Cancer immunotherapies targeting the PD-1 signaling pathway

Journal of Biomedical Science

Volumn 24, Issue 1, 2017, Pages

  Iwai, Yoshiko ^a   Hamanishi, Junzo ^b   Chamoto, Kenji ^b   Honjo, Tasuku ^b  

^a UNIVERSITY OF OCCUPATIONAL AND ENVIRONMENTAL HEALTH   (Japan)

^b KYOTO UNIVERSITY   (Japan)

Author keywords

Cancer immunotherapy; Immune checkpoint; PD 1; PD L1

Indexed keywords

ALPHA INTERFERON; ATEZOLIZUMAB; AVELUMAB; B7 ANTIGEN; BEVACIZUMAB; BMS 936559; CD28 ANTIGEN; CD86 ANTIGEN; CYTOTOXIC T LYMPHOCYTE ANTIGEN 4; DACARBAZINE; DOCETAXEL; DURVALUMAB; ENOBLITUZUMAB; EVEROLIMUS; GAMMA INTERFERON; IPILIMUMAB; LIRILUMAB; NIVOLUMAB; OLAPARIB; OSIMERTINIB; PEMBROLIZUMAB; PROGRAMMED DEATH 1 LIGAND 1; PROGRAMMED DEATH 1 LIGAND 2; PROTEIN KINASE ZAP 70; PROTEIN TYROSINE PHOSPHATASE SHP 2; SUNITINIB; TRANSCRIPTION FACTOR NFAT; UNINDEXED DRUG; URELUMAB; VARLILUMAB; ANTINEOPLASTIC AGENT; IMMUNOLOGIC FACTOR; MONOCLONAL ANTIBODY; PDCD1 PROTEIN, HUMAN; PROGRAMMED DEATH 1 RECEPTOR;

ADRENAL INSUFFICIENCY; ADVANCED CANCER; AUTOIMMUNITY; BLADDER CANCER; BRAIN DISEASE; BREAST CANCER; CANCER IMMUNOTHERAPY; CANCER SURVIVAL; CLASSICAL HODGKIN LYMPHOMA; CLINICAL EFFECTIVENESS; COLITIS; COLON DISEASE; CYTOKINE PRODUCTION; DIFFUSE LARGE B CELL LYMPHOMA; DIGESTIVE SYSTEM PERFORATION; ENDOMETRIUM CARCINOMA; ESOPHAGUS CANCER; FOLLICULAR LYMPHOMA; GUILLAIN BARRE SYNDROME; HEAD AND NECK CANCER; HEART FAILURE; HODGKIN DISEASE; HUMAN; IMMUNE RESPONSE; IMMUNOREGULATION; INTERSTITIAL LUNG DISEASE; INTERSTITIAL PNEUMONIA; KIDNEY CARCINOMA; LIVER CELL CARCINOMA; LYMPHOCYTE ACTIVATION; MELANOMA; MERKEL CELL TUMOR; MYASTHENIA GRAVIS; MYCOSIS FUNGOIDES; MYELITIS; MYOCARDITIS; NEPHRITIS; NEUROLOGIC DISEASE; NEUTROPENIA; NON SMALL CELL LUNG CANCER; NONHODGKIN LYMPHOMA; NONHUMAN; OVARY CANCER; OVERALL SURVIVAL; PERIPHERAL T CELL LYMPHOMA; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PROGRESSION FREE SURVIVAL; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN TARGETING; REVIEW; SEPSIS; SIGNAL TRANSDUCTION; SKIN MANIFESTATION; SMALL CELL LUNG CANCER; SOLID TUMOR; STOMACH CANCER; THROMBOCYTOPENIA; THYROID CANCER; TREATMENT DURATION; TUMOR IMMUNITY; UNSPECIFIED SIDE EFFECT; UTERINE CERVIX CANCER; UTERUS CANCER; IMMUNOTHERAPY; METABOLISM; NEOPLASM;

ANTIBODIES, MONOCLONAL; ANTINEOPLASTIC AGENTS; HUMANS; IMMUNOLOGIC FACTORS; IMMUNOTHERAPY; NEOPLASMS; PROGRAMMED CELL DEATH 1 RECEPTOR; SIGNAL TRANSDUCTION;

EID: 85016724516     PISSN: 10217770     EISSN: 14230127     Source Type: Journal    
DOI: 10.1186/s12929-017-0329-9     Document Type: Review

References (114)

1. Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 2011;480:480-9.
2. Steinman RM, Cohn ZA. Identification of a novel cell type in peripheral lymphoid organs of mice. I. Morphology, quantitation, tissue distribution. J Exp Med. 1973;137:1142-62.
3. Lemaitre B, Nicolas E, Michaut L, Reichhart JM, Hoffmann JA. The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell. 1996;86:973-83.
4. van der Bruggen P, et al. A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. Science. 1991;254:1643-7.
5. Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science. 2011;331:1565-70.
6. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12:252-64.
7. Lenschow DJ, Walunas TL, Bluestone JA. CD28/B7 system of T cell costimulation. Annu Rev Immunol. 1996;14:233-58.
8. Okazaki T, Chikuma S, Iwai Y, Fagarasan S, Honjo T. A rheostat for immune responses: the unique properties of PD-1 and their advantages for clinical application. Nat Immunol. 2013;14:1212-8.
9. Freeman GJ, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 2000;192:1027-34.
10. Latchman Y, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol. 2001;2:261-8.
11. Ishida Y, Agata Y, Shibahara K, Honjo T. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J. 1992;11:3887-95.
12. Agata Y, et al. Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Int Immunol. 1996;8:765-72.
13. Iwai Y, et al. Microanatomical localization of PD-1 in human tonsils. Immunol Lett. 2002;83:215-20.
14. Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T. PD-1 immunoreceptor inhibits B cell receptor-mediated signaling by recruiting src homology 2-domain-containing tyrosine phosphatase 2 to phosphotyrosine. Proc Natl Acad Sci U S A. 2001;98:13866-71.
15. Yokosuka T, et al. Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2. J Exp Med. 2012;209:1201-17.
16. Oestreich KJ, Yoon H, Ahmed R, Boss JM. NFATc1 regulates PD-1 expression upon T cell activation. J Immunol. 2008;181:4832-9.
17. Terawaki S, et al. IFN-alpha directly promotes programmed cell death-1 transcription and limits the duration of T cell-mediated immunity. J Immunol. 2011;186:2772-9.
18. Youngblood B, et al. Chronic virus infection enforces demethylation of the locus that encodes PD-1 in antigen-specific CD8(+) T cells. Immunity. 2011;35:400-12.
19. Staron MM, et al. The transcription factor FoxO1 sustains expression of the inhibitory receptor PD-1 and survival of antiviral CD8(+) T cells during chronic infection. Immunity. 2014;41:802-14.
20. Nishimura H, Nose M, Hiai H, Minato N, Honjo T. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity. 1999;11:141-51.
21. Nishimura H, et al. Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science. 2001;291:319-22.
22. Okazaki T, et al. Autoantibodies against cardiac troponin I are responsible for dilated cardiomyopathy in PD-1-deficient mice. Nat Med. 2003;9:1477-83.
23. Wang J, et al. Establishment of NOD-Pdcd1−/− mice as an efficient animal model of type I diabetes. Proc Natl Acad Sci U S A. 2005;102:11823-8.
24. Linsley PS, et al. CTLA-4 is a second receptor for the B cell activation antigen B7. J Exp Med. 1991;174:561-9.
25. Walker LS. Treg and CTLA-4: two intertwining pathways to immune tolerance. J Autoimmun. 2013;45:49-57.
26. Iwai Y, Terawaki S, Ikegawa M, Okazaki T, Honjo T. PD-1 inhibits antiviral immunity at the effector phase in the liver. J Exp Med. 2003;198:39-50.
27. Barber DL, et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature. 2006;439:682-7.
28. Shiratori T, et al. Tyrosine phosphorylation controls internalization of CTLA-4 by regulating its interaction with clathrin-associated adaptor complex AP-2. Immunity. 1997;6:583-9.
29. Stamper CC, et al. Crystal structure of the B7-1/CTLA-4 complex that inhibits human immune responses. Nature. 2001;410:608-11.
30. Schwartz JC, Zhang X, Fedorov AA, Nathenson SG, Almo SC. Structural basis for co-stimulation by the human CTLA-4/B7-2 complex. Nature. 2001;410:604-8.
31. Qureshi OS, et al. Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4. Science. 2011;332:600-3.
32. Parry RV, et al. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol. 2005;25:9543-53.
