Reducing GVHD Following Transplant in Lymphoma

While allogenic hematopoietic stem cell transplants (ASCT) is curative, it is associated with complications of relapse and graft-versus-host disease (GVHD). Researchers from the Memorial Sloan Kettering Cancer Center (MSKCC) have developed a novel method using modified donor T cells ways to make stem cell transplants both safer and more effective for treating blood cancers.

Led by Marcel van den Brink, MD, PhD, head of the Division of Hematologic Oncology and co-director of the Parker Institute for Cancer Immunotherapy at MSKCC, and Michel Sadelain, MD, PhD director of the Center for Cell Engineering at MSKCC, this preliminary research suggests that genetically engineered immune cells from a donor cause less GVHD than unmodified donor immune cells.

A bone marrow transplant is often the last, best chance at a cure for people with advanced blood cancers. But the procedure is not without risks. The most significant risk is GVHD, when donor white blood cells attack healthy tissues in the recipient. In severe cases, it can be fatal.

CD19, a protein expressed on the surface of normal as well as malignant B cells, has been used in chimeric antigen receptor (CAR) T-cell treatments. Allogeneic CAR-T cells can increase the risk of the occurrence of GVHD, although this has not been reported in selected patients infused with donor-derived CD19 CAR T cells after ASCT. To better understand the mechanism whereby allogeneic CD19 CAR T cells may mediate anti-lymphoma activity without increasing the incidence of GVHD, the team at MSKCC studied donor-derived CD19 CAR T cells in ASCT and lymphoma models in mice. Specifically, the model used CD19-specific CD28z CARs.

The data showed that alloreactive T cells expressing CD19-specific CD28z CARs undergo cumulative activation in response to dual-specificity T cell receptor and CAR signaling, resulting in loss of T cell function and the possible deletion of these cells. Presence of CD19+ targets can mediate the inhibition of the potential of m1928z t cells to cause GVHD.

The clinical implications of these results are that relapse following a bone marrow transplant (BMT) can be safely and effectively treated with CAR modified donor T cells instead of unmodified T cells, which is the existing standard treatment in these patients. The authors are planning a phase I study of using donor-derived CAR T cells to prevent relapse after BMT is being planned and is scheduled to open at MSK later this year.

Reference

Ghosh A, Smith M, James SE, et al. Donor CD19 CAR T cells exert potent graft-versus-lymphoma activity with diminished graft-versus-host activity [published online January 9, 2016]. Nat Med. doi: 10.1038/nm.4258.