Radiation and CSPG4-specifc CAR T cell based combinatorial therapy for the in vivo treatment of TNBC

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Project Summary/Abstract Effective treatment options for triple negative breast cancer (TNBC) are lacking due to chemotherapy and radiation resistance and low therapeutic efficacy of novel targeted therapies. Because of these disappointing clinical results, we have assessed the potential therapeutic clinical application of a CSPG4-specific chimeric antigen receptor (CAR) T cell-based therapy for the treatment of TNBC. CSPG4 has been selected as the target, since this tumor antigen (TA) is expressed in about 70% of primary and metastatic TNBC tumors. Furthermore, CSPG4 is expressed on TNBC cancer initiating cells (CICs), which are believed to play a role in metastatic spreading and disease recurrence, the two major causes of patients' morbidity and mortality. Lastly, CSPG4 is not detectable on normal cells with the exception of activated pericytes in the tumor microenvironment (TME). We have shown that CSPG4 CAR T cells are effective in eliminating differentiated TNBC cells and TNBC CICs in vitro, but are not able to completely eradicate TNBC tumors grafted in immunodeficient mice. This discrepancy may reflect the negative impact of TME on CSPG4-specific CAR T cell-TNBC cell interactions as well as poor T cell infiltration of the tumor. To counteract these obstacles to the successful application of CAR T cell therapy, we will combine CSPG4-specific CAR T cells with radiation. This combinatorial strategy is based on our preliminary results, which in combination with the information in the literature show that tumor radiation can enhance the antitumor activity of CSPG4-specific CAR T cells with TNBC cells. This effect appears to be mediated by multiple mechanisms, of which, a significant upregulation of CSPG4 expression on TNBC cells, modulation of molecules involved in cell apoptosis and increased T cell infiltration and persistence seem to be involved. The specific aims of this proposal are to i) evaluate whether tumor radiation enhances the ability of CSPG4-specific CAR T cells to eradicate human TNBC cells orthotopically grafted in NRG mice and ii) assess the molecular mechanism(s) underlying the increased ability of CSPG4-specific CAR T cells in combination with radiation to eradicate human TNBC cells orthotopically grafted in NRG mice. These results will contribute to optimize a combinatorial radiation and CSPG4-specific CAR T cell-based strategy for the treatment of TNBC.