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Induction of T-cell immunity overcomes complete resistance to PD-1 and CTLA-4
blockade and improves survival in pancreatic carcinoma
Rafael Winograd1, Katelyn T. Byrne1,6, Rebecca A. Evans1,6, Pamela M. Odorizzi3,
Anders R. L. Meyer5, David L. Bajor1,2,4, Cynthia Clendenin1, Ben Z. Stanger1,2,4,
Emma E. Furth5, E. John Wherry3, and Robert H. Vonderheide1,2,4,*
1Abramson Family Cancer Research Institute 2Abramson Cancer Center 3Department of Microbiology 4Department of Medicine 5Department of Pathology and Laboratory Medicine Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA USA 19104 6equal contribution *Correspondence: Robert H. Vonderheide, MD, DPhil
Abramson Family Cancer Research Institute Perelman School of Medicine, University of Pennsylvania 8-121 TRC, Building 421 3400 Civic Center Blvd Philadelphia, PA 19104 Phone: 215-573-4265 Fax : 215-573-2652 Email: [email protected]
Running title: Inducing T-cell immunity overcomes resistance to checkpoint blockade
in pancreatic cancer Keywords: Pancreatic cancer, PD-1, CTLA-4, immunotherapy, CD40 Funding: NIH grants: R01 CA169123 (R.H.V. and B.Z.S.), T32 CA009140 (R.W.),
T32 HL007439 (K.T.B.), T32 HL007775 (D.L.B), P30 CA016520 (R.H.V.), U19 AI 082630, P01 AI112521 (E.J.W.) Stand Up To Cancer (R.H.V.) Pancreatic Action Cancer Network-AACR (R.H.V.) Translational Center of Excellence in Pancreatic Cancer of the Abramson Cancer Center (R.H.V., C.C., E.E.F.)
5999 words, 5 figures, 8 supplementary figures The authors declare no conflict of interest.
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on February 12, 2015; DOI: 10.1158/2326-6066.CIR-14-0215
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on February 12, 2015; DOI: 10.1158/2326-6066.CIR-14-0215
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on February 12, 2015; DOI: 10.1158/2326-6066.CIR-14-0215
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on February 12, 2015; DOI: 10.1158/2326-6066.CIR-14-0215
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on February 12, 2015; DOI: 10.1158/2326-6066.CIR-14-0215
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on February 12, 2015; DOI: 10.1158/2326-6066.CIR-14-0215
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on February 12, 2015; DOI: 10.1158/2326-6066.CIR-14-0215
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on February 12, 2015; DOI: 10.1158/2326-6066.CIR-14-0215
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on February 12, 2015; DOI: 10.1158/2326-6066.CIR-14-0215
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on February 12, 2015; DOI: 10.1158/2326-6066.CIR-14-0215
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on February 12, 2015; DOI: 10.1158/2326-6066.CIR-14-0215
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on February 12, 2015; DOI: 10.1158/2326-6066.CIR-14-0215
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on February 12, 2015; DOI: 10.1158/2326-6066.CIR-14-0215
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on February 12, 2015; DOI: 10.1158/2326-6066.CIR-14-0215
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on February 12, 2015; DOI: 10.1158/2326-6066.CIR-14-0215
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on February 12, 2015; DOI: 10.1158/2326-6066.CIR-14-0215
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on February 12, 2015; DOI: 10.1158/2326-6066.CIR-14-0215
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on February 12, 2015; DOI: 10.1158/2326-6066.CIR-14-0215
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on February 12, 2015; DOI: 10.1158/2326-6066.CIR-14-0215
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on February 12, 2015; DOI: 10.1158/2326-6066.CIR-14-0215
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on February 12, 2015; DOI: 10.1158/2326-6066.CIR-14-0215
1. Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 2014;74:2913-21. 2. Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, et al FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364:1817-25. 3. Hoff von DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, et al Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369:1691-703. 4. Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science. 2011;331:1565-70. 5. Odorizzi PM, Wherry EJ. Inhibitory receptors on lymphocytes: insights from infections. J Immunol. 2012;188:2957-65. 6. Sznol M, Chen L. Antagonist antibodies to PD-1 and B7-H1 (PD-L1) in the treatment of advanced human cancer. Clin Cancer Res. 2013;19:1021-4. 7. Page DB, Postow MA, Callahan MK, Allison JP, Wolchok JD. Immune Modulation in Cancer with Antibodies. Annu Rev Med. 2014;65:185-202. 8. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer. 2012;12:252-64. 9. Powles T, Eder JP, Fine GD, Braiteh FS, Loriot Y, Cruz C, et al MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature. 2014;515:558-62. 10. Herbst RS, Soria J, 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. 11. Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711-23. 12. Brahmer JR, Tykodi SS, Chow LQM, Hwu W, Topalian SL, Hwu P, et al Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366:2455-65. 13. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443-54. 14. Hamid O, Robert C, Daud A, Hodi FS, Hwu W, Kefford R, et al Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med. 2013;369:134-44. 15. Blackburn SD, Shin H, Haining WN, Zou T, Workman CJ, Polley A, et al Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat Immunol. 2009;10:29-37. 16. Crawford A, Angelosanto J, Kao C, Doering T, Odorizzi P, Barnett B, et al Molecular and transcriptional basis of CD4+ T cell dysfunction during chronic infection. Immunity. 2014;40:289-302. 17. Nishimura H, Okazaki T, Tanaka Y, Nakatani K, Hara M, Matsumori A, et al Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science. 2001;291:319-22. 18. Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008;26:677-704. 19. Curiel TJ, Wei S, Dong H, Alvarez X, Cheng P, Mottram P, et al Blockade of B7-H1 improves myeloid dendritic cell-mediated antitumor immunity. Nat Med. 2003;9:562-7.
