMID: 24872026
38. Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013; 369:122-33. doi: 10.1056/NEJMoa1302369 PMID: 23724867
39. Postow MA, Chesney J, Pavlick AC, Robert C, Grossmann K, McDermottD, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015; 372:2006-17. doi: 10.1056/ NEJMoa1414428 PMID: 25891304
40. Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I, Kobayashi SV, et al. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol. 2005; 25:9543-53. PMID: 16227604
41. Patsoukis N, Brown J, Petkova V, Liu F, Li L, Boussiotis VA. Selective effects of PD-1 on Akt and Ras pathways regulate molecular components of the cell cycle and inhibit T cell proliferation. Sci Signal. 2012; 5(230)ra46. doi: 10.1126/scisignal.2002796 PMID: 22740686
42. Gubin MM, Zhang X, Schuster H, Caron E, Ward JP, Noguchi T, et al. Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature. 2014; 515:577-81. doi: 10.1038/ nature13988 PMID: 25428507
43. Nakamoto N, Cho H, Shaked A, Olthoff K, Valiga ME, Kaminski M, et al. Synergistic reversal of intrahepatic HCV-specific CD8 T cell exhaustion by combined PD-1/CTLA-4 blockade. PLoS Pathog. 2009; 5 (2):e1000313. doi: 10.1371/journal.ppat.1000313 PMID: 19247441
44. Ahmadzadeh M, Johnson LA, Heemskerk B, Wunderlich JR, Dudley ME, White DE, et al. Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood. 2009; 114:1537-44. doi: 10.1182/blood-2008-12-195792 PMID: 19423728
45. Antonia SJ, López-Martin JA, Bendell J, Ott PA, Taylor M, Eder JP, et al. Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032) 032): a multicentre,openlabel, phase 1/2 trial Lancet Oncol. 2016 Jun 3. pii: S1470-2045(16)30098-5. [Epub ahead of print].
46. Hellman MD, Gettinger SN, Goldman JW, Brahmer JR, Borghaei H, Chow LQ, et al. CheckMate 012: Safety and efficacy of first-line (1L) nivolumab (nivo; N) and ipilimumab (ipi; I) in advanced (adv). J Clin Oncol. 34, 2016 (suppl: ; abstr 3001).
47. Wolchok JD, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey L, et al. Updated results from a phase III trial of nivolumab (NIVO) combined with ipilimumab (IPI) in treatment-naive patients (pts) with advanced melanoma (MEL) (CheckMate 067). J Clin Oncol. 34, 2016 (suppl: ; abstr 9505).
48. Overman MJ, Kopetz S, McDermott RS, Leach J, Lonardi S, Lenz HJ, et al, Nivolumab ± ipilimumab in treatment (tx) of patients (pts) with metastatic colorectal cancer (mCRC) with and without high microsatellite instability (MSI-H): CheckMate-142 interim results. J Clin Oncol. 34, 2016 (suppl: ; abstr 3501).
49. Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pagès C, et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 2006; 313:1960-4. PMID: 17008531
50. Taube JM, Anders RA, Young GD, Xu H, Sharma R, McMiller TL, et al. Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci Transl Med. 2012; 4 (127):127ra37. doi: 10.1126/scitranslmed.3003689 PMID: 22461641
51. Herbst RS, Soria JC, Kowanetz M, Fine GD, Hamid O, Gordon MS, et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature. 2014; 515:563-7. doi: 10. 1038/nature14011 PMID: 25428504
52. Dahan R, Sega E, Engelhardt J, Selby M, Korman AJ, Ravetch JV. FcãRs modulate the anti-tumor activity of antibodies targeting the PD-1/PD-L1 axis. Cancer Cell. 2015; 28:285-95. doi: 10.1016/j.ccell. 2015.08.004 PMID: 26373277
53. Ngiow SF, Young A, Jacquelot N, Yamazaki T, Enot D, Zitvogel L, et al. A Threshold Level of Intratumor CD8+ T-cell PD1 Expression Dictates Therapeutic Response to Anti-PD1. Cancer Res. 2015; 75:3800-11. doi: 10.1158/0008-5472.CAN-15-1082 PMID: 26208901
54. Peng W, Liu C, Xu C, Lou Y, Chen J, Yang Y, et al. PD-1 blockade enhances T-cell migration to tumors by elevating IFN-ã inducible chemokines. Cancer Res. 2012; 72:5209-18. doi: 10.1158/0008-5472. CAN-12-1187 PMID: 22915761
55. Lebel-Binay S, Laguerre B, Quintin-Colonna F, Conjeaud H, Magazin M, Miloux B, et al. Experimental gene therapy of cancer using tumor cells engineered to secrete interleukin-13. Eur J Immunol. 1995; 25:2340-8. PMID: 7664796
56. Saraiva M O'Garra A. The regulation of IL-10 production by immune cells. Nature Rev Immunol. 2010; 10:170-81.
57. Mumm JB, Emmerich J, Zhang X, Chan I, Wu L, Mauze S, et al. IL-10 elicits IFNã-dependent tumor immune surveillance. Cancer Cell. 2011; 20:781-96. doi: 10.1016/j.ccr.2011.11.003 PMID: 22172723