Intrinsic tumor resistance to CAR T cells is a dynamic transcriptional state that is exploitable with low-dose radiation

Chimeric antigen receptor (CAR) T-cell therapy represents a major advancement for hematologic malignancies, with some patients achieving long-term remission. However, the majority of treated patients still die of their disease. A consistent predictor of response is tumor quantity, wherein a higher disease burden before CAR T-cell therapy portends a worse prognosis. Focal radiation to bulky sites of the disease can decrease tumor quantity before CAR T-cell therapy, but whether this strategy improves survival is unknown. We find that substantially reducing systemic tumor quantity using high-dose radiation to areas of bulky disease, which is commonly done clinically, is less impactful on overall survival in mice achieved by CAR T cells than targeting all sites of disease with low-dose total tumor irradiation (TTI) before CAR T-cell therapy. This finding highlights another predictor of response, tumor quality, the intrinsic resistance of an individual patient's tumor cells to CAR T-cell killing. Little is known about whether or how an individual tumor's intrinsic resistance may change under different circumstances. We find a transcriptional death receptor score that reflects a tumor's intrinsic sensitivity to CART cells can be temporarily increased by low-dose TTI, and the timing of this transcriptional change correlates with improved in vivo leukemia control by an otherwise limited number of CAR T cells. This suggests an actionable method for potentially improving outcomes in patients predicted to respond poorly to this promising therapy and highlights that intrinsic tumor attributes may be equally or more important predictors of CAR T-cell response as tumor burden.

Automated summary

Chimeric antigen receptor (CAR) T-cell therapy is a significant breakthrough for hematologic malignancies, but majority of patients still die from the disease. Tumor quantity and quality are predictors of response, with higher disease burden and intrinsic tumor resistance leading to worse prognosis. High-dose radiation to bulky disease areas reduces systemic tumor quantity, but low-dose total tumor irradiation (TTI) targeting all disease sites before CAR T-cell therapy has a greater impact on overall survival in mice. This study suggests that intrinsic tumor attributes are equally or more important predictors of CAR T-cell response as tumor burden, and low-dose TTI can temporarily increase tumor sensitivity to CAR T cells.