Combining Oncolytic Adenovirus (OncAd) with Tumor Directed, Adenovirus-specific T-cells for the Treatment of Neuroblastoma: Effects of OncAds on Immunosuppressive Myeloid Cells

Background

T-cells have proved safe and effective for the treatment of certain types of cancer. However, T-cell efficacy against most solid tumors is limited by the immunosuppressive microenvironment generated by tumor cells and their infiltrating stroma. Myeloid-derived cells are potent controllers of the tumor microenvironment and can alter the fate of tumor-specific T-cells.

Oncolytic adenoviruses (OncAd) can reduce bulky tumors. They can alter the tumor environment by activating immune responses, including adenovirus-specific T-cells (AdVSTs). Unfortunately, AdVSTs ultimately limit virus spread and prevent complete tumor eradication.

We plan to harness this characteristic of OncAds, by modifying AdVSTs with tumor-specific receptors (CARs). When activated by the OncAds, AdVSTs can eliminate residual tumor and un-injected metastases.

Project Goal

Our preliminary data suggest that OncAds can reverse the immunosuppressive phenotype developed by human monocytes after cultured with tumor cells. This project will evaluate the effects of neuroblastoma and sarcoma cells on the immunophenotype and antigen-presenting function of monocytes. It will determine if their immunosuppressive function can be reversed by OncAds both in vitro and mouse tumor models. It will also compare the abilities of different OncAd transgenes to enhance the activation and function of CAR-modified AdVSTs.