Lymphodepletion chemotherapy in chimeric antigen receptor-engineered T (CAR-T) cell therapy in lymphoma

Abstract

The development of chimeric antigen receptor (CAR) T-cells, engineered from peripheral T-lymphocytes of a patient with lymphoma, in order to specifically target tumor cells, has been a revolution in adoptive cell therapy (ACT). As outlined in this review, ACT was initiated by hematopoietic cell transplantation (HSCT) and re-injection of interleukin-boosted tumor-infiltrating lymphocytes (TIL). The innovative venture of genetically modifying autologous peripheral T-cells to target them to cell-surface tumoral antigens through an antibody-derived structure (i.e. independent of major histocompatibility antigen presentation, physiologically necessary for T-cell activation), and intracytoplasmic T-cell costimulatory peptides, via a novel membrane CAR, has been an outstanding breakthrough. Here, focusing on B-cell hematological malignancies and mostly non-Hodgkin lymphoma, attention is brought to the importance of providing an optimal microenvironment for such therapeutic cells to proliferate and positively develop anti-tumoral cytotoxicity. This, perhaps paradoxically, implies a pre-infusion step of deep lymphopenia and deregulation of immunosuppressive mechanisms enhanced by tumoral cells. Fludarabine and cyclophosphamide appear to be the most efficient lymphodepletive drugs in this context, dosage being of importance, as will be illustrated by a thorough literature review.

Fig. 1. Schematic representation of the effects of lymphodepletion (1) on tumor cells and their immune microenvironment before CAR T-cells infusion (2).

Lymphodepletion (LD), primarily consisting of combined fludarabine and cyclophosphamide (FluCy), is administered to induce changes in host cells and the microenvironment. The key effects of LD are: a Elimination of endogenous immune cells (T regs and probably NK cells); enhancing the recognition of tumor antigens by mature dendritic cells (DC) and M1 macrophages. b Induction of immunogenic cell death in tumor cells, which includes the downregulation of 2,3-dioxygenase (IDO), an enzyme that can suppress immune responses. c Improved availability of homeostatic cytokines (IL-7, IL-15, IL-21), which are crucial for survival and proliferation of transferred donor T cells. The final impact will induce the expansion of CAR T-cells (3).