Pancreatic cancer will be responsible for over 44,000 deaths in the US this year and is currently the 3rd leading cause of cancer mortality; survival in this disease has not changed in the last 40 years. Although immune checkpoint inhibitors have emerged as highly effective approaches for tumors with high mutational burden, such is not the case with pancreatic cancer which lacks a significant endogenous tumor-reactive T cell population. Adoptively transfer of antigen-specific T cells would provide an effector substrate for immune checkpoint inhibition and we reason that such a combination strategy would be desirable. In this proposal we address two major challenges to advancing the use of adoptive cellular therapy (ACT) for pancreatic cancers: 1. a paucity of proven immunogenic targets for pancreatic cancer and, 2., a means of rapidly deploying antigen-specific cellular therapy targeting such antigens. In this proposal we plan to target a tumor cell-associated target antigen (VCY) and a tumor stroma-associated target (COL6A3), both highly prevalent (> 70% of tumors), and highly immunogenic. Our scientific premise is that strategies that address the lack of tumor-reactive T cells in pancreatic cancer, where the mutational burden and immunogenicity is significantly lower, would be desirable and achievable by the adoptive transfer of tumor-reactive T cells recognizing pancreatic cancer-associated antigens. Adoptive cellular therapy (ACT) is a promising form of immunotherapy that involves the ex vivo isolation and expansion of antigen-specific T cells for infusion. Based on the premise that strategies to extend in vivo persistence of transferred T cells and induce antigen-spreading will lead to improved clinical response following ACT, we hypothesize that adoptive transfer of long-lasting central memory type T cells in combination with PD1 blockade will lead to extended in vivo survival and enhanced activation of endogenous T cells recognizing non-targeted antigens (antigen-spreading). Our ETC (endogenous T cell therapy) approach to ACT was to pioneer a strategy that uses peripheral blood as a source of T cells. Using a combination of IL-21 priming (to enrich for central memory type T cells) and tetramer-guided cell sorting, we can routinely isolate rare tumor-reactive T cells from the peripheral blood ( < 1:100,000) and expand these to a > 20 billion uniformly defined central memory ? type specific T cells with defined specificity and high replicative capacity as demonstrated by several prior studies demonstrating months-long in vivo persistence at frequencies 1-10 % commensurate with durable clinical responses. We propose a Phase IB trial targeting COL6A3 and VCY in patients with refractory pancreatic adenocarcinoma, first in a dose escalation cohort, and when a dose has been identified, an expansion cohort in combination with PD1 blockade.
Patients with pancreatic cancer have few therapeutic options and immune-based therapies have largely been ineffective due in part to the absence of T cells recognizing immunogenic targets. We have developed an adoptive cell therapy strategy requiring only peripheral blood as a source to generate central memory T cells targeting two highly prevalent antigens expressed by pancreatic adenocarcinoma. We propose a clinical trial to evaluate the safety, feasibility and potential anti-tumor efficacy of using adoptively transferred antigen-specific T cells in combination with checkpoint blockade in patients with advanced pancreatic cancer.
