Enhancing iNKT cell immunotherapy through the integration of optimized CAR endodomains and iNKT engagers
- Kanagaraju Ponnusamy
- Klesti Karaxhuku
- Yuchao Jiang
- Lyra Randzavola
- Hongwei Ren
- Ilia Leontari
- Bryan Lye
- Mehmood Zaidi
- Edward J. 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
2026-08-14
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.