Antigen-dependent IL-12 signaling in CAR T cells promotes regional to systemic disease targeting

• Published in: Nature communications Vol. 14; no. 1; pp. 4737 - 16
• Main Authors: Lee, Eric Hee Jun, Murad, John P., Christian, Lea, Gibson, Jackson, Yamaguchi, Yukiko, Cullen, Cody, Gumber, Diana, Park, Anthony K., Young, Cari, Monroy, Isabel, Yang, Jason, Stern, Lawrence A., Adkins, Lauren N., Dhapola, Gaurav, Gittins, Brenna, Chang, Wen-Chung, Martinez, Catalina, Woo, Yanghee, Cristea, Mihaela, Rodriguez-Rodriguez, Lorna, Ishihara, Jun, Lee, John K., Forman, Stephen J., Wang, Leo D., Priceman, Saul J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07.08.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 631/250/127/1213; 631/250/251; 631/250/2520; 631/61/2296; Animal models; Animals; Anticancer properties; Antigens; Antitumor agents; Cancer; CD28 antigen; Cell Line, Tumor; Cell proliferation; Chimeric antigen receptors; Effectiveness; Effector cells; Female; Glycoproteins; Humanities and Social Sciences; Humans; Immunomodulation; Immunotherapy, Adoptive; Interleukin 12; Lymphocytes; Lymphocytes T; Membranes; Metastases; Mice; multidisciplinary; Ovarian cancer; Ovarian Neoplasms - therapy; Receptors; Receptors, Chimeric Antigen - genetics; Science; Science (multidisciplinary); Solid tumors; Systemic diseases; T-Lymphocytes; Tumor Microenvironment; Xenograft Model Antitumor Assays; Xenotransplantation; γ-Interferon
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-40115-1

Chimeric antigen receptor (CAR) T cell therapeutic responses are hampered by limited T cell trafficking, persistence, and durable anti-tumor activity in solid tumors. However, these challenges can be largely overcome by relatively unconstrained synthetic engineering strategies. Here, we describe CAR T cells targeting tumor-associated glycoprotein-72 (TAG72), utilizing the CD28 transmembrane domain upstream of the 4-1BB co-stimulatory domain as a driver of potent anti-tumor activity and IFNγ secretion. CAR T cell-mediated IFNγ production facilitated by IL-12 signaling is required for tumor cell killing, which is recapitulated by engineering an optimized membrane-bound IL-12 (mbIL12) molecule in CAR T cells. These T cells show improved antigen-dependent T cell proliferation and recursive tumor cell killing in vitro, with robust in vivo efficacy in human ovarian cancer xenograft models. Locoregional administration of mbIL12-engineered CAR T cells promotes durable anti-tumor responses against both regional and systemic disease in mice. Safety and efficacy of mbIL12-engineered CAR T cells is demonstrated using an immunocompetent mouse model, with beneficial effects on the immunosuppressive tumor microenvironment. Collectively, our study features a clinically-applicable strategy to improve the efficacy of locoregionally-delivered CAR T cells engineered with antigen-dependent immune-modulating cytokines in targeting regional and systemic disease. Targeting solid tumours by chimeric antigen receptor (CAR) T cells require strategies that improve trafficking and effector function of these cells in the immunologically hostile cancer microenvironment. Here, authors show that CAR T cells engineered with incorporation of the CD28 transmembrane domain to the 4-1BB costimulatory domain and a membrane-bound form of IL-12 can achieve efficient anti-tumour activity and promote systemic disease targeting via regional T cell delivery in multi-metastatic disease models.