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

Area of Science:

• Immunology
• Oncology
• Pharmacology

Background:

• Chimeric antigen receptor (CAR)-T cell therapy shows promise for B cell tumors but faces challenges like cancer recurrence.
• Gene-modified cell therapies, including CAR-T, TCR-T, and CAR-NK cells, are under investigation for cancer treatment.
• Inhibitor of apoptosis proteins (IAP) antagonists, like tolinapant, possess immunomodulatory activity.

Purpose of the Study:

• To investigate if combining CAR-T cells with tolinapant can enhance anti-tumor effects.
• To evaluate the potential of tolinapant to overcome limitations in current cell-based cancer therapies.

Main Methods:

• In vitro and in vivo studies combining CAR-T cells with tolinapant.
• Assessment of cancer cell death induction by tolinapant in the presence of TNF-α.
• Evaluation of tumor killing by CAR-T, TCR-T, and CAR-NK cells with and without tolinapant.
• Analysis of CAR-T cell expansion in response to tolinapant treatment.

Main Results:

• Tolinapant induced cancer cell death in a TNF-α-dependent manner.
• Tolinapant enhanced tumor killing by CAR-T, TCR-T, and CAR-NK cells in vitro and in vivo.
• Tolinapant promoted TNF-α secretion from CAR-T cells, leading to bystander killing of antigen-negative cancer cells.
• Tolinapant treatment accelerated the proliferation of CAR-T cells both in vitro and in vivo.

Conclusions:

• The combination of tolinapant with cell-based therapies, including CAR-T, TCR-T, and CAR-NK cells, significantly improves anti-cancer efficacy.
• Tolinapant enhances cell-based cancer therapies by simultaneously inducing cancer cell death and promoting effector cell proliferation.
• This combination strategy holds potential for overcoming existing challenges and improving outcomes in cell-based cancer treatments.