Within the Collaborative Research Centre/Transregio (CRC/TR) 221 innovative immune modulation strategies will be investigated to separate GvHD from GvL effects in order to enhance the safety and efficacy of allo-HSCT in the future.
Allogeneic hematopoietic stem-cell transplantation (allo-HSCT) is a curative treatment option for patients with high-risk leukemia and lymphoma and for some inherited or acquired hematopoietic deficiencies. Around half a million transplantations have been performed to date and approximately 28 million voluntary stem cell donors are currently registered world-wide. The curative potential of allo-HSCT is based on the replacement of the patient´s hematopoiesis by hematopoietic stem cells derived from a healthy donor and the immunologic eradication of residual patient hematopoietic cells by co-transplanted lymphocytes.
The graft-versus-hematopoiesis reaction is mainly mediated by alloreactive donor T cells and affects also malignant hematopoietic cells, thereby evoking potent graft-versus-leukemia / lymphoma (GvL) effects. Although allo-HSCT offers a unique chance to rescue patients with otherwise incurable hematologic malignancies, still around one quarter of allo-HSCT recipients develop disease relapse or progression after transplantation. Thus, there is an urgent need to better understand and ultimately strengthen GvL responses to prevent tumor escape.
GvL-promoting strategies carry the inherent risk of inducing graft-versus-host disease (GvHD), where donor T cells attack and damage non-hematopoietic tissues. The efficient prevention and treatment of severe GvHD is a pivotal prerequisite to benefit from allo-HSCT and its potent GvL effects. Hence, the elucidation of basic mechanisms in tissue-directed graft-versus-host responses is essential to reduce the high treatment-related morbidity and mortality in allo-HSCT. GvHD-free allo-HSCT is then an ideal immunotherapy platform to boost GvL responses for the cure of patients, including those with residual disease or relapse after transplantation.
Within the Collaborative Research Centre/Transregio (CRC/TR) 221 innovative immune modulation strategies will be investigated to separate GvHD from GvL effects in order to enhance the safety and efficacy of allo-HSCT in the future. Briefly, the projects in area A explore T cell redirection tools (i.e. T cell receptors, chimeric antigen receptors, minor histocompatibility antigens, multi-specific antibodies) for the augmentation of hematopoiesis-specific GvL activity, and examine the reactivation of silenced GvL responses by checkpoint inhibition and through enhanced metabolic "fitness" of donor immune cells. The projects in area B investigate cell signaling pathways (i.e. TNFR2, CD28, Wnt, NFAT, IL-7R/Batf/CSF2) and immune regulatory/suppressive cells and networks including regulatory T cells, mesenchymal stromal cells and dendritic cells to prevent and/or treat acute and chronic GvHD. They also study the modulation of GvHD-promoting co-factors such as tissue inflammation, microbiome alterations, epithelial and endothelial damage for effective prophylaxis and therapy of severe GvHD.