Stimulating Lymphocyte Activation Combined with Inhibition of Immunosuppressive Signals in Colon Cancer Metastases

University Of California, San Francisco, San Francisco CA

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Abstract

Project Summary/Abstract Colon cancer and colorectal liver metastases (CRLM) are a significant and lethal disease. Though there is a strong scientific premise to harness the immune system to treat this cancer, there remains a fundamental gap in understanding of how immunotherapies can be utilized, particularly microsatellite stable cancers. The central hypothesis is that the tumor microenvironment can be manipulated to enhance cytotoxic lymphocyte infiltration and activation, and that checkpoint blockade can be simultaneously utilized to incite a clinically relevant immune response. This “one-two punch” hypothesis has been formulated on the basis of preliminary data wherein in- creased T-cell trafficking to tumors, when combined with CTLA4 blockade, resulted in complete CRLM regres- sions. The rationale for the proposed research is that once it is known how to enhance immunostimulatory signals in the microenvironment and simultaneously suppress inhibitory influences, a new strategy for the management of colon cancer is possible. This hypothesis will be tested by pursuing three specific aims: 1) Determine mecha- nisms to enhance lymphocyte proliferation and anti-tumor specific immune responses in colon cancer by manip- ulating immunosuppressive signals, 2) Examine mechanisms that supply immunostimulatory influences directly into the tumor; and 3) Combine checkpoint blockade with selective delivery of human LIGHT to treat surgically resected tumors and human CRLM in a pre-clinical autologous system. Under the first aim we expect to increase lymphocyte infiltration, proliferation and activation while simultaneously curbing immunosuppressive signals/cells in the microenvironment utilizing a validated pre-clinical model established by the applicants. In the second aim, a clinically relevant method to safely increase LIGHT expression within colon cancer tumors using novel tumor- specific viral delivery mechanisms engineered by the applicants will be analyzed. Under the third aim, patient tumors will be utilized in an autologous humanized mouse model and treated with CTLA4 blockade combined with oncolytic viral delivery mechanisms to increase LIGHT expression. Additionally, will test a mechanism to deliver LIGHT in various formulations to therapeutic effect in CRLM through direct hepatic artery infusion (HAI). This will be tested using 1.) a nanoparticle encapsulating LIGHT RNA and 2.) Ad-LIGHT. The proposed research is innovative, because the multi-combination therapy of LIGHT expression in CRLM with tumor-specific oncolysis and checkpoint blockade will deliver an inventive approach that will be universally applicable from patient to patient. New horizons that will stem from this innovative strategy include a better understanding of anti-CTLA4 biology that may not only enhance response rates, but also vastly increase indications for its use in previously “cold” tumors, including microsatellite stable gastrointestinal cancer. This contribution will be significant because it will establish a synergistic combination of immunotherapies that will have direct translational impact on one of the deadliest cancers worldwide. The implications of our results may improve patient quality of life and provide survival advantages over the best current surgical and chemotherapeutic strategies for this disease.