Armed with IL-2 based fusion protein improves CAR-T cell fitness and efficacy against solid tumors

• Published in: Biochimica et biophysica acta. Molecular basis of disease Vol. 1870; no. 5; p. 167159
• Main Authors: Li, Sijin, Xia, Yifei, Hou, Rui, Wang, Xu, Zhao, Xuan, Guan, Zhangchun, Ma, Wen, Xu, Yutong, Zhang, Wei, Liu, Dan, Zheng, Junnian, Shi, Ming
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.06.2024
• Subjects: Adoptive cellular immunotherapy; Animals; Antigens, Neoplasm - genetics; Antigens, Neoplasm - immunology; Cell engineering; Cell Line, Tumor; Cytokine; Humans; Immunotherapy, Adoptive - methods; Interleukin-2 - genetics; Interleukin-2 - immunology; Mice; Neoplasms - genetics; Neoplasms - immunology; Neoplasms - therapy; Receptors, Chimeric Antigen - genetics; Receptors, Chimeric Antigen - immunology; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - immunology; T cell; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Tumor microenvironment; Tumor Microenvironment - immunology; Xenograft Model Antitumor Assays; Adoptive cellular immunotherapy; Tumor microenvironment; T cell; Cell engineering; Cytokine
• ISSN: 0925-4439; 1879-260X; 1879-260X
• DOI: 10.1016/j.bbadis.2024.167159

Chimeric antigen receptor T (CAR-T) cell therapy is regarded as a potent immunotherapy and has made significant success in hematologic malignancies by eliciting antigen-specific immune responses. However, response rates of CAR-T cell therapy against solid tumors with immunosuppressive microenvironments remain limited. Co-engineering strategies are advancing methods to overcome immunosuppressive barriers and enhance antitumor responses. Here, we engineered an IL-2 mutein co-engineered CAR-T for the improvement of CAR-T cells against solid tumors and the efficient inhibition of solid tumors. We equipped the CAR-T cells with co-expressing both tumor antigen-targeted CAR and a mutated human interleukin-2 (IL-2m), conferring enhanced CAR-T cells fitness in vitro, reshaped immune-excluded TME, enhanced CAR-T infiltration in solid tumors, and improved tumor control without significant systemic toxicity. Overall, this subject demonstrates the universal CAR-T cells armed strategy for the development and optimization of CAR-T cells against solid tumors. •IL2m-CAR-T cells exhibit augmented proliferation in response to antigenic stimulation.•IL2m-CAR-T cells augment in vitro fitness including reduced exhaustion and improved memory characteristic of CAR-T cells.•IL2m-CAR-T cells promote TME remodeling including regulating PD-1 CD8+ T cells, NK, Treg and M2 macrophage.•IL2m-CAR-T cells have superior proliferation and antitumor activity in murine tumor models.