33. Waterhouse P, et al. Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science. 1995;270:985-8.
34. Hodi FS, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711-23.
35. Topalian SL, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443-54.
36. Ishida M, et al. Differential expression of PD-L1 and PD-L2, ligands for an inhibitory receptor PD-1, in the cells of lymphohematopoietic tissues. Immunol Lett. 2002;84:57-62.
37. Yamazaki T, et al. Expression of programmed death 1 ligands by murine T cells and APC. J Immunol. 2002;169:5538-45.
38. Eppihimer MJ, et al. Expression and regulation of the PD-L1 immunoinhibitory molecule on microvascular endothelial cells. Microcirculation. 2002;9:133-45.
39. Keir ME, et al. Tissue expression of PD-L1 mediates peripheral T cell tolerance. J Exp Med. 2006;203:883-95.
40. Iwai Y, et al. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci U S A. 2002;99:12293-7.
41. Thompson RH, et al. Costimulatory B7-H1 in renal cell carcinoma patients: Indicator of tumor aggressiveness and potential therapeutic target. Proc Natl Acad Sci U S A. 2004;101:17174-9.
42. Okazaki T, Honjo T. PD-1 and PD-1 ligands: from discovery to clinical application. Int Immunol. 2007;19:813-24.
43. Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science. 1996;271:1734-6.
44. Peggs KS, Quezada SA, Korman AJ, Allison JP. Principles and use of anti-CTLA4 antibody in human cancer immunotherapy. Curr Opin Immunol. 2006;18:206-13.
45. van Elsas A, Hurwitz AA, Allison JP. Combination immunotherapy of B16 melanoma using anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and granulocyte/macrophage colony-stimulating factor (GM-CSF)-producing vaccines induces rejection of subcutaneous and metastatic tumors accompanied by autoimmune depigmentation. J Exp Med. 1999;190:355-66.
46. Iwai Y, Terawaki S, Honjo T. PD-1 blockade inhibits hematogenous spread of poorly immunogenic tumor cells by enhanced recruitment of effector T cells. Int Immunol. 2005;17:133-44.
47. Nakanishi J, et al. Overexpression of B7-H1 (PD-L1) significantly associates with tumor grade and postoperative prognosis in human urothelial cancers. Cancer Immunol Immunother. 2007;56:1173-82.
48. Ohigashi Y, et al. Clinical significance of programmed death-1 ligand-1 and programmed death-1 ligand-2 expression in human esophageal cancer. Clin Cancer Res. 2005;11:2947-53.
49. Nomi T, et al. Clinical significance and therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in human pancreatic cancer. Clin Cancer Res. 2007;13:2151-7.
50. Hamanishi J, et al. Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer. Proc Natl Acad Sci U S A. 2007;104:3360-5.
51. Wu C, et al. Immunohistochemical localization of programmed death-1 ligand-1 (PD-L1) in gastric carcinoma and its clinical significance. Acta Histochem. 2006;108:19-24.
52. Ghebeh H, et al. The B7-H1 (PD-L1) T lymphocyte-inhibitory molecule is expressed in breast cancer patients with infiltrating ductal carcinoma: correlation with important high-risk prognostic factors. Neoplasia. 2006;8:190-8.
53. Gao Q, et al. Overexpression of PD-L1 significantly associates with tumor aggressiveness and postoperative recurrence in human hepatocellular carcinoma. Clin Cancer Res. 2009;15:971-9.
54. Brahmer JR, et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol. 2010;28:3167-75.
55. Brahmer JR, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366:2455-65.
56. Gubin MM, et al. Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature. 2014;515:577-81.
57. Brahmer J, et al. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med. 2015;373:123-35.
58. Callahan MK, Postow MA, Wolchok JD. Targeting T Cell Co-receptors for Cancer Therapy. Immunity. 2016;44:1069-78.
59. Hamanishi J, et al. Efficacy and safety of anti-PD-1 antibody (Nivolumab: BMS-936558, ONO-4538) in patients with platinum-resistant ovarian cancer. 2014 ASCO Annual Meeting. J Clin Oncol. 2014;32:5s (suppl; abstr 5511).
60. Hamanishi J, et al. Safety and Antitumor Activity of Anti-PD-1 Antibody, Nivolumab, in Patients With Platinum-Resistant Ovarian Cancer. J Clin Oncol. 2015;33:4015-22.
