Tumor Regression and Delayed Onset Toxicity Following B7-H4 CAR T Cell Therapy

Area of Science:

• Immunology
• Oncology
• Cell Therapy

Background:

• B7-H4 protein is overexpressed in ovarian cancer, making it a potential therapeutic target.
• Chimeric antigen receptor (CAR) T cell therapy shows promise for cancer treatment.

Purpose of the Study:

• To engineer and evaluate B7-H4-specific CAR T cells for ovarian cancer therapy in preclinical models.
• To assess the safety and efficacy of B7-H4 CAR T cell therapy.

Main Methods:

• Engineered T cells with novel B7-H4-specific CARs targeting human and murine B7-H4.
• Tested CAR T cells in preclinical models with B7-H4-positive ovarian cancer xenografts.
• Assessed B7-H4 protein distribution in normal murine and human tissues.

Main Results:

• B7-H4 CAR T cells demonstrated specific IFN-γ secretion and lysis of B7-H4-positive targets.
• In vivo, B7-H4 CAR T cells exhibited antitumor activity against ovarian cancer xenografts.
• Delayed, lethal toxicity was observed 6-8 weeks post-therapy, linked to B7-H4 expression in normal tissues (ductal, mucosal epithelia).
• Histologic lesions in mice correlated with B7-H4 expression and were distinct from graft-versus-host disease.

Conclusions:

• B7-H4 CAR T cell therapy can control cancer outgrowth but carries a risk of lethal off-tumor toxicity due to widespread normal tissue expression of B7-H4.
• The preclinical model is valuable for evaluating safety strategies to mitigate CAR T cell-mediated toxicity.
• Understanding B7-H4 distribution in normal human tissues is crucial for advancing CAR T cell therapy development.