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Updated: Jan 14, 2026
Testing Cancer Immunotherapeutics in a Humanized Mouse Model Bearing Human Tumors
Published on: December 16, 2022
Collagen-binding IL-12-armoured STEAP1 CAR-T cells reduce toxicity and treat prostate cancer in mouse models
Koichi Sasaki1, Vipul Bhatia2,3, Yuta Asano4
1Department of Bioengineering, Imperial College London, London, UK.
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-γ 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.
Insights
Chimaeric antigen receptor (CAR)-T cell therapy for solid tumors is improved by fusing interleukin 12 (IL-12) to a collagen-binding domain (CBD). This CBD-IL-12 enhances anti-tumor activity and reduces toxicity, paving the way for clinical translation.
Area of Science:
- Oncology
- Immunotherapy
- Biotechnology
Background:
- Solid tumors present challenges for CAR-T cell therapy due to immunosuppressive microenvironments and antigen heterogeneity.
- Previous attempts to enhance CAR-T cells with immunostimulatory molecules like IL-12 resulted in significant toxicity.
- Targeting solid tumors requires novel strategies to improve CAR-T cell efficacy and safety.
Purpose of the Study:
- To investigate the efficacy and safety of collagen-binding domain-fused IL-12 (CBD-IL-12) armored CAR-T cells for solid tumor treatment.
- To evaluate the retention and activity of CBD-IL-12 within the tumor microenvironment.
- To assess the potential of CBD-IL-12 armored CAR-T cells in combination with immune checkpoint inhibitors for tumor eradication.
Main Methods:
- Development of CAR-T cells engineered to secrete CBD-IL-12 targeting STEAP1.
- Administration of CBD-IL-12 armored CAR-T cells in murine prostate cancer models and 22Rv1 xenografts.
- Assessment of intratumoral cytokine levels, immune cell infiltration, and anti-tumor efficacy.
- Evaluation of toxicity profiles, including hepatotoxicity and off-target organ infiltration.
Main Results:
- CBD-IL-12 secreted by CAR-T cells was retained within murine prostate tumors, increasing intratumoral interferon-γ levels.
- CBD-IL-12 armored CAR-T cells demonstrated potent anti-tumor activity without significant hepatotoxicity or off-target T cell infiltration.
- Combination therapy with CBD-IL-12 armored CAR-T cells and immune checkpoint inhibitors eradicated established prostate tumors.
- Human CBD-IL-12 armored CAR-T cells showed efficacy in a 22Rv1 xenograft model with reduced circulating IL-12 levels.
Conclusions:
- CBD fusion to IL-12 represents a promising strategy to enhance CAR-T cell therapy for solid tumors by improving local retention and reducing systemic toxicity.
- This approach activates both innate and adaptive immune compartments, leading to recognition of diverse tumor antigens.
- CBD-IL-12 armored CAR-T cells, particularly in combination therapy, offer a potential breakthrough for overcoming obstacles in the clinical translation of CAR-T cell therapy for solid tumors.
