PILOT: Combination Immunotherapy for PD1 Refractory Tumors

TITLE: Combination Immunotherapy for PD1 refractory tumors ABSTRACT T-cell immune checkpoint inhibitor therapy, using PD1/PL-1 blockade antibody, is one of the widely used immunotherapy to treat many cancers. Though blocking PD1/PDL1 signal has proven to be beneficial in most cases, some of the patents eventually become refractory to PD1/PDL1 blocking therapy. Those checkpoint inhibitor refractory patients rely on combination immunotherapies with or without PD1/PDL1 blockade that target tumor evasive mechanisms, alter tumor suppressive microenvironment, and re-invigorate T cell homing and functions. A rational approach to developing an effective combination therapy must carefully evaluate how drug combinations complement and synergize with each other to drive effective anti-tumor immunity with limited or no drug-related toxicities. In this application, we propose to evaluate the efficacy of a combination therapy containing cancer vaccine and NHS-IL-12 (a tumor-targeting form of IL-12) with or without PD1 CHI in promoting tumor regression in PD1 refractory tumors. We hypothesize that a cancer vaccine and IL-12 can overcome the mechanisms driving the PD1 CHI insensitivity in promoting anti-tumor activity. Our lab has access, through our collaboration with biotech partners, to both NHS-IL12, a tumor-targeting and low-toxic version of IL-12, and a cancer vaccine (PDS0103) containing agonist-enhanced CD8 T cell peptides derived from human mucin 1 oncogene. This gives us a unique advantage and opportunity to perform the proposed investigations. In this proposal, we aim to test our underlying hypothesis and investigate the mechanisms by which IL-12 can complement the PD1 checkpoint immunotherapy. To investigate this, we will implant mice with a colon adenocarcinoma cells CT-26 expressing human mucin 1 and assess how IL-12 and a cancer vaccine targeting human mucin 1 will overcome PD1/PDL-1 therapy failure. We will have two main specific aims to characterize tumor microenvironment in tumor-bearing mice treated with the combination therapy containing IL-12, a cancer vaccine and the PD1 blockade antibody (specific aim 1) and to assess how IL-12 modulates CD8 T cells priming and its recruitment to the tumors (Specific aim 2). The successful execution of this project will form the foundation for developing a combination immunotherapy to overcome PD1/PDL-1 refractory cancer. Hence, this project is highly relevant to cancer research.