Hematopoietic Stem Cell Transplantation (HSCT)

HSCT provides donor stem cells that reach the bone marrow and thymus, engraft and repopulate a functional immune system. Mocravimod in combination with HSCT sequesters donor-derived mature alloreactive T cells in bone marrow, lymph nodes and other secondary lymphoid organs.

The sequestration of alloreactive donor T-cells has two highly beneficial effects:

  1. Graft-versus-Host Disease (GvHD) is reduced as the alloreactive donor T cells do not migrate to peripheral tissues
  2. The retained alloreactive donor T-cells in the lymphoid organs, specifically the bone marrow, eliminate residual malignant leukemic cells that escape conditioning or chemotherapy.

A. No Treatment

Following allogeneic HSCT, alloreactive donor T-cells migrate to secondary lymphoid organs, where they are activated and proliferate. Activated alloreactive donor T-cells are capable of killing leukemic cells through a process called graft-versus-leukemia (GvL). Alloreactive donor T-cells express S1PR1 on their surface. ,Signalling through this receptor regulates egress from secondary lymphoid organs to the peripheral tissues, such as the gut, skin, liver and lung. Through allo-recognition of their target tissue, donor T cells can cause inflammation and tissue damage resulting in graft-versus-host disease (GvHD).

B. Immunosuppressant 

Reduced GVHD at the expense of reduced GvL

Immunosuppressive drugs are used for the prevention and treatment of GvHD. However, T-cell suppression is non-specific and therefore the beneficial GvL reaction is also suppressed. Reduced GvL bears the risk of increased relapse and limits the successful outcome of allogeneic HSCT. In conclusion, GvHD is suppressed at the expense of also suppressing GvL.

 

Suppression of all donor T cells:

 GvL

GvHD

B. Immunosuppressant 

Reduced GvL

Immunosuppressive drugs are used for the prevention and treatment of GvHD. However, T-cell suppression is non-specific and therefore the beneficial GvL reaction is also suppressed. Reduced GvL bears the risk of increased relapse and limits the successful outcome of allogeneic HSCT. In conclusion, GvHD is suppressed at the expense of also suppressing GvL.

Suppression of allo donor T cells

 GvL

GvHD

 

C. Mocravimod 

Maintained GvL while reducing GVHD

Mocravimod, a pharmacological modulator of S1PR signaling, blocks the signal required by T-cells to migrate from the secondary lymphoid organs to the periphery, but does not suppress T cell function. Consequently, fewer alloreactive donor T cells migrate to peripheral tissues, resulting in reduced tissue damage and GvHD. The beneficial GvL effect, however, is maintained as the T cells remain functional, and thuscontinue to efficiently kill leukemic cells. In conclusion, GvL is maintained while GvHD is suppressed.

 

Allo donor T cells retained in lymphoid tissue
Co-localisation with leukemic cells
No T cell suppression:
 GvL

GvHD