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on February 12, 2015; DOI: 10.1158/2326-6066.CIR-14-0215
20. 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. 21. 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. 22. Tivol EA, Borriello F, Schweitzer AN, Lynch WP, Bluestone JA, Sharpe AH. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity. 1995;3:541-7. 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. 2009;206:1717-25. 24. 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. 25. Selby MJ, Engelhardt JJ, Quigley M, Henning KA, Chen T, Srinivasan M, Korman AJ. Anti-CTLA-4 antibodies of IgG2a isotype enhance antitumor activity through reduction of intratumoral regulatory T cells. Cancer Immunol Res. 2013;1:32-42. 26. Kvistborg P, Philips D, Kelderman S, Hageman L, Ottensmeier C, Joseph-Pietras D, et al Anti-CTLA-4 therapy broadens the melanoma-reactive CD8+ T cell response. Sci Transl Med. 2014;6:254ra128. 27. Zamarin D, Holmgaard RB, Subudhi SK, Park JS, Mansour M, Palese P, et al Localized oncolytic virotherapy overcomes systemic tumor resistance to immune checkpoint blockade immunotherapy. Sci Transl Med. 2014;6:226ra32. 28. Gajewski TF, Louahed J, Brichard VG. Gene signature in melanoma associated with clinical activity: a potential clue to unlock cancer immunotherapy. Cancer J. 2010;16:399-403. 29. Ji R, Chasalow SD, Wang L, Hamid O, Schmidt H, Cogswell J, et al An immune-active tumor microenvironment favors clinical response to ipilimumab. Cancer Immunol Immunother. 2011;61:1019-31. 30. Royal RE, Levy C, Turner K, Mathur A, Hughes M, Kammula US, et al Phase 2 trial of single agent Ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J Immunother. 2010;33:828-33. 31. Le DT, Lutz E, Uram JN, Sugar EA, Onners B, Solt S, et al Evaluation of ipilimumab in combination with allogeneic pancreatic tumor cells transfected with a GM-CSF gene in previously treated pancreatic cancer. J Immunother. 2013;36:382-9. 32. 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. 33. 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;4:127ra37. 34. Taube JM, Klein A, Brahmer JR, Xu H, Pan X, Kim JH, 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 Can Res. 2014;20:5064-74. 35. Lyford-Pike S, Peng S, Young GD, Taube JM, Westra WH, Akpeng B, et al Evidence for a role of the PD-1:PD-L1 pathway in immune resistance of HPV-associated head and neck squamous cell carcinoma. Cancer Res. 2013;73:1733-41. 36. Spranger S, Spaapen RM, Zha Y, Williams J, Meng Y, Ha TT, 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;5:200ra116.
