SUMMARY OF INVENTION

Memorial Sloan Kettering (MSK) investigators have developed high-affinity T-cell receptors (TCRs) targeting NRAS Q61R, Q61K, and Q61L “public” neoantigens, providing a novel cancer immunotherapy approach for NRAS-mutated cancers when embodied as either a recombinant bispecific T-cell engager or cell therapy product. NRAS mutations occur in ~19% of metastatic cancers and are associated with poor therapeutic responses to current treatments, including immune checkpoint inhibitors and targeted therapies.

Lead TCRs specifically recognize NRAS Q61R, Q61K, and Q61L mutations (>90% of all NRAS Q61 mutations) presented on a highly prevalent HLA allele (HLA-A*01:01). These TCRs were identified through a comprehensive screening platform using patient-derived biospecimens. The technology enables development of “off-the-shelf” TCR redirected T-cell therapies targeting multiple cancer types harboring NRAS mutations.

Significantly, this is a first-in-class approach that targets NRAS driver mutations through validated cross-reactive TCRs. It offers a compelling new therapeutic approach that addresses a patient population lacking effective therapies.

ADVANTAGES

• High avidity, with demonstrated specificity for mutant NRAS peptides.
• Cross-protective TCRs: a subset of TCRs physiologically recognize multiple NRAS Q61 hotspot mutations.
• Validated target expression: Target expression across multiple cancer types has been validated.
• Compatibility with standard protocols: Compatible with standard TCR-T cell manufacturing protocols.
• Multiple modalities: Therapy enables rapid development of TCR-T cell therapies or reformatting into soluble T-cell engagers.
• Manufacturing advantages: Easier to manufacture than personalized approaches, facilitating development of off-the-shelf therapeutics.

MARKET OPPORTUNITY

NRAS mutations present a significant therapeutic target across various high-value cancer indications. The market potential is significant, with NRAS Q61 mutations occurring in cancers such as melanoma, colorectal, thyroid, bladder, lung, and ovarian cancers.

In melanoma, for example, approximately 20% of cases exhibit NRAS mutations, which are linked to a poor response to anti-PD-1 therapy. Thyroid cancer also shows a high prevalence of NRAS Q61 mutations, for which there are limited therapeutic options, while in colorectal cancer, NRAS mutations are associated with resistance to anti-EGFR therapy.

PATENT INFORMATION

US National Application (18/660,551) filed May 2024

LEAD INVESTIGATOR

Christopher A. Klebanoff, MD, Laboratory Head, Immuno-Oncology Program; Associate Attending; MSK

CONTACT INFORMATION

James Delorme, PhD

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