SUMMARY OF INVENTION
MSK investigators have developed a novel T-cell receptor (TCR) therapy targeting NKD1, a WNT signaling-associated oncofetal antigen presented by HLA-A2 in microsatellite stable (MSS) metastatic colorectal cancer (mCRC). Using a patient-derived colorectal cancer organoid system, researchers identified NKD1-derived peptides that are uniformly expressed across colorectal cancer samples but absent in healthy adult tissue.
The TCR lead candidate demonstrates potent cytotoxic activity against both colorectal cancer cell lines and patient-derived organoids while showing no reactivity against normal tissue. This engineered TCR recognizes tumor-specific peptide-HLA complexes, induces inflammatory cytokine production, and effectively kills cancer cells at low effector-to-target ratios.
The therapy leverages the fetal WNT developmental program that is reactivated during cancer progression and metastasis, providing a shared, scalable target for the majority of MSS mCRC patients. The TCR can be further developed into a cell therapy or a bispecific format.
ADVANTAGES
- First-in-class shared antigen approach: Targets approximately 34% of all MSS mCRC patients (APC-mutant, HLA-A2+).
- Tumor-specific targeting: NKD1 expression is restricted to fetal development and re-expressed in disease, with minimal expression in healthy adult tissues.
- Potent anti-tumor activity: Demonstrates robust cytotoxic activity against multiple patient-derived organoid models and cancer cell lines.
- Favorable safety profile: X-scan data suggests minimal off-target reactivity.
- Combination potential: Can be enhanced with engineered CD8 molecules and may synergize with checkpoint inhibitors.
MARKET OPPORTUNITY
The global market for MSS mCRC represents a significant unmet medical need. With approximately 500,000 new colorectal cancer cases annually in the US and EU, and 22% progressing to metastatic disease, the addressable market for NKD1-TCR therapy includes:
- Initial target population: ~35,000 patients per year (APC-mutant, HLA-A2+, MSS mCRC)
- Expansion opportunities: Additional indications include endometrial cancer, liver cancer, and familial adenomatous polyposis
Currently, no FDA-approved TCR-based therapeutics exist for colorectal cancer, and existing treatments provide minimal survival benefit beyond first-line therapy. NKD1-TCR therapy addresses this critical gap with a novel mechanism targeting the oncogenic WNT pathway.
PATENT INFORMATION
Provisional application filed (Application #63/748,114)
LEAD INVESTIGATORS
- David A. Scheinberg, MD, PhD - Vincent Astor Chair and Chairman, Center for Experimental Therapeutics, Deputy Director for Therapeutic Discovery, Sloan Kettering Institute, MSK
- Karuna Ganesh, MD, PhD - Associate Professor, Gastrointestinal Oncology Service, Director of Metastasis Research, Center for Colorectal Cancer, MSK
- Josh Jaeyop Lee, MD, PhD - Faculty, Cell Therapy Service, MSK
CONTACT INFORMATION
James Delorme, PhD
Senior Licensing Manager
E-mail: [email protected]