61. Hamanishi J, et al. Durable tumor remission in patients with platinum-resistant ovarian cancer receiving nivolumab. 2015 ASCO Annual Meeting. J Clin Oncol. 2015;33(suppl; abstr 5570).
62. Hamanishi J, Mandai M, Konishi I. Immune checkpoint inhibition in ovarian cancer. Int Immunol. 2016;28:339-48.
63. Varga A, et al. Antitumor activity and safety of pembrolizumab in patients (pts) with PD-L1 positive advanced ovarian cancer: Interim results from a phase Ib study. 2015 ASCO Annual Meeting. J Clin Oncol. 2015;33(suppl; abstr 5510).
64. Disis ML, et al. Avelumab (MSB0010718C; anti-PD-L1) in patients with recurrent/refractory ovarian cancer from the JAVELIN Solid Tumor phase Ib trial: Safety and clinical activity. 2015 ASCO Annual Meeting. J Clin Oncol. 2015;34(suppl; abstr 5533).
65. Wolchok JD, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369:122-33.
66. Postow MA, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015;372:2006-17.
67. Hammers HJ, et al. Phase I study of nivolumab in combination with ipilimumab in metastatic renal cell carcinoma (mRCC). 2014 ASCO Annual Meeting. J Clin Oncol.2014;32(suppl; abstr 4504).
68. Patnaik A, et al. Phase 1 study of pembrolizumab (pembro; MK-3475) plus ipilimumab (IPI) as second-line therapy for advanced non-small cell lung cancer (NSCLC): KEYNOTE-021 cohort D. 2015 ASCO Annual Meeting. J Clin Oncol. 2015;33(suppl; abstr 8011).
69. Naidoo J, et al. Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. Ann Oncol. 2015;26:2375-91.
70. Ahn MJ, et al. 136O: Osimertinib combined with durvalumab in EGFR-mutant non-small cell lung cancer: Results from the TATTON phase Ib trial. J Thorac Oncol. 2016;11:S115.
71. Snyder A, et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med. 2014;371:2189-99.
72. Rizvi NA, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348:124-8.
73. Le DT, et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med. 2015;372:2509-20.
74. Tumeh PC, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 2014;515:568-71.
75. Hamanishi J, et al. PD-1/PD-L1 blockade in cancer treatment: perspectives and issues. Int J Clin Oncol. 2016;21:462-73.
76. Dudley JC, Lin MT, Le DT, Eshleman JR. Microsatellite Instability as a Biomarker for PD-1 Blockade. Clin Cancer Res. 2016;22:813-20.
77. Ma W, Gilligan BM, Yuan J, Li T. Current status and perspectives in translational biomarker research for PD-1/PD-L1 immune checkpoint blockade therapy. J Hematol Oncol. 2016;9:47.
78. Festino L, et al. Cancer Treatment with Anti-PD-1/PD-L1 Agents: Is PD-L1 Expression a Biomarker for Patient Selection? Drugs. 2016;76:925-45.
79. Muro K, et al. Pembrolizumab for patients with PD-L1-positive advanced gastric cancer (KEYNOTE-012): a multicentre, open-label, phase 1b trial. Lancet Oncol. 2016;17:717-26.
80. Ribas A, et al. Association of response to programmed death receptor 1 (PD-1) blockade with pembrolizumab (MK-3475) with an interferon-inflammatory immune gene signature. 2015 ASCO Annual Meeting. J Clin Oncol. 2015;33(suppl; abstr 3001).
81. Mandai M, et al. Anti-PD-L1/PD-1 immune therapies in ovarian cancer: basic mechanism and future clinical application. Int J Clin Oncol. 2016;21:456-61.
82. Sunshine J, Taube JM. Pd-1/Pd-L1 Inhibitors. Curr Opin Pharmacol. 2015;23:32-8.
83. Hugo W, et al. Genomic and Transcriptomic Features of Response to Anti-PD-1 Therapy in Metastatic Melanoma. Cell. 2016;165:35-44.
84. Postow MA. Managing immune checkpoint-blocking antibody side effects. Am Soc Clin Oncol Educ Book. 2015;76-83. doi:10.14694/EdBook_AM.2015.35.76.
85. Weber JS, Yang JC, Atkins MB, Disis ML. Toxicities of Immunotherapy for the Practitioner. J Clin Oncol. 2015;33:2092-9.
86. Naidoo J, et al. Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. Ann Oncol. 2016;27:1362.
87. Champiat S, et al. Management of immune checkpoint blockade dysimmune toxicities: a collaborative position paper. Ann Oncol. 2016;27:559-74.
88. Ribas A et al. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 2015;16:908-18.
89. Robert C et al. Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med. 2015;372:2521-32.
90. Weber JS et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2015;16:375-84.
91. Garon EB et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015;372:2018-28.
