Imperial College London researchers developed an optimized invariant natural killer T (iNKT) cell immunotherapy that improves anti-tumor activity against multiple myeloma, according to a study published in Nature Communications.
The study evaluated five different chimeric antigen receptor (CAR) endodomains to determine which structure maximizes anti-cancer responses against the blood cancer. Among the five tested designs, BCMA CD28z CAR-iNKT cells exerted the highest anti-myeloma activity and outperformed their conventional CAR-T counterparts. Researchers found this activity is underpinned by increased avidity alongside a cross talk between Plexin D1 on CAR-iNKT cells and Semaphorin 4 A on myeloma cells.
To broaden treatment efficacy, the authors designed and validated a BCMA iNKT-specific engager that produced significant anti-myeloma activity when paired with adoptively transferred iNKT cells. The team also evaluated a dual-target, dual-modality combination using FCRL5 CAR-iNKT cells and BCMA iNKT engagers. This combined regimen outperformed FCRL5 CAR-iNKT therapy alone and limited the immune escape of FCRL5-negative myeloma cells.
Co-lead authors Kanagaraju Ponnusamy and Klesti Karaxhuku conducted the research with collaborators across Imperial College London, the University of Oxford, University of Ioannina Medical School, Hammersmith Hospital, and Lumicks. Funding was provided by Blood Cancer UK, the Kay Kendall Leukaemia Fund, Cancer Research UK, the Imperial UKRI Impact Acceleration award, an MRC UKRI-AstraZeneca Fellowship, and the Imperial NIHR Biomedical Research Centre. Authors Anastasios Karadimitris and Ponnusamy disclosed holding shares or options in Arovella Therapeutics Ltd.
