The IAP antagonist tolinapant enhances the anti-tumor activity of cell therapies

Various gene-modified cell therapies have been investigated in clinical trials, among which chimeric antigen receptor (CAR)-T cell therapy has been approved for the treatment of B cell tumors and has shown remarkable therapeutic effects. However, challenges, such as, Cancer recurrence and manufacturing issues remain. To overcome such limitations, we investigated whether combining CAR-T cells with tolinapant, an inhibitor of Apoptosis proteins (IAP) antagonist with immunomodulatory activity, could enhance the anti-tumor effect. Tolinapant induced Cancer cell death in the presence of TNF-α. Tumor killing by CAR-T, TCR-T or CÊNK cells was enhanced by tolinapant in vitro in a TNF-α-dependent manner. TNF-α secreted from CAR-T cells, in the presence of tolinapant, also induced cell death of antigen-negative Cancer cells not in cell-cell contact with CAR-T cells. Addition of tolinapant potentiated efficacy of not only two different CAR-T, but also TCR-T and CAR-NK cells in vivo. Tolinapant treatment led to faster expansion of stimulated CAR-T cells in vitro and in vivo. Our study suggests that the combination of tolinapant improves the efficacy of cell-based Cancer therapies by inducing both Cancer cell death and CAR-T cell proliferation. This combination therapy may overcome the current limitations of cell-based therapies and enhance their anti-cancer effect.