Hematopoietic stem cell transplantation and cellular therapy

Abstract

Allogeneic stem cell transplantation is a form of immunotherapy that has increased the chances of survival for patients with relapsed leukemia and high risk leukemia in remission. The major obstacles are graft-vs-host disease (GVHD) involving vital organs and infections. A most efficacious prophylaxis of GVHD is by depleting of T cells from the graft. However, problems of T-depleted transplants are rejection, slow recovery of the immune system and high incidence of relapse of leukemia and myeloma. The major problem of allogeneic transplantation is the separation of a graft-vs-leukemia (GVL) effect from GVHD. This review will summarize the factors influencing GVHD, ways to exploit rapid advances in our knowledge of histocompatibility, chimerism and tolerance for fostering GVL over GVHD, and in particular the use of cellular therapies including donor lymphocyte infusions for disease control.

Cells to prevent/treat relapse following allogeneic stem cell transplantation

“…However, relapse-free survival has been achieved in 20% to 45% of the select group that can undergo a second HSCT. 11,12 As with the first transplant, complications include treatment-related mortality, infection, GVHD, and relapse, 3,13 with higher risks after second HSCT such that nonrelapse mortality can exceed 40%. 5 Factors such as favorable performance status, longer duration of remission after first HSCT, minimal disease status at time of second HSCT, and younger age have all been associated with improved outcomes.…”

“…13,17,21-23 T-cell receptors from allogeneic donor leukemia-reactive CTLs can be cloned into autologous T cells for management of posttransplant relapse. 13 Notably, expanded g-d T cells have been shown to be reactive against cytomegalovirus and leukemia blasts, raising the possibility that adoptive cell therapy could be used to reduce the risk of both posttransplant cytomegalovirus reactivation and leukemia relapse. 24 This type of cellular therapy has been shown to be feasible, safe, and, in some cases, effective.…”

“…3 DLI can be used either as treatment, or more optimally in a prophylactic or preemptive manner for mixed chimerism and/or presence of MRD. 13 Combination approaches have been used to try to improve the results of DLI, for example, a-interferon and other cytokines to augment GVL, lymphodepletion, targeted agents, and checkpoint inhibitors. 3,5,13,16 The primary complication of DLI is GVHD.…”

“…13 Combination approaches have been used to try to improve the results of DLI, for example, a-interferon and other cytokines to augment GVL, lymphodepletion, targeted agents, and checkpoint inhibitors. 3,5,13,16 The primary complication of DLI is GVHD. Methods designed to reduce the risk of or reverse GVHD include chemotherapy, immunosuppressive medications, and the use of selected T-cell subsets and/or modified T cells (eg, suicide gene insertion) as the DLI product.…”

“…Unmanipulated, unselected DLI is a well-established therapy in the management of posttransplant relapse, 13 and many newer cellular therapies have been judged in relationship to outcomes from DLI and second HSCT. 5 The efficacy of DLI is limited by high disease burden and proliferative rate and also possibly by immune escape mechanisms underlying relapse.…”