Allogeneic hematopoietic stem cell transplantation (HSCT) is a widely used and effective treatment for advanced hematopoietic malignancies. While donor T cells have clearly defined roles in the process of engraftment, eliminating residual disease, and offering immunity, they contribute to graft-versus-host disease (GvHD) and the associated morbidity and mortality. Taking this into consideration, complete T-cell depletion (TCD) can substantially reduce GvHD rates but can also delay immune reconstitution and increase rates of opportunistic infections and relapse.
Here, we summarize a recent podcast from Marie Bleakley, exploring current progress in the use of naïve T cells (TN)-depleted peripheral blood stem cell (PBSC) grafts, recently published in Blood Advances.1
Severe acute and chronic GvHD cause significant morbidity, mortality, disability, and social handicap, following allogeneic HSCT. T cells are central to the pathology of GvHD since donor T cells are activated mostly by intestinal antigen-presenting cells, then proliferate and migrate to epithelial tissues where they release cytokines and mediate direct cytotoxicity.
In HLA-mismatched transplantation, donor T cells recognize different alloantigens, including mismatched HLA molecules/peptide complexes, and polymorphic peptides presented by HLA molecules which are called minor histocompatibility (MHC) antigens.1 By contrast, in HLA-matched transplantation, donor T cells recognize mostly MHC antigens on the surfaces of host cells.1
Although donor T cells cause GvHD in HSCT, they also facilitate engraftment and protect against opportunistic pathogens. A key role of donor T cells, alongside offering resistance to infection and facilitating engraftment, is to mediate the immune attack on residual malignant cells, known as graft-versus-leukemia (GvL) or graft-versus-tumor (GvT). These processes are essential to long-term remission and preventing relapse.
TCD can be achieved by several processes, such as CD34+ cell selection, and has been shown to reduce both acute and chronic GvHD.1 However, previous research has also indicated that complete TCD (pan-TCD) can delay immune reconstitution, and increase rates of opportunistic infections, EBV-posttransplantation lymphoproliferative disease, and relapse. Therefore, current research has moved away from the concept of complete TCD.
T cells can be divided into antigen-inexperienced TN or antigen-experienced T cells, including effector memory T cells (TM). TM populations represent a pool of expanded T cells that are specific for pathogens experienced through prior infection.1 However, murine models have shown that TN are consistently identified as responsible for GvHD, whereas TM subsets, with their restricted T-cell receptor repertoire, cause little or no GvHD while maintaining adequate GvL effects after transplantation.1
Bleakley succinctly summarises studies on murine models that reflect the importance of specific T-cell subsets in the development of GvHD and GvL. It has been shown in mouse experiments, including those with genetically manipulated immune responses, and GvHD models that TN induced GvHD in a consistent and reproducible way. Furthermore, within TM cells, studies have observed different outcomes between effector TM (TEM), which never caused GvHD, and central TM (TCM), which caused only mild GvHD, with it being rarely lethal.1
Bleakley M. et al. undertook in vitro studies, coculturing monocyte-derived dendritic cells from one sibling, with TN and TM from another sibling, finding that minor MHC antigen-specific T cells were up to 20 times higher in the TN than the TM population.1 Expanding T cells from these experiments showed a complete loss of cytotoxic activity in the TM cell lines, but not in the TN, suggesting than TN-depleted grafts may reduce the risk of GvHD.
Further work has established that using anti-CD34 enrichment and anti-CD45RA-depletion processes, has consistently made possible to produce sufficiently large cell numbers for transplant procedures (CD34+ > 5 million/kg, TM of 10 million T cells/kg, and < 50,000 TN/kg).
While summarizing their own clinical experience on trials (NCT00914940) using HSCT with TN-depleted PBSC, in more than 140 patients in total, the authors observed
- a consistent and substantial reduction in chronic GvHD
- low rates of serious acute GvHD
- long GvHD-free, relapse-free survival
These studies established the technical feasibility of TN-depletion for unrelated donor peripheral blood stem cell transplantation (PBSCT), and have demonstrated that lower intensity conditioning is sufficient to ensure PBSC engraftment. The fact that patients still develop GvHD has been partly attributed to the presence of TCM in the TN-depleted PBSC.
Two further trials are currently ongoing, both directly comparing TN-depleted PBSCT with standard unmanipulated HSCT:
- NCT03779854, is a Pediatric Transplantation and Cellular Therapy Consortium, eight-center trial, that randomizes children with leukemia between TN-depleted PBSC and unselected bone marrow transplantation
- NCT03970096, is a multicentre trial for adults or children with leukemia that randomizes patients to one of the following four arms: a) TN-depleted PