Sasaki et al. addressed the toxicity of IL-12 that has caused dose-limiting immune-related adverse events (irAEs). Compared to unmodified IL-12, fusing a collagen-binding domain to IL-12 (CBD–IL-12) improved the potency of CAR T cells targeting STEAP1 in both mouse and human prostate cancer models by (1) enhancing intratumoral IFNγ levels and IL-12 retention in the TME, and (2) reducing irAEs, such as hepatotoxicity and T cell infiltration into non-target organs. In an established mouse prostate tumor model, CBD–IL-12 armored CAR T cells combined with checkpoint inhibitors showed strong antitumor efficacy, and extended survival with immune memory.
Contributed by Katherine Turner
ABSTRACT: Immunosuppressive microenvironments, the lack of immune infiltration, and antigen heterogeneity pose challenges for chimaeric antigen receptor (CAR)-T cell therapies applied to solid tumours. Previously, CAR-T cells were armoured with immunostimulatory molecules, such as interleukin 12 (IL-12), to overcome this issue, but faced high toxicity. Here we show that collagen-binding domain-fused IL-12 (CBD-IL-12) secreted from CAR-T cells to target human six transmembrane epithelial antigen of prostate 1 (STEAP1) is retained within murine prostate tumours. This leads to high intratumoural interferon-_ levels, without hepatotoxicity and infiltration of T cells into non-target organs compared with unmodified IL-12. Both innate and adaptive immune compartments are activated and recognize diverse tumour antigens after CBD-IL-12-armoured CAR-T cell treatment. A combination of CBD-IL-12-armoured CAR-T cells and immune checkpoint inhibitors eradicated large tumours in an established prostate cancer mouse model. In addition, human CBD-IL-12-armoured CAR-T cells showed potent anti-tumour efficacy in a 22Rv1 xenograft while reducing circulating IL-12 levels compared with unmodified IL-12-armoured CAR-T cells. CBD fusion to potent payloads for CAR-T therapy may remove obstacles to their clinical translation towards elimination of solid tumours.
Author Info: (1) Department of Bioengineering, Imperial College London, London, UK. (2) Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, USA. Division of Hematology/Oncology,
Author Info: (1) Department of Bioengineering, Imperial College London, London, UK. (2) Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, USA. Division of Hematology/Oncology, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. (3) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA, USA. (4) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA, USA. (5) Department of Bioengineering, Imperial College London, London, UK. (6) Department of Bioengineering, Imperial College London, London, UK. (7) Department of Bioengineering, Imperial College London, London, UK. (8) Department of Bioengineering, Imperial College London, London, UK. (9) Department of Bioengineering, Imperial College London, London, UK. (10) Department of Microbiology, Immunology and Molecular Genetics, UCLA, Duarte, CA, USA. (11) Department of Bioengineering, Imperial College London, London, UK. (12) Department of Bioengineering, Imperial College London, London, UK. (13) Department of Bioengineering, Imperial College London, London, UK. (14) Department of Bioengineering, Imperial College London, London, UK. (15) Division of Hematology/Oncology, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. (16) Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, USA. Division of Hematology/Oncology, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. (17) Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USA. Department of Immuno-Oncology, Beckman Research Institute of City of Hope, Duarte, CA, USA. (18) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA, USA. Division of Medical Oncology, University of Washington, Seattle, WA, USA. (19) Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, USA. jklee@mednet.ucla.edu. Division of Hematology/Oncology, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. jklee@mednet.ucla.edu. Parker Institute for Cancer Immunotherapy at UCLA, Los Angeles, CA, USA. jklee@mednet.ucla.edu. (20) Department of Bioengineering, Imperial College London, London, UK. j.ishihara@imperial.ac.uk. Exploratory Oncology Research and Clinical Trial Center (EPOC), National Cancer Center, Chiba, Japan. j.ishihara@imperial.ac.uk.
