CDI Laboratory Zeroes in On Protein Which May Drive Stem Cell Transplant Rejection

A protein which may be a culprit in driving much of the dangerous rejection of stem cell transplants - known as graft-versus-host disease (GVHD) - could soon be a promising target to limit the side effects while keeping cancer immunotherapies effective, according to a new paper by scientists from the Hackensack Meridian Center for Discovery and Innovation (CDI).

Gene-editing Id3, the DNA-binding inhibitor, to make it ineffective could limit GVHD without impacting the effectiveness of cancer treatments, according to the paper in the journal Blood which was co-written by Yi Zhang, M.D., Ph.D., director member of the CDI and its Institute for Immunologic Intervention (3i). The first author of the paper is Ying Wang, Ph.D., an assistant member of the Zhang Laboratory.

“These findings identify that Id3 is an important target to reduce GVHD, and gene-editing program of Id3 may have broad implications in T cell-based immunotherapy,” write the authors. “Id3 represents a unique target to reduce GVHD in the local tissue while preserving anti-tumor activity and avoiding systemic immunosuppression.”

The paper used preclinical models of allogeneic hematopoietic stem cell transplantation to demonstrate that by knocking out, or ablating, Id3, it was restraining the chromatin accessibility for transcription for PD-1, exuberant effector differentiation, and interferon responses and the dysfunction of activated T cells. Taken together, by clipping out Id3, it prevented much of the downstream GVHD effects seen in the control groups.

“This study paves a way to do gene-editing of ID3 for GVHD treatment and improving CAR-T cell efficacy,” said Dr. Zhang, also a professor of medical sciences at the Hackensack Meridian School of Medicine.

“A universal ‘off-the-shelf’ CAR-T cell (treatment) remains a goal: such products can be readily available, provide a more-consistent product, and improved access to the therapy,” adds the paper. “Targeting Id3 in human CAR-T cells may be a potential approach to reduce alloreactivity but retain anti-tumor activity.”