Date of Award

2015

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

Robert H. Vonderheide

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. Certain tumors, especially pancreatic carcinoma, are fully refractory to these antibodies. As reported in this thesis, I used a genetically engineered mouse model of pancreatic carcinoma in which spontaneous immunity is minimal, and found that PD-L1 is prominent in the tumor microenvironment, a phenotype confirmed in patients. Tumor infiltrating T cells express PD-1 even more prominently than T cells in a classical model of chronic infection, in which anti-PD-1 mAb mediates clinical benefit. Despite this striking expression of PD-1 and PD-L1 in the pancreatic tumor microenvironment, treatment with anti-PD-1 mAb, with or without anti-CTLA-4 mAb, fails in well-established tumors, recapitulating clinical results. Agonist anti-CD40 mAb with chemotherapy, deployed as a vaccine, induces T cell immunity and reverses the complete resistance of pancreatic tumors to anti-PD-1 and anti-CTLA-4. The combination of anti-CD40/chemotherapy plus anti-PD-1 and/or anti-CTLA-4 induces regression of subcutaneous tumors, improves overall survival, and confers curative protection from multiple rechallenges, consistent with immune memory not otherwise achievable. Combinatorial treatment nearly doubles survival of mice with spontaneous pancreatic cancers, revealing a clinical opportunity. These findings suggest that in non immunogenic tumors, epitomized by pancreatic carcinoma, baseline refractoriness to checkpoint inhibitors may be rescued by the priming of a T cell response with an antitumor vaccine. These studies indicate that understanding the immunobiology of differing tumor types may improve the ability to rationally design combinatorial immunotherapies in oncology.

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