SUMMARY OF INVENTION

MSK investigators have developed a novel platform of vector-encoded NFAT and NFκB inhibitors that significantly enhance CAR T-cell therapy by addressing two critical barriers: T-cell exhaustion and treatment-related toxicity. 

The technology employs engineered calcineurin/NFAT antagonist peptides, including optimized VIVIT mutants (Vmut1-5) with enhanced affinity, that prevent upregulation of exhaustion markers PD-1 and LAG-3. Complementary NFκB inhibitors using degradation-resistant NFKBIAm effectively reduce cytokine release syndrome (CRS) and other toxicities. 

Key innovations include:

• Drug-regulated control: DHFR-DD and FKBP-DD fusion systems enable optional drug-controlled expression.
• Smart feedback circuits: NFAT and NFκB-inducible negative feedback loops provide self-regulating, graded inhibition.
• Modular design: Compatible with leucine zipper sorting technology and enables multi-CAR formats.

In preclinical studies, NFAT inhibition improved T-cell persistence, enhanced anti-leukemia activity, and significantly extended survival. NFκB inhibition prevented lethal dual-4-1BB CAR toxicity while retaining partial therapeutic efficacy.

ADVANTAGES

• Dual-mechanism platform: Simultaneously addresses T-cell exhaustion (NFAT) and treatment toxicity (NFκB)—the the two primary limitations of current CAR T-cell therapies.
• Tunable and controllable: Drug-regulated and feedback systems allow precise modulation without constant cellular modification.
• Maintains therapeutic efficacy: NFAT inhibitors preserve target cell killing while reducing exhaustion; NFκB inhibitors reduce toxicity with partial activity retention.
• Broad compatibility: Works across first-, second-, and third-generation CAR designs; integrates with existing manufacturing workflows.
• Validated biological rationale: Targets well-characterized pathways with demonstrated roles in T-cell dysfunction and inflammatory toxicity.

MARKET OPPORTUNITY

The rapidly expanding CAR T-cell therapy market faces critical challenges that limit patient access and treatment success. With many patients experiencing disease relapse due to T-cell exhaustion, and others suffering from cytokine release syndrome, there is an urgent need for platform technologies that enhance both safety and efficacy. These technologies address these fundamental barriers across the CAR T-cell market, positioning them as potential enablers for the next generation of cell therapies.

PATENT INFORMATION

PCT patent application filed January 2024 (PCT/US2024/010515)

LEAD INVESTIGATOR

• Scott James, MD, PhD, Assistant Clinical Professor, Department of Hematology & Hematopoietic Cell Transplantation, City of Hope (formerly at MSK)
• Marcel van den Brink, MD, PhD – President, City of Hope Los Angeles and City of Hope National Medical Center (formerly at MSK)

CONTACT INFORMATION

James Delorme, PhD

Senior Licensing Manager
E-mail: delormej@mskcc.org