Unedited allogeneic iNKT cells show extended persistence in MHC-mismatched canine recipients
Antonia Rotolo, Eoin C. Whelan, Matthew J. Atherton, Irina Kulikovskaya, Danuta Jarocha, Joseph A. Fraietta, Michele M. Kim, Eric S. Diffenderfer, Keith A. Cengel, Martina Piviani, Enrico Radaelli, Raimon Duran‐Struuck, Nicola J. Mason
Abstract
Allogeneic invariant natural killer T cells (allo-iNKTs) induce clinical remission in patients with otherwise incurable cancers and COVID-19-related acute respiratory failure. However, their functionality is inconsistent among individuals, and they become rapidly undetectable after infusion, raising concerns over rejection and limited therapeutic potential. We validate a strategy to promote allo-iNKT persistence in dogs, an established large-animal model for novel cellular therapies. We identify donor-specific iNKT biomarkers of survival and sustained functionality, conserved in dogs and humans and retained upon chimeric antigen receptor engineering. We reason that infusing optimal allo-iNKTs enriched in these biomarkers will prolong their persistence without requiring MHC ablation, high-intensity chemotherapy, or cytokine supplementation. Optimal allo-iNKTs transferred into MHC-mismatched dogs remain detectable for at least 78 days, exhibiting sustained immunomodulatory effects. Our canine model will accelerate biomarker discovery of optimal allo-iNKT products, furthering application of MHC-unedited allo-iNKTs as a readily accessible universal platform to treat incurable conditions worldwide.