An international collaboration of researchers, including Imperial College London and UCLA, has developed a collagen-binding interleukin 12 strategy that lets CAR-T cells treat prostate cancer in mice while curbing previously encountered cytokine-related toxicity.
Blood cancer successes for CAR-T therapy have not fully carried over to solid tumors, where immunosuppressive microenvironments and antigen heterogeneity restrict infiltration.
Interleukin 12 (IL-12) can drive anti-tumor immunity by inducing cytokines (IFN?) that reduce tumor growth and enhance chemokine signaling. Excessive levels of IFN? can drive strong pro-inflammatory responses and are associated with chronic inflammatory and autoimmune disorders, where the immune system attacks healthy tissues. Clinical application of IL-12 has been limited by severe dose-dependent immune toxicities.
Previous attempts to introduce IL-12 delivery by tumor-reactive T cells produced high-grade hepatotoxicity in early trials, pointing to a potential delivery problem beyond the IL-12 payload issue.
In the study, “Collagen-binding IL-12-armoured STEAP1 CAR-T cells reduce toxicity and treat prostate cancer in mouse models,” published in Nature Biomedical Engineering, researchers engineered cell protein STEAP1-targeted CAR-T cells to secrete an IL-12 variant fused to the von Willebrand factor A3 collagen-binding domain, aiming to tether IL-12 within the tumor stroma, lowering systemic exposure.
Single-chain IL-12 variants carried a von Willebrand factor A3 collagen-binding domain at the N terminus, C terminus, or both. This allows the IL-12 to tether to collagen within the tumor stroma, restricting its diffusion and concentrating cytokine activity in the local tumor environment.
Results show IL-12 armored with STEAP1 CAR-T cells increased lysis of hSTEAP1-positive targets and elevated IFN? in vitro. In a mouse tumor model, single collagen-binding domain-IL-12-armored CAR-T cells delayed growth and produced complete responses in a subset of mice. Intratumoral IL-12 was higher and serum IL-12 lower with collagen-binding domain fusion, consistent with a retention in the tumor and reduced off-target leakage.
The two-collagen-binding domain (both termini) variant had poor expression in primary mouse T cells and underperformed in vivo.
Monotherapy with collagen-binding domain-IL-12 CAR-T cells achieved an 80% complete response rate. Combination therapy initiated against larger established tumors yielded 80% to 100% complete responses depending on treatment timing, without weight loss and with lower serum IFN? than the unmodified IL-12 combo.
The authors conclude that collagen-binding IL-12 secretion from STEAP1 CAR-T cells localizes cytokine activity, strengthens innate and adaptive anti-tumor responses, reduces hepatic and off-target T cell toxicities in mouse prostate cancer models.
The redesigned treatment has the potential to apply CAR-T therapy to solid tumors while minimizing systemic IL-12 exposure and possibly reducing reliance on chemotherapy pre-conditioning.
Written for you by our author Justin Jackson, edited by Sadie Harley, —this article is the result of careful human work. We rely on readers like you to keep independent science journalism alive.
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More information:
Koichi Sasaki et al, Collagen-binding IL-12-armoured STEAP1 CAR-T cells reduce toxicity and treat prostate cancer in mouse models, Nature Biomedical Engineering (2025). DOI: 10.1038/s41551-025-01508-3
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