Summary: 

Scientists at the National Cancer Institute (NCI) have developed 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) while improving safety. The NCI seeks research co-development partners and/or licensees to advance this technology toward clinical translation. 

Description of Technology: 

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.

The NCI invites industry partners and translational researchers to collaborate or license this technology for the next generation of safer, more effective ACT-based immunotherapies.

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