Location, location, location: fighting hematological malignancies by trapping T cells in lymphoid tissue

A crucial factor that determines the effectiveness of HSCT in AML is whether the patient develops graft-versus-leukemia, in which transplanted alloge- neic T cells attack and eliminate host leukemic cells (Fig. 1). Notably, the beneficial alloreactive T cells responsible for GvL are the same T cells that medi- ate GvHD. However, despite the fact that GvL and GvHD are driven by the same cells, they manifest in different parts of the body. GvL mainly occurs in lymphoid tissues, such as bone marrow and lymph nodes, where the malignant hematological cells reside. GvHD, by contrast, occurs throughout the body after donor T cells become activated by anti- gen-presenting cells and migrate out of lymphoid tissues to the gastrointestinal tract, liver, lung, and skin, where they attack host cells.

HSCT would be much more effective, and less prone to severe side effects, if alloreactive T cells remained in lymphoid tissues, mediating GvL but unable to attack the rest of the body to elicit GvHD.

This is mocravimod’s mode of action, which has been shown in a clinical proof-of-concept study. Mocravimod, a propane-1,3-diol derivative, is a novel, synthetic sphingosine 1-phosphate receptor (S1PR) agonist with a long half-life in the body. Delivered as a prodrug during and after HSCT, mocravimod is phosphorylated in vivo to generate the active moi- ety, mocravimod phosphate, which binds to S1PR, a receptor that plays a crucial role in lymphocyte trafficking from lymphoid tissues to peripheral blood.

By interfering with S1PR signalling, mocravimod sequesters donor T cells in lymphoid tissue, but with- out affecting their cytotoxic, leukaemia-cell-killing power, which facilitates the emergence of disease- eliminating GvL. At the same time, because the allore- active T cells cannot leave lymphoid tissues to attack other tissues within the body, the potential for GvHD is greatly reduced.