Tumor-Targeted Nonablative Radiation Promotes Solid Tumor CAR T-cell Therapy Efficacy

Area of Science:

• Immunology
• Oncology
• Radiotherapy

Background:

• T-cell infiltration into tumors is crucial for effective immunotherapy of solid tumors.
• Chimeric antigen receptor (CAR) T-cell therapy holds promise but faces challenges in solid tumor treatment.

Purpose of the Study:

• To investigate the impact of tumor-targeted radiation on CAR T-cell therapy efficacy in mesothelioma and non-small cell lung cancer models.
• To assess if pre-treatment with radiation enhances CAR T-cell infiltration, proliferation, and antitumor activity.

Main Methods:

• Utilized a nonablative dose of tumor-targeted radiation before systemic administration of mesothelin-targeted CAR T cells.
• Evaluated CAR T-cell infiltration, proliferation, functional persistence, and antitumor efficacy in preclinical models.
• Analyzed chemokine and chemokine receptor expression in tumors and T cells.

Main Results:

• Tumor-targeted radiation significantly increased early and sustained CAR T-cell infiltration and proliferation.
• Radiation promoted chemokine expression in tumors and chemokine receptor expression in T cells, facilitating infiltration into distant sites.
• Enhanced CAR T-cell efficacy was observed in both mesothelioma and lung cancer models.

Conclusions:

• Combining tumor-targeted radiation with CAR T-cell therapy can substantially improve treatment outcomes for solid tumors.
• This approach enhances CAR T-cell trafficking and activity, overcoming delivery barriers.
• A 'sandwich' cell therapy strategy combining sequential radiation and CAR T cells is proposed for solid tumors.