Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Department of Hematology, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain.
J Clin Invest. 2020 Jun 1;130(6):3087-3097. doi: 10.1172/JCI133215.
Chimeric antigen receptor-T (CAR-T) cell therapies can eliminate relapsed and refractory tumors, but the durability of antitumor activity requires in vivo persistence. Differential signaling through the CAR costimulatory domain can alter the T cell metabolism, memory differentiation, and influence long-term persistence. CAR-T cells costimulated with 4-1BB or ICOS persist in xenograft models but those constructed with CD28 exhibit rapid clearance. Here, we show that a single amino acid residue in CD28 drove T cell exhaustion and hindered the persistence of CD28-based CAR-T cells and changing this asparagine to phenylalanine (CD28-YMFM) promoted durable antitumor control. In addition, CD28-YMFM CAR-T cells exhibited reduced T cell differentiation and exhaustion as well as increased skewing toward Th17 cells. Reciprocal modification of ICOS-containing CAR-T cells abolished in vivo persistence and antitumor activity. This finding suggests modifications to the costimulatory domains of CAR-T cells can enable longer persistence and thereby improve antitumor response.
嵌合抗原受体-T（CAR-T）细胞疗法可以消除复发和难治性肿瘤，但抗肿瘤活性的持久性需要体内持续存在。通过 CAR 共刺激结构域的差异信号转导可以改变 T 细胞代谢、记忆分化，并影响长期持久性。用 4-1BB 或 ICOS 共刺激的 CAR-T 细胞在异种移植模型中持续存在，但用 CD28 构建的 CAR-T 细胞则迅速清除。在这里，我们表明 CD28 中的单个氨基酸残基驱动 T 细胞耗竭，并阻碍基于 CD28 的 CAR-T 细胞的持久性，并且将这种天冬酰胺改变为苯丙氨酸（CD28-YMFM）可促进持久的抗肿瘤控制。此外，CD28-YMFM CAR-T 细胞表现出减少的 T 细胞分化和耗竭以及向 Th17 细胞的倾斜增加。含有 ICOS 的 CAR-T 细胞的相互修饰消除了体内持久性和抗肿瘤活性。这一发现表明对 CAR-T 细胞的共刺激结构域进行修饰可以实现更长的持久性，从而改善抗肿瘤反应。
