Abstract Background: Adoptive transfer of engineered natural killer (NK) cells has emerged as a promising strategy for solid and hematologic malignancies; however, the absence of a physiological T-cell receptor (TCR) limits the spectrum of antigens for targeting and prevents recognition of intracellular targets. To address this challenge, we developed a n NK-TCR platform that enables stable expression of fully functional TCRs in NK cells without inducing alloreactivity or GvHD. Using this system, we generated two lead NK-TCR products targeting the intracellular tumor antigens NY-ESO-1 and PRAME, with additional TCRs in development. Methods: Primary human NK cells were engineered to express either an NY-ESO-1-specific TCRα/β receptor or a PRAME TCRα/β receptor recognizing target peptides presented on HLA-A*02:01. Both products incorporated the full CD3 signaling complex (ζ, ε, γ, δ) and a chimeric CD28-CD3ζ costimulatory module, and IL-15 to support activation and in vivo persistence. Each NK-TCR cell product was evaluated independently for in vitro for cytotoxicity, cytokine production, proliferation and serial-killing capacity against multiple tumor cell lines, including Saos-2 (osteosarcoma), A375 (melanoma), U266B1 (multiple myeloma), and THP-1 (AML). Results: NY-ESO-1-TCR NK cells showed potent antigen specific activity, efficiently eliminating Saos-2, A375 and U266B1 cells, with strong cytokine production, sustained serial killing and superior persistence relative to non-transduced NK cells. The PRAME TCR NK cells showed equally strong activity against U266B1, Saos2, and A375 cells. In vivo, NY-ESO-1 TCR NK cells mediated rapid tumor regression and prolonged survival in multiple myeloma xenograft models, with durable persistence and no signs of exhaustion or toxicity. PRAME TCR NK cells achieved similarly superior in vivo activity in a U266B.1 Multiple Myeloma model compared to non-engineered controls. Based on the strength of these findings, NY-ESO-1-TCR NK cells are now under evaluation in multiple myeloma with a separate study in synovial sarcoma, and PRAME TCR NK cells have entered clinical evaluation for AML and melanoma. Together, these data establish NK-TCR platform as a next-generation cellular therapy approach with broad applicability and the capacity to extend NK-cell therapies to intracellular antigen targets. Citation Format: Nadima Uprety, Bin Liu, Rafet Basar, Rejeena Shrestha, Francia Reyes Silva, May Daher, Katayoun Rezvani. NK-TCR cells: A next-generation platform expanding NK-cell therapeutic potential abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4010.
Uprety et al. (Fri,) studied this question.