肿瘤细胞治疗研究
英文原题：Systemic pre-conditioning favors effector over exhausted CD8 T-cell subsets following Sup2-IL33 armored CAR T-cell therapy.
与未预处理或局部预处理的小鼠相比，接受Sup2-IL33 CAR T细胞治疗的全身预处理小鼠表现出更好的肿瘤控制效果和更长的总生存期。
背景：嵌合抗原受体（CAR）T细胞输注前的全身性预处理可增强植入，并提高过继转移细胞在肿瘤内的浸润和活性。尽管部分患者已有良好应答，仍需其他策略提高CAR T细胞治疗实体瘤的整体疗效。使CAR T细胞表达免疫调节性细胞因子，可增强治疗效果。本研究在B16F10黑色素瘤模型中评估全身预处理对CAR T细胞单独治疗以及联合白细胞介素2超激动剂（Sup2）和IL-33细胞因子装甲化的影响。 方法：在免疫功能完整的B16F10黑色素瘤小鼠中，评估局部和全身预处理方案与靶向TRP1的CAR T细胞联用的效果，CAR T细胞可单独使用或经Sup2和IL-33装甲化。采用生物发光成像、流式细胞术和单细胞RNA测序评估CAR T细胞扩增动力学及表型。 结果：与未预处理或局部预处理小鼠相比，全身预处理后接受Sup2-IL33 CAR T细胞治疗的小鼠肿瘤控制更好、总生存期更长。在预处理小鼠中清除Sup2-IL33 CAR T细胞会导致持久肿瘤控制丧失。全身照射（TBI）预处理增加了未装甲CAR T细胞的植入；Sup2-IL33装甲则提高效应细胞的肿瘤浸润，相较TOX+耗竭细胞更为明显。RNA速率轨迹分析预测，肿瘤浸润祖细胞可向效应T细胞或耗竭T细胞分化，形成不同轨迹。 结论：全身预处理增强了转移CAR T细胞的扩增和持久性。TBI预处理联合细胞因子装甲促进多样化效应表型形成，并与Sup2-IL33 CAR T细胞在B16F10黑色素瘤中的疗效增强相关。尽管Sup2-IL33装甲能够诱导内源性肿瘤免疫，联合治疗产生持久应答和生存延长仍需CAR T细胞持续存在。
BACKGROUND: Systemic pre-conditioning prior to chimeric antigen receptor (CAR) T-cell infusion enhances engraftment and increases infiltration and activity of adoptively transferred cells within the tumor. Despite promising responses in some patients, additional strategies are needed to enhance overall efficacy of CAR T cells in patients with solid tumors. Armoring CAR T cells to express immunomodulatory cytokines can enhance treatment efficacy. In this study, we assess how systemic pre-conditioning impacts CAR T cells alone and in combination with interleukin (IL)-2 superkine (Sup2) and IL-33 cytokine armoring in the context of B16F10 melanoma. METHODS: Local and systemic pre-conditioning regimens were assessed in combination with TRP1-specific CAR T cells with or without Sup2 and IL-33 armoring in immunocompetent mice with B16F10 melanoma. CAR T-cell expansion kinetics and phenotype were evaluated with luminescence imaging, flow cytometry, and single-cell RNA sequencing. RESULTS: Systemically preconditioned mice treated with Sup2-IL33 CAR T cells elicited greater tumor control and extended overall survival compared with non-conditioned or locally preconditioned mice. Depletion of Sup2-IL33 CAR T cells in preconditioned mice resulted in loss of durable tumor control. While total body irradiation (TBI) increased unarmored CAR T-cell engraftment, Sup2-IL33 armoring increased tumor infiltration of effector cells over TOX+exhausted cells. RNA velocity trajectory analysis predicted divergent differentiation of tumor-infiltrating progenitor cells into either effector or exhausted T cells. CONCLUSIONS: Systemic preconditioning increased the expansion and persistence of transferred CAR T cells.TBI preconditioning in combination with cytokine armoring promoted the emergence of diverse effector phenotypes that correlated with enhanced efficacy of Sup2-IL33 CAR T cells in the context of B16F10 melanoma. Durable responsiveness and extended survival following combined therapy required continued CAR T-cell persistence despite the ability of Sup2-IL33 armoring to induce endogenous tumor immunity.
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