Ionizing radiation enhances CAR T-cell infiltration and efficacy in solid tumors

Area of Science:

• Oncology
• Immunotherapy
• Radiation Oncology

Background:

• Chimeric antigen receptor (CAR) T-cell therapy shows promise for hematological malignancies but faces challenges in solid tumors due to the tumor microenvironment.
• Improving CAR T-cell delivery and infiltration is crucial for enhancing their efficacy in solid tumors.

Purpose of the Study:

• To investigate the potential of ionizing radiation to enhance CAR T-cell therapy for solid tumors.
• To evaluate the impact of radiation on tumor vascular perfusion and CAR T-cell delivery in a melanoma model.

Main Methods:

• Utilized an EGFRvIII-expressing B16F10 melanoma mouse model.
• Administered single doses of ionizing radiation (2-12 Gy) and assessed tumor perfusion using fluorescent dyes.
• Evaluated CAR T-cell accumulation, tumor growth, and survival following irradiation prior to CAR T-cell infusion.

Main Results:

• A single 8-Gy radiation dose significantly increased tumor perfusion 4 hours post-irradiation.
• Irradiation 4 hours before CAR T-cell administration led to higher intratumoral CAR T-cell accumulation.
• This combined approach significantly delayed tumor growth and improved survival compared to monotherapy.
• CD28ζ CAR T-cells showed superior efficacy over 4-1BBζ CAR T-cells in irradiated tumors.

Conclusions:

• Ionizing radiation can overcome barriers to CAR T-cell therapy in solid tumors by improving perfusion and delivery.
• The co-stimulatory domain of CAR T-cells plays a critical role in their in vivo function.
• Pre-irradiation is a viable strategy to enhance CAR T-cell infiltration and therapeutic efficacy in solid tumors.