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Cancer Immunology Research
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Research Article

Induction of T cell immunity overcomes complete resistance to PD-1 and CTLA-4 blockade and improves survival in pancreatic carcinoma

Rafael Winograd, Katelyn T Byrne, Rebecca A Evans, Pamela M Odorizzi, Anders R.L. Meyer, David L Bajor, Cynthia Clendenin, Ben Z Stanger, Emma E Furth, E. John Wherry and Robert H Vonderheide
Rafael Winograd
1Medicine, University of Pennsylvania
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Katelyn T Byrne
2Microbiology and Immunology and the Norris-Cotton Cancer Center, Geisel School of Medicine at Dartmouth
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Rebecca A Evans
3Abramson Family Cancer Research Institute, University of Pennsylvania
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Pamela M Odorizzi
4Abramson Cancer Center, University of Pennsylvania School of Medicine
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Anders R.L. Meyer
5Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine
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David L Bajor
6University of Pennsylvania, Abramson Family Cancer Research Institute
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Cynthia Clendenin
4Abramson Cancer Center, University of Pennsylvania School of Medicine
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Ben Z Stanger
1Medicine, University of Pennsylvania
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Emma E Furth
5Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine
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E. John Wherry
7Microbiology, U. Pennsylvania School of Medicine
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Robert H Vonderheide
4Abramson Cancer Center, University of Pennsylvania School of Medicine
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  • For correspondence: rhv@exchange.upenn.edu
DOI: 10.1158/2326-6066.CIR-14-0215
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Abstract

Disabling the function of immune checkpoint molecules can unlock T cell immunity against cancer, yet despite remarkable clinical success with monoclonal antibodies (mAb) that block PD-1 or CTLA-4 resistance remains common and essentially unexplained. To date, pancreatic carcinoma is fully refractory to these antibodies. Here, using a genetically engineered mouse model of pancreatic ductal adenocarcinoma in which spontaneous immunity is minimal, we found that PD-L1 is prominent in the tumor microenvironment, a phenotype confirmed in patients; however, tumor PD-L1 was found to be independent of IFN-γ in this model. Tumor T cells expressed PD-1 as prominently as T cells from chronically infected mice, but treatment with PD-1 mAb, with or without CTLA-4 mAb, failed in well-established tumors, recapitulating clinical results. Agonist CD40 mAb with chemotherapy induced T cell immunity and reversed the complete resistance of pancreatic tumors to PD-1 and CTLA-4. The combination of αCD40/chemotherapy plus PD-1 and/or CTLA-4 induced regression of subcutaneous tumors, improved overall survival, and confered curative protection from multiple rechallenges, consistent with immune memory not otherwise achievable. Combinatorial treatment nearly doubled survival of mice with spontaneous pancreatic cancers although no cures were observed. Our findings suggest that in pancreatic carcinoma, a non-immunogenic tumor, baseline refractoriness to checkpoint inhibitors can be rescued by the priming of a T cell response with αCD40/chemotherapy.

  • Received November 16, 2014.
  • Revision received February 6, 2015.
  • Accepted February 6, 2015.
  • Copyright © 2015, American Association for Cancer Research.
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This OnlineFirst version was published on February 24, 2015
doi: 10.1158/2326-6066.CIR-14-0215

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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 Winograd, Katelyn T Byrne, Rebecca A Evans, Pamela M Odorizzi, Anders R.L. Meyer, David L Bajor, Cynthia Clendenin, Ben Z Stanger, Emma E Furth, E. John Wherry and Robert H Vonderheide
Cancer Immunol Res February 24 2015 DOI: 10.1158/2326-6066.CIR-14-0215

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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 Winograd, Katelyn T Byrne, Rebecca A Evans, Pamela M Odorizzi, Anders R.L. Meyer, David L Bajor, Cynthia Clendenin, Ben Z Stanger, Emma E Furth, E. John Wherry and Robert H Vonderheide
Cancer Immunol Res February 24 2015 DOI: 10.1158/2326-6066.CIR-14-0215
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