Abstract 4087: Co-expression of membrane bound IL-15 enhanced anti-tumor response of CAR-T
Authors: Yang Cuiqing , Jiang Fuwei , Wang Yifang , Liu Tingting , Wang Chao , Wang Qingyang , Wang Qin , Ye Gang , Tang Renhong , Cao Zhuoxiao 
Published: April 2023

Introduction: Chimeric antigen receptors (CARs) T cells have been used successfully to treat patients with hematologic malignancies, but showed less effective in solid tumors. We investigated multiple approaches to engineer and enhance CAR-T activity in solid tumors. It has been previously reported that improvement in the quality of CAR-T cells, through CAR design or manufacturing optimization, could enhance the therapeutic potential of CAR-T cells. One parameter influencing the effectiveness of CAR-T cell therapy is the differentiation status of the final product: CAR-T cells that are less-differentiated and less exhausted are more therapeutically potent. It is well known that IL-2 is the main cytokine used to culture cells for adoptive cell therapy, as it plays an important role in the proliferation and functional effect of T cells. However, it has been noted T cells cultured with IL-2 are phenotypically heterogeneous, being predominantly composed of effector memory cells. In comparison with IL2, IL-15 can induce a memory stem-like T cell phenotype, which is less differentiated and with a superior capacity for cell expansion and survival. Several groups reported that compared with cells cultured with IL-2, CAR-T cells expanded with IL-15 preserve a less-differentiated stem cell memory (Tscm) phenotype and exhibited reduced expression of exhaustion markers, higher antiapoptotic properties, increased proliferative capacity upon antigen challenge, and promoted superior anti-tumor responses in vivo.

Method: To provide localized IL-15 mediated signaling to T cells, we constructed a version of IL-15 as a membrane-bound molecule (mIL-15) designed to stimulate T cells in cis and in trans, and mIL-15 is tethered to the cell surface and functions locally to enhance the functionality of the CAR-T cell without systemic delivery of IL-15.

Result: Expression of mbIL-15 is shown to enhance T cell expansion, preserve a less-differentiated Tscm phenotype and prevent CAR-T cell exhaustion, leading to longer persistence and an enduring anti-tumor response over the conventional CAR-T cells.

Conclusion: We demonstrate that CAR-T activity and persistence can be enhanced by simultaneous expression of mIL-15, which preserves the CAR-T cell Tscm phenotype and improves their metabolic fitness, resulting in superior antitumor activity. These preclinical data support the notion that CAR-T cells are designed and optimized to persist in the hostile tumor microenvironment and potentially improve efficacy against solid tumors.

Citation Format: Cuiqing Yang, Fuwei Jiang, Yifang Wang, Tingting Liu, Chao Wang, Qingyang Wang, Qin Wang, Gang Ye, Renhong Tang, Zhuoxiao Cao. Co-expression of membrane bound IL-15 enhanced anti-tumor response of CAR-T. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4087.