Cimons Jennifer M, DeGolier Kole R, Burciaga Samuel D, Yarnell Michael C, Novak Amanda J, Rivera-Reyes Amalia M, Kohler M Eric, Fry Terry J
Pediatrics Hematolgy/Oncology/Bone Marrow Transplant, University of Colorado Anschutz Medical Campus School of Medicine, Aurora, Colorado, USA.
Pediatrics, Children's Hospital Colorado, Aurora, Colorado, USA.
J Immunother Cancer. 2025 Apr 17;13(4):e010962. doi: 10.1136/jitc-2024-010962.
T cells modified to express a chimeric antigen receptor (CAR) are successful against B-lineage malignancies but fail to induce durable remissions in up to half of patients and have shown limited efficacy against other types of cancer. Strategies to improve CAR T cell potency and responses to low antigen densities without inducing CAR T cell dysfunction or limiting persistence are necessary to expand durability of remissions.
We overexpressed T-bet in human and mouse CAR T cells to mimic exposure to signal 3 cytokines during T cell priming to promote T helper cell 1 (Th1) polarization of CD4+CAR T cells with the goal of enhancing antitumor activity. Using human CAR T cells and xenograft models we interrogated the impact of T-bet overexpression on CAR T cell antitumor activity in vitro and in vivo. We also used a syngeneic murine CAR T cell model to study the impact of T-bet overexpression on long-term persistence and secondary responses to tumor rechallenge.
T-bet overexpression reduced expression of the Th2 cytokine interleukin 4 and promoted polyfunctional production of Th1-associated cytokines in response to CAR stimulation. T-bet overexpression enhanced some effector functions in vitro but did not improve CAR T cell-mediated control of leukemia expressing high levels of antigen in vivo. T-bet overexpression also improved effector function of murine CD19 CAR T cells with no impairment to the persistence or ability of persistent CAR T cells to re-expand and clear a secondary leukemia challenge. Finally, T-bet overexpression promoted enhanced in vitro function against leukemia expressing low levels of CD19, which translated to improved control of CD19lo leukemia in vivo by human C19 CAR T cells containing a 4-1BB costimulatory domain.
Together, our data demonstrate that T-bet overexpression induces a reduction in Th2 cytokine production, an increase in polyfunctional Th1 cytokine production and enhances 4-1BB CAR T cell activity against cancers expressing low levels of target antigen without promoting a loss in functional CAR T cell persistence.
经改造表达嵌合抗原受体（CAR）的T细胞对B系恶性肿瘤有效，但在高达半数的患者中未能诱导持久缓解，且对其他类型癌症的疗效有限。为了延长缓解的持续时间，有必要采取策略提高CAR T细胞的效力，并增强对低抗原密度的反应，同时不诱导CAR T细胞功能障碍或限制其持久性。
我们在人和小鼠的CAR T细胞中过表达T-bet，以模拟T细胞活化过程中暴露于信号3细胞因子的情况，从而促进CD4+CAR T细胞向辅助性T细胞1（Th1）极化，目标是增强抗肿瘤活性。我们使用人CAR T细胞和异种移植模型，研究T-bet过表达对体外和体内CAR T细胞抗肿瘤活性的影响。我们还使用同基因小鼠CAR T细胞模型，研究T-bet过表达对长期持久性以及对肿瘤再次攻击的二次反应的影响。
T-bet过表达降低了Th2细胞因子白细胞介素4的表达，并促进了Th1相关细胞因子在CAR刺激下的多功能产生。T-bet过表达在体外增强了一些效应功能，但在体内并未改善CAR T细胞对高表达抗原的白血病的控制。T-bet过表达还改善了小鼠CD19 CAR T细胞的效应功能，且不损害持久性CAR T细胞重新扩增和清除二次白血病攻击的能力。最后，T-bet过表达促进了对低表达CD19的白血病的体外功能增强，这转化为含4-1BB共刺激结构域的人C19 CAR T细胞在体内对CD19lo白血病的更好控制。
总之，我们的数据表明，T-bet过表达可导致Th2细胞因子产生减少、多功能Th1细胞因子产生增加，并增强4-1BB CAR T细胞对低表达靶抗原癌症的活性，同时不促进功能性CAR T细胞持久性的丧失。
Zotero 插件
