CAR T细胞疗法代表了造血系统恶性肿瘤的重大进展，一些患者可实现长期缓解。然而，大多数接受治疗的患者仍死于疾病。响应的一个一致性预测因子是肿瘤数量，在CAR T细胞疗法之前较高疾病负担预示着更差的预后。在CAR T细胞疗法之前，对疾病的臃肿部位进行局部放疗可以降低肿瘤数量，但目前不清楚这种策略是否能改善生存率。我们发现，通过以低剂量全身肿瘤放疗（TTI）靶向所有疾病部位，在CAR T细胞疗法中实现的小鼠整体生存率比常规使用高剂量辐射靶向臃肿病变较少影响该生存率的CAR T细胞更高。这一发现突显了另一种响应预测因子-肿瘤质量，即患者肿瘤细胞对CAR T细胞杀伤的内在抵抗力。关于个体肿瘤的内在抵抗力在不同情况下是否会发生改变，目前知之甚少。我们发现，反映肿瘤对CAR T细胞的内在敏感性的转录"死亡受体得分"可以通过低剂量TTI暂时增加，并且这种转录变化的时间与受CAR T细胞数量限制的体内白血病控制改善相关。这表明了一种可行的方法，可以潜在地改善对这种有前途的疗法响应不佳的患者的预后，并突显了内在肿瘤属性可能是CAR T细胞响应的同等或更重要的预测因子于肿瘤负担。版权所有©2023年美国血液学会。

CAR T-cell therapy represents a major advance 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 higher disease burden before CAR T-cell therapy portends a worse prognosis. Focal radiation to bulky sites of disease can decrease tumor quantity prior to 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 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 radiation (TTI) prior to CAR T-cells. 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 CAR T-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.Copyright © 2023 American Society of Hematology.