Evaluation of the efficacy and safety of LILRB3-targeted immunotherapies in preclinical models of human AML

Acute myeloid leukaemia (AML) is a rapidly progressing blood cancer requiring urgent diagnosis and treatment. Leukocyte immunoglobulin-like receptor 3 (LILRB3) is an immunoinhibitory receptor overexpressed on myelomonocytic AML cells and has been proposed as a potential target for AML immunotherapy. Previously engineered monoclonal antibodies (mAb) against LILRB3 were tested for their binding specificity and therapeutic potential. Chimeric antigen receptor (CAR) T adoptive cellular therapy (ACT) represents a promising alternative to conventional treatments that offers advantages such as long-term persistence and reduced long-term toxicity through single-dose infusion. LILRB3 mAbs were engineered on a 2nd generation CAR backbone and their safety and therapeutic potential was investigated. Autologous CAR T cells are patient-specific, posing challenges in manufacturing and patient selection, and can cause off-tumour myelosuppression and cytokine release syndrome. Therefore, we further investigated CAR-engineered iNKT cells as an alternative ACT platform, given their HLA-independent targeting capacity, enabling allogeneic application, and favourable safety profile. Both autologous CAR T cells (engineered from HIS mouse splenocytes) and allogeneic CAR iNKTs (engineered from a human donor) demonstrated a good safety profile. Collectively, these results highlight the crucial role of ectodomain epitope targeting in designing effective immunotherapies against human LILRB3.