SUMMARY OF INVENTION

MSK investigators have developed novel switch receptor arrays that significantly enhance CAR T-cell activity by delivering “on-demand” tumor necrosis factor receptor superfamily (TNFRSF) signaling to overcome treatment resistance and immune evasion. 

With applicability to both approved hematologic products and emerging solid tumor programs, multi-switch receptor arrays offer a platform solution to enhance virtually any CAR T-cell therapy encountering tumor-mediated immune suppression.

The technology features engineered switch receptors that convert inhibitory tumor signals into stimulatory ones:

• CD200R-CD27 switch receptor: Converts CD200-mediated inhibition into CD27 costimulation.
• PD-1-OX40 switch receptor: Transforms PD-L1 suppression into OX40 activation.

When integrated into CAR-T cells using MSK’s Zip Sorting System, these multi-switch CAR T cells demonstrate superior NFκB signaling, enhanced T-cell expansion, and improved in vivo anti-leukemia activity. Notably, the switch receptors create a compensatory feedback system: CD200R-CD27 and PD-1-OX40 attenuate the CD200 and PD-L1 upregulation caused by FasBB signaling, resulting in balanced and sustained T-cell activation.

ADVANTAGES

• Converts inhibition to activation: Transforms major tumor immune evasion mechanisms (CD200, PD-L1) into pro-survival and costimulatory signals.
• Self-regulating system: Switch receptors create negative feedback loops that prevents excessive inflammatory responses while maintaining therapeutic activity.
• Broad tumor coverage: Simultaneously addresses multiple immune checkpoint pathways used by diverse cancer types.
• Validated efficacy: Demonstrated robust survival rates in preclinical models with challenging antigen-loss escape and inhibitory ligand combinations.
• Safety profile: Multi-switch systems show enhanced activity without the toxicity associated with constitutively active receptors.

MARKET OPPORTUNITY

CAR T-cell therapies face significant resistance from tumor immune evasion strategies, with many patients experiencing treatment failure due to immunosuppressive signals including CD200, PD-L1, and FasL expression by cancer cells. This technology addresses a critical unmet need across the CAR T-cell market by converting the most common immune checkpoint mechanisms into therapeutic advantages.

PATENT INFORMATION

PCT patent application filed January 2024 (PCT/US2024/010502)

LEAD INVESTIGATOR

• Scott James, MD, PhD, Assistant Clinical Professor, Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center (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