Membrane-bound IL-7 immobilized by the CD8 transmembrane region improves efficacy of CD19 CAR-T cell therapy

Abstract

Abstract Enhancing the efficacy of CD19 CAR-T cell therapy can significantly improve patient outcomes by reducing relapse rates in CD19 + B cell malignancies. Exogenous or transgenic cytokines are often used to boost the expansion and durability of CAR-T cells but pose risks of severe toxicities. A promising approach to address these limitations is to immobilize cytokines on the surface of CAR-T cells using transmembrane (TM) anchor domains. Given IL-7 can enhance T-cell proliferation and antitumor activity, our study developed membrane-bound IL-7 constructs using different TM anchor domains (CD8, CD28 and B7-1). We primarily found that the CD8 TM provided superior anchoring for IL-7 compared to CD28 and B7-1. Moreover, the IL-7 construct with a CD8 TM (IL7/CD8) enhanced naïve T cell proliferation and effector functions, and improved the in vitro and in vivo antitumor activity of CD19 CAR-T cells. Importantly, although IL7/CD8 could promote T-cell proliferation, it did not sustain long-term autonomous expansion, which could ensure the safety of CD19 CAR-T cells expressing IL7/CD8 in clinical applications. Collectively, the IL7/CD8 construct represents a promising strategy for enhancing the therapeutic potential of CD19 CAR-T cell therapy.

Keywords

• Membrane-bound IL-7
• CD19 CAR-T
• Hematologic malignancy