Redesigning CAR therapy to tackle immune effector cell-associated hematotoxicity.

Although recognized, the field has yet to fully explore the mechanisms and solutions to Immune effector Cell-Associated Hematotoxicity (ICAHT) - a major contributor to long term morbidity and mortality following CAR therapy. About 20–40% of the patients develop ICAHT of grade 3 or above, with at least 33% developing late ICAHT across both CD28 and 4-1BB CAR. ICAHT post-CAR therapy influences the effectiveness of the subsequent treatment and incidence of secondary malignancies. Aside from CAR-HEMATOTOX model, N-ICAHT and T-ICAHT grading system is engaged to monitor the neutropenia and thrombocytopenia, respectively. Based on the reported clinical data, the incidence of ICAHT across the FDA-approved CAR T cells distinctly varies, with low baseline blood count with inflammatory mediators being the predisposing factors. Significantly, Stem cell boost therapy was reported to replenish the bone marrow and palliate ICAHT in the clinics. Although dysfunctional stem cell populations and clonal haematopoiesis contribute to the pathophysiology, the detailed cellular and molecular mechanisms of ICAHT remain elusive. IL-18 and Clonally expanded bystander CX3CR1hi cytotoxic T cells expressing high IFN-γ in the CAR T cell formulation is currently attributed to the HSC dysfunction and possibly the hypocellular marrow, with Emapalumab being tested for hematologic complications of CAR therapy. Nonetheless, how impaired clonal hematopoiesis can be resolved by redesigning the CAR configurations and T-cell formulations itself is not yet addressed. We argue that engineering selected CAR configurations on pathogen-specific T cells can be a strategy to palliate ICAHT induced infections. In the light of the emerging real world clinical data, investigating the mechanistic impact of compounding factors such as lympho-depletive therapy regimen and gut microbial populations would further enhance the novel therapeutic combinations to reset healthy hematopoiesis in patients.