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

Colon cancer and colorectal liver metastases (CRLM) are a significant and increasingly 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 for the majority of these tumors, 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 produced by our laboratory where increased T-cell trafficking to tumors, when combined with CTLA4 blockade, resulted in complete CRLM regressions.

The rationale current 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. Supported by a very strong scientific premise based on published papers and robust preliminary data, this hypothesis will be tested by pursuing three specific aims:

1) Determine mechanisms to enhance lymphocyte proliferation and anti-tumor specific immune responses in colon cancer by manipulating immunosuppressive signals. 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 in our lab

2) Examine mechanisms that supply immunostimulatory influences directly into the tumor, using a viral delivery system engineered in our lab

3) Combine checkpoint blockade with selective delivery of human LIGHT to treat surgically resected tumors and human CRLM in a preclinical autologous system. To achieve this 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.

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. 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.