IL-7/IL-15/IL-21 细胞因子融合支架生成富含长寿命 T 记忆干细胞的强功能 CAR-T 细胞

Functional persistence of chimeric antigen receptor T cells (CAR T cells) is limited by conventional CAR T cell manufacturing using anti-CD3/CD28 ( CD3/28) stimulation, which generates terminally differentiated and shorter-lived CAR T cells.

We demonstrated that HCW9206, a unique protein scaffold linking interleukin-7 (IL-7), an IL-15/IL-15 receptor (IL-15R ) complex, and IL-21, generates CAR T cells without requiring CD3/28 activation, which are highly enriched in long-lived T memory stem cells (T SCM cells) (>50%) and display potent activity across distinct disease models, HIV-1 or B cell leukemia. In a humanized mouse HIV infection model, HCW9206-generated anti-HIV duoCAR T cells suppressed viremia more effectively than CD3/28-generated anti-HIV duoCAR T cells.

In a xenograft leukemia mouse model, a recall proliferative response and complete clearance of leukemia rechallenge were displayed by HCW9206-generated but not by CD3/28-generated anti-CD19 CAR T cells.

HCW9206, a first-in-class cytokine scaffold-based platform, enables production of more potent CAR T cell-based immunotherapies by generating a CAR T cell population, which is highly functional and also markedly enriched for long-lived T SCM cells. This strategy is broadly applicable to increase persistence and functionality of CAR T cells, enhancing their efficacy for treating infectious disease and cancer.