Concise Review: Boosting T-Cell Reconstitution Following Allogeneic Transplantation-Current Concepts and Future Perspectives

Abstract

Allogeneic hematopoietic stem cell transplantation (HSCT) is the treatment of choice for a large number of malignant and nonmalignant (inherited) diseases of the hematopoietic system. Nevertheless, non-HLA identical transplantations are complicated by a severe T-cell immunodeficiency associated with a high rate of infection, relapse and graft-versus-host disease. Initial recovery of T-cell immunity following HSCT relies on peripheral expansion of memory T cells mostly driven by cytokines. The reconstitution of a diverse, self-tolerant, and naive T-cell repertoire, however, may take up to 2 years and crucially relies on the interaction of T-cell progenitors with the host thymic epithelium, which may be altered by GvHD, age or transplant-related toxicities. In this review, we summarize current concepts to stimulate reconstitution of a peripheral and polyclonal T-cell compartment following allogeneic transplantation such as graft manipulation (i.e., T-cell depletion), transfusion of ex vivo manipulated donor T cells or the exogenous administration of cytokines and growth factors to stimulate host-thymopoiesis with emphasis on approaches which have led to clinical trials. Particular attention will be given to the development of cellular therapies such as the ex vivo generation of T-cell precursors to fasten generation of a polyclonal and functional host-derived T-cell repertoire. Having been tested so far only in preclinical mouse models, clinical studies are now on the way to validate the efficacy of such T-cell progenitors in enhancing immune reconstitution following HSCT in various clinical settings. Stem Cells Translational Medicine 2019;00:1-8.

Keywords: Cellular therapy; Hematologic malignancies; Hematopoietic stem cell transplantation; Immune reconstitution; Immunodeficiency; T-cell; Thymus.

Figure 1

Strategies to accelerate T‐cell reconstitution following allogeneic‐hematopoietic stem cell transplantation (HSCT). Immunological consequences of allogeneic HSCT are depicted in blue boxes. The differential strategies to overcome immunodeficiency following allogeneic‐HSCT are shown on the left in green. Their respective impact on the reconstitution of the T‐cell repertoire is shown on the right side of the diagram.

Figure 2

Ex vivo generation of human T lymphoid progenitors (HTLPs). (A): Human T‐cell development. (B): Experimental protocol for the 7‐day generation of CD7+ T‐cell precursors (=HTLPs) from hematopoietic stem and precursor cells (HSPCs) by coculture with an immobilized Notch ligand DL4 and a cocktail of cytokines. Specifically, CD34+ hematopoietic stem and progenitor cells are seeded on day 0 in culture wells coated with immobilized DL‐4/Fc fusion protein and Retronectin. After addition of cytokines (IL7, TPO, FLT‐3, and SCF) cells are cultured for 7 days with medium change at day 3. HTLPs on day 7 display an early ETP/pro‐T differentiation phenotype as shown by expression of CD7 and downregulation of CD34.