SUPPLEMENTARY INFORMATION:

ACT offers hope for patients with refractory or metastatic cancers, but effectiveness is frequently undermined by the immunosuppressive tumor microenvironment and T-cell dysfunction. Interleukin-12 (IL-12), a powerful cytokine with strong anti-tumor properties, has long been recognized for its potential to invigorate T-cell responses within tumors. However, systemic administration of IL-12 results in severe toxicity. Further, prior gene therapy strategies failed to provide sufficient control over IL-12 expression. These two factors compromise safety and therapeutic performance.

This invention introduces a Nuclear Factor of Activated T cells (NFAT)-inducible, drug-regulatable, membrane-bound IL-12 (DRIM-IL-12) system that delivers spatiotemporally controlled cytokine expression within the engineered T cell therapy product. This platform ensures IL-12 is expressed only upon T-cell activation. Concurrently, the degron (D) sequence confers lenalidomide-dependent proteasome-mediated degradation—serving as a drug-controlled safety switch to limit systemic toxicity. A transmembrane (TM) domain anchors IL-12 in the plasma membrane, preventing unintended secretion and promoting localized immune modulation. When paired with tumor-specific TCRs or CARs ( e.g., anti-mutant p53 or KRAS TCRs, or CD19 CAR), this platform enhances tumor cell killing and long-term survival in preclinical models. In a mouse model, DRIM-IL-12 demonstrated substantially improved safety compared to the previous generation of NFAT-inducible IL-12. The inventors also demonstrate that DRIM-IL-12 expression can be dialed down or fine-tuned to prevent T-cell exhaustion or differentiation, which can occur with uncontrolled IL-12 expression.

“This Notice is in accordance with 37 CFR 404.4 Authority to grant licenses.”

NIH Reference Number: E-217-2023.

Related Technologies: N/A.

Product Type: Therapeutic.

Therapeutic Area(s): Immunology | Oncology.

Development Stage: Pre-clinical ( in vivo validation).

Publications:

• Kim SP, et al. Drug-regulatable, inducible, and membrane-bound interleukin 12 (IL-12TM-D) for use in adoptive cell therapies against advanced cancers.https://doi.org/​10.1136/​jitc-2024-SITC2024.0344.

Patents: PCT/US2025/031121, filed May 28,2025.

Potential Commercial Applications:

• Solid tumors expressing p53 or KRAS mutations.
• Hematologic malignancies.
• Melanoma.

Competitive Advantages:

• Versatile platform for inducible cytokine regulation.
• Superior survival in mouse models compared with TCR-only T-cells.
• Enhanced tumor cell killing and long-term survival in murine models.
• Decreased IL-12-associated toxicity.
• Maintenance of higher IL-12 expression.
• Improved sensitivity to lenalidomide-mediated degradation.

Collaboration Opportunity: Researchers at the NCI seek licensing and/or co-development research collaborations for developing a novel tightly regulated drug-responsive, membrane-bound IL-12 cytokine platform, that enhances anti-tumor efficacy in adoptive cell therapy (ACT) with engineered T-cells (CAR, TCR, TILs).