92. Borghaei H et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med. 2015;373:1627-39.
93. Spira AI et al. Efficacy, safety and predictive biomarker results from a randomized phase II study comparing MPDL3280A vs docetaxel in 2L/3L NSCLC (POPLAR). J Clin Oncol. 2015;33.
94. Ott PA et al. A phase I study to evaluate the safety and tolerability of MEDI4736, an anti- programmed cell death-ligand-1 (PD-L1) antibody, in combination with tremelimumab in patients with advanced solid tumors. J Clin Oncol. 2015;33.
95. Antonia SJ et al. Phase I/II study of nivolumab with or without ipilimumab for treatment of recurrent small cell lung cancer (SCLC): CA209-032. J Clin Oncol. 2015;33.
96. Segal NH et al. Safety and efficacy of MEDI4736, an anti-PD-L1 antibody, in patients from a squamous cell carcinoma of the head and neck (SCCHN) expansion cohort. J Clin Oncol. 2015;33.
97. Seiwert TY et al. Antitumor activity and safety of pembrolizumab in patients (pts) with advanced squamous cell carcinoma of the head and neck (SCCHN): Preliminary results from KEYNOTE-012 expansion cohort. J Clin Oncol. 2015;33.
98. Motzer RJ et al. Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med. 2015;373:1803-13.
99. Rosenberg JE et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet. 2016;387:1909-20.
100. Plimack ER et al. Pembrolizumab (MK-3475) for advanced urothelial cancer: Updated results and biomarker analysis from KEYNOTE-012. J Clin Oncol. 2015;33.
101. Disis ML et al. Avelumab (MSB0010718C; anti-PD-L1) in patients with recurrent/refractory ovarian cancer from the JAVELIN Solid Tumor phase Ib trial: Safety and clinical activity. 2016 ASCO Annual Meeting. J Clin Oncol. 2016;34 (suppl; abstr 5533).
102. Ott PA et al. Pembrolizumab in advanced endometrial cancer: Preliminary results from the phase Ib KEYNOTE-028 study. 2016 ASCO Annual Meeting. J Clin Oncol. 2016;34 (suppl; abstr 5581).
103. Frenel et al. Pembrolizumab in patients with advanced cervical squamous cell cancer: Preliminary results from the phase Ib KEYNOTE-028 study. 2016 ASCO Annual Meeting. J Clin Oncol. 2016;34 (suppl; abstr 5515).
104. George et al. Phase 2 study of nivolumab in metastatic leiomyosarcoma of the uterus. 2016 ASCO Annual Meeting. J Clin Oncol. 2016;34 (suppl; abstr 11007).
105. Doi T et al. Updated results for the advanced esophageal carcinoma cohort of the phase Ib KEYNOTE-028 study of pembrolizumab (MK-3475). J Clin Oncol. 2016;34.
106. Fader AN. et al. Preliminary results of a phase II study: PD-1 blockade in mismatch repair-deficient, recurrent or persistent endometrial cancer. The 47th Annual Meeting of the Society of Gynecologic Oncology Late-breaking 2014 (Abstract 3).
107. Sangro B. et al. Safety and antitumor activity of nivolumab (nivo) in patients (pts) with advanced hepatocellular carcinoma (HCC): Interim analysis of dose-expansion cohorts from the phase 1/2 CheckMate-040 study. 2016 ASCO Annual Meeting. J Clin Oncol 34, 2016 (suppl; abstr4078).
108. Emens LA. et al. Inhibition of PD-L1 by MPDL3280A leads to clinical activity in patients with metastatic triple-negative breast cancer. Thirty-Seventh Annual Meeting of CTRC-AACR San Antonio Breast Cancer Symposium, 2015;Abstract P D1-6.
109. Nanda R et al. Pembrolizumab in Patients With Advanced Triple-Negative Breast Cancer: Phase Ib KEYNOTE-012 Study. J Clin Oncol. 2016;34:2460-7.
110. Nghiem PT et al. PD-1 Blockade with Pembrolizumab in Advanced Merkel-Cell Carcinoma. N Engl J Med. 2016;374:2542-52.
111. Mehnert JM et al. Pembrolizumab for advanced papillary or follicular thyroid cancer: preliminary results from the phase 1b KEYNOTE-028 study. 2016 ASCO Annual Meeting. J Clin Oncol. 2016;34 (suppl; abstr6091).
112. Ansell SM et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. N Engl J Med. 2015;372:311-9.
113. Armand P et al. Programmed Death-1 Blockade With Pembrolizumab in Patients With Classical Hodgkin Lymphoma After Brentuximab Vedotin Failure. J Clin Oncol. 2016.
114. Lesokhin AM et al. Nivolumab in Patients With Relapsed or Refractory Hematologic Malignancy: Preliminary Results of a Phase Ib Study. J Clin Oncol. 2016;34:2698-704.