Enhancing iNKT cell immunotherapy through the integration of optimized CAR endodomains and iNKT engagers
Abstract
Abstract iNKT cells are emerging as a highly promising immunotherapy platform for the treatment of cancer. To maximise the anti-cancer activity of CAR-iNKT against the blood cancer multiple myeloma we investigated optimal CAR designs and their combination with new iNKT-specific engagers. We find that amongst five different CAR endodomains, underpinned by increased avidity and a cross talk between Plexin D1 on CAR-iNKT and Semaphorin 4 A on myeloma cells, BCMA CD28z CAR-iNKT exert the highest anti-myeloma activity. Notably, CD28z CAR-iNKT outperform their CAR-T counterparts. To expand the anti-myeloma potential of CAR-iNKT, we designed and validated a high efficacy BCMA iNKT-specific engager which exerts significant anti-myeloma activity in conjunction with adoptively transferred iNKT cells. Finally, combined, dual target therapy with FCRL5 CAR-iNKT and BCMA iNKT engagers outperforms FCRL5 CAR-iNKT and limits immune escape of FCRL5-negative myeloma. Thus, optimised iNKT-based, dual-target, dual-modality immunotherapy has enhanced anti-tumor activity against multiple myeloma and potentially other malignancies.
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Authors: Kanagaraju Ponnusamy, Klesti Karaxhuku, Yuchao Jiang, Lyra Randzavola, Hongwei Ren, Ilia Leontari, Bryan Lye, Mehmood Zaidi, Edward Bartlett, Edward W. Tate, Vasileios Pardalis, Dimitrios Leonardos, Reza Nadafi, Irene Sarkar, Rogier M. Reijmers, Marco Bua, Maria Atta, Alexia Katsarou, Irene AG Roberts, Aristeidis Chaidos, Anastasios Karadimitris
Institutions: Imperial College London, University of Oxford, University of Ioannina, Imperial College Healthcare NHS Trust, Hammersmith Hospital