Enhancing T cell reconstitution after hematopoietic stem cell transplantation: A brief update of the latest trends

Abstract

Hematopoietic stem cell transplantation (HSCT) is associated with a period of immune incompetence that particularly affects the T cell lineage. Strategies to enhance T cell reconstitution could significantly improve the survival of HSCT recipients by decreasing the incidence of fatal infectious complications and by enhancing graft-versus-tumor activity. In recent years, a variety of promising strategies have been established in preclinical models to improve T cell recovery in particular after allogeneic T cell-depleted HSCT, without aggravating graft-versus-host disease while preserving or even improving graft-versus-tumor activity. These therapies include treatment with keratinocyte growth factor (KGF), growth hormone (GH), LHRH agonists, interleukin 7 (IL-7) and interleukin 15 (IL-15). Thanks to the establishment of Notch-based culture systems, adoptive cellular therapies with T lineage-committed precursor cells have become feasible, since early T cell progenitors can now easily be generated in vitro in large quantities and have been proven to be very effective in enhancing T cell reconstitution and anti-tumor activity after allogeneic T cell-depleted HSCT. The translation of most of these strategies into clinical trials is likely and in some cases Phase I/II studies are already underway.

Cytomegalovirus shapes long-term immune reconstitution after allogeneic stem cell transplantation

“…It is interesting to note that CMV-specific memory T cells cross react with alloantigens 45,46 and have long been suspected to be involved in the pathogenesis of GvHD through molecular mimicry. Finally, although ATG has been reported to influence early immune reconstitution, 20,21,43,44 its role in influencing long-term reconstitution was weak in the present study, possibly because of the late time point considered.…”

“…Chronic GvHD was, as expected, the second major event to shape long-term immune reconstitution. Chronic GvHD has already been reported to influence Band T-cell reconstitution 3,8,9,20,21,43,44 but none of these studies provided a broad overview as allowed here by CA. It is interesting to note that CMV-specific memory T cells cross react with alloantigens 45,46 and have long been suspected to be involved in the pathogenesis of GvHD through molecular mimicry.…”

Long-term immune deficiency after allogeneic stem cell transplantation: B-cell deficiency is associated with late infections

“…After resolution of peri-transplantation neutropenia infections ranged from 40% to nearly 80%. 1 In contrast to the relatively early recovery of innate immunity, all, but especially adult, recipients of an allogeneic hematopoietic stem cell transplantation experience post-transplant deficiencies in B-and T-cell reconstitution. This delay in function recovery may persist for more than one year.…”

“…This delay in function recovery may persist for more than one year. [1][2][3][4] Although the T-cell component of the immune defect has been relatively well defined, the long-term B-cell component is less well known. The majority of current studies focus on immune parameters measured sequentially to one year post-transplant.…”

Inducible T-cell receptor expression in precursor T cells for leukemia control

“…4 Since preTs are still subject to thymic maturation, they develop into fully functional T cells in vivo being tolerant to both donor and recipient. 5 The anti-tumor effects of preTs can be improved by genetically enforced expression of chimeric antigen receptors (CARs). 6 However, their antigen recognition pattern contains a target cell surface antibody-binding domain while many attractive leukemia-specific antigens 7 represent intracellularly-processed antigens that are generally difficult to target by CARs.…”