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on February 12, 2015; DOI: 10.1158/2326-6066.CIR-14-0215
37. Bald T, Landsberg J, Lopez-Ramos D, Renn M, Glodde N, Jansen P, et al Immune cell-poor melanomas benefit from PD-1 blockade after targeted type I IFN activation. Cancer Discov. 2014;4:674-87. 38. Zhou Q, Xiao H, Liu Y, Peng Y, Hong Y, Yagita H, et al Blockade of programmed death-1 pathway rescues the effector function of tumor-infiltrating T cells and enhances the antitumor efficacy of lentivector immunization. J Immunol. 2010;185:5082-92. 39. Hingorani SR, Wang L, Multani AS, Combs C, Deramaudt TB, Hruban RH, et al Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell. 2005;7:469-83. 40. Clark CE, Hingorani SR, Mick R, Combs C, Tuveson DA, Vonderheide RH. Dynamics of the immune reaction to pancreatic cancer from inception to invasion. Cancer Res. 2007;67:9518-27. 41. Clark CE, Beatty GL, Vonderheide RH. Immunosurveillance of pancreatic adenocarcinoma: insights from genetically engineered mouse models of cancer. Cancer Lett. 2008;279:1-7. 42. Beatty GL, Chiorean EG, Fishman MP, Saboury B, Teitelbaum UR, Sun W, et al CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science. 2011;331:1612-6. 43. Bayne L, Beatty G, Jhala N, Clark C, Rhim A, Stanger B, et al Tumor-derived granulocyte-macrophage colony-stimulating factor regulates myeloid inflammation and T cell immunity in pancreatic cancer. Cancer Cell. 2012;21:822-35. 44. Elgueta R, Benson MJ, de Vries VC, Wasiuk A, Guo Y, Noelle RJ. Molecular mechanism and function of CD40/CD40L engagement in the immune system. Immunol Rev. 2009;229:152-72. 45. Nowak AK, Robinson BWS, Lake RA. Synergy between chemotherapy and immunotherapy in the treatment of established murine solid tumors. Cancer Res. 2003;63:4490-6. 46. Rhim AD, Mirek ET, Aiello NM, Maitra A, Bailey JM, McAllister F, et al EMT and dissemination precede pancreatic tumor formation. Cell. 2012;148:349-61. 47. Paley MA, Kroy DC, Odorizzi PM, Johnnidis JB, Dolfi DV, Barnett BE, et al Progenitor and terminal subsets of CD8+ T cells cooperate to contain chronic viral infection. Science. 2012;338:1220-5. 48. Doering TA, Crawford A, Angelosanto JM, Paley MA, Ziegler CG, Wherry EJ. Network analysis reveals centrally connected genes and pathways involved in CD8+ T cell exhaustion versus memory. Immunity. 2012;37:1130-44. 49. Wherry EJ, Ha S, Kaech SM, Haining WN, Sarkar S, Kalia V, et al Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity. 2007;27:670-84. 50. Barber DL, Wherry EJ, Masopust D, Zhu B, Allison JP, Sharpe AH, et al Restoring function in exhausted CD8 T cells during chronic viral infection. Nature. 2006;439:682-7. 51. Blackburn SD, Shin H, Freeman GJ, Wherry EJ. Selective expansion of a subset of exhausted CD8 T cells by PD-L1 blockade. Proc Natl Acad Sci U S A. 2008;105:15016-21. 52. Galon J, Angell H, Bedognetti D, Marincola F. The continuum of cancer immunosurveillance: prognostic, predictive, and mechanistic signatures. Immunity. 2013;39:11-26. 53. Cho H, Celis E. Optimized peptide vaccines eliciting extensive CD8 T-cell responses with therapeutic antitumor effects. Cancer Res. 2009;69:9012-9. 54. Buhtoiarov IN, Sondel PM, Wigginton JM, Buhtoiarova TN, Yanke EM, Mahvi DA, et al Anti-tumour synergy of cytotoxic chemotherapy and anti-CD40 plus CpG-ODN immunotherapy through repolarization of tumour-associated macrophages. Immunology. 2010;132:226-39. 55. Vonderheide RH, Bajor DL, Winograd R, Evans RA, Bayne LJ, Beatty GL. CD40 immunotherapy for pancreatic cancer. Cancer Immunol Immunother. 2013;62:949-54. 56. Shepard HM, Jacobetz MA, Chan DS, Neesse A, Bapiro TE, Cook N, et al Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer. Gut. 2012;62:112-20.
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on February 12, 2015; DOI: 10.1158/2326-6066.CIR-14-0215
57. Provenzano P, Cuevas C, Chang A, Goel V, Von Hoff D, Hingorani S. Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell. 2012;21:418-29. 58. Rhim A, Oberstein P, Thomas D, Mirek E, Palermo C, Sastra S, et al Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell. 2014;25:735-47. 59. Vonderheide RH, Bayne LJ. Inflammatory networks and immune surveillance of pancreatic carcinoma. Curr. Opin. Immunol. 2013;25:200-5. 60. Hiraoka N, Onozato K, Kosuge T, Hirohashi S. Prevalence of FOXP3+ regulatory T cells increases during the progression of pancreatic ductal adenocarcinoma and its premalignant lesions. Clin Can Res. 2006;12:5423-34. 61. De Monte L, Reni M, Tassi E, Clavenna D, Papa I, Recalde H, et al Intratumor T helper type 2 cell infiltrate correlates with cancer-associated fibroblast thymic stromal lymphopoietin production and reduced survival in pancreatic cancer. J Exp Med. 2011;208:469-78. 62. Fukunaga A, Miyamoto M, Cho Y, Murakami S, Kawarada Y, Oshikiri T, et al CD8+ tumor-infiltrating lymphocytes together with CD4+ tumor-infiltrating lymphocytes and dendritic cells improve the prognosis of patients with pancreatic adenocarcinoma. Pancreas. 2004;28:e26-31. 63. Bernstorff von W, Voss M, Freichel S, Schmid A, Vogel I, Jöhnk C, et al Systemic and local immunosuppression in pancreatic cancer patients. Clin Can Res. 2001;7:925s-32s. 64. Zhang Y, Yan W, Mathew E, Bednar F, Wan S, Collins MA, et al CD4+ T lymphocyte ablation prevents pancreatic carcinogenesis in mice. Cancer Immunol Res. 2014;2:423-35. 65. Feig C, Jones JO, Kraman M, Wells RJB, Deonarine A, Chan DS, et al Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc Natl Acad Sci U S A. 2013;110:20212-7. 66. Zhu Y, Knolhoff BL, Meyer MA, Nywening TM, West BL, Luo J, et al CSF1/CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T-cell checkpoint immunotherapy in pancreatic cancer models. Cancer Res. 2014;74:5057-69. 67. Sherman MH, Yu RT, Engle DD, Ding N, Atkins AR, Tiriac H, et al Vitamin d receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy. Cell. 2014;159:80-93. 68. Olive KP, Jacobetz MA, Davidson CJ, Gopinathan A, McIntyre D, Honess D, et al Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science. 2009;324:1457-61. 69. Pylayeva-Gupta Y, Lee K, Hajdu C, Miller G, Bar-Sagi D. Oncogenic Kras-induced GM-CSF production promotes the development of pancreatic neoplasia. Cancer Cell. 2012;21:836-47. 70. 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. 71. Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science. 1996;271:1734-6. 72. Mangsbo SM, Sandin LC, Anger K, Korman AJ, Loskog A, Tötterman TH. Enhanced tumor eradication by combining CTLA-4 or PD-1 blockade with CpG therapy. J Immunother. 2010;33:225-35. 73. Williams EL, Dunn SN, James S, Johnson PW, Cragg MS, Glennie MJ, et al Immunomodulatory monoclonal antibodies combined with peptide vaccination provide potent immunotherapy in an aggressive murine neuroblastoma model. Clin Can Res. 2013;19:3545-55. 74. Sandin LC, Eriksson F, Ellmark P, Loskog AS, Tötterman TH, Mangsbo SM. Local CTLA4 blockade effectively restrains experimental pancreatic adenocarcinoma growth in vivo. Oncoimmunology. 2014;3:e27614.
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75. Nomi T, Sho M, Akahori T, Hamada K, Kubo A, Kanehiro H, et al Clinical significance and therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in human pancreatic cancer. Clin Can Res. 2007;13:2151-7. 76. Jones S, Zhang X, Parsons DW, Leary RJ, Angenendt P, Mankoo P, et al Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science. 2008;321:1801-6. 77. Ho P, Meeth KM, Tsui Y, Srivastava B, Bosenberg MW, Kaech SM. Immune-based antitumor effects of BRAF inhibitors rely on signaling by CD40L and IFNγ. Cancer Res. 2014;74:3205-3217. 78. Richman LP and Vonderheide RH. Role of crosslinking for agonistic CD40 monoclonal antibodies as immune therapy of cancer. Cancer Immunol Res. 2014; 2:19-26. 79. Velcheti V, Schalper KA, Carvajal DE, Anagnostou VK, Syrigos KN, Sznol M, et al Programmed death ligand-1 expression in non-small cell lung cancer. Lab. Invest. 2013;94:107-16. 80. Akbay EA, Koyama S, Carretero J, Altabef A, Tchaicha JH, Christensen CL, et al Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors. Cancer Discov. 2013;3:1355-63.
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on February 12, 2015; DOI: 10.1158/2326-6066.CIR-14-0215
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on February 12, 2015; DOI: 10.1158/2326-6066.CIR-14-0215
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on February 12, 2015; DOI: 10.1158/2326-6066.CIR-14-0215
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on February 12, 2015; DOI: 10.1158/2326-6066.CIR-14-0215
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on February 12, 2015; DOI: 10.1158/2326-6066.CIR-14-0215
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on February 12, 2015; DOI: 10.1158/2326-6066.CIR-14-0215
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on February 12, 2015; DOI: 10.1158/2326-6066.CIR-14-0215
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on February 12, 2015; DOI: 10.1158/2326-6066.CIR-14-0215
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on February 12, 2015; DOI: 10.1158/2326-6066.CIR-14-0215
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on February 12, 2015; DOI: 10.1158/2326-6066.CIR-14-0215
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on February 12, 2015; DOI: 10.1158/2326-6066.CIR-14-0215
Published OnlineFirst February 12, 2015.Cancer Immunol Res Rafael Winograd, Katelyn T Byrne, Rebecca A Evans, et al. carcinomaPD-1 and CTLA-4 blockade and improves survival in pancreatic Induction of T cell immunity overcomes complete resistance to
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Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on February 12, 2015; DOI: 10.1158/2326-6066.CIR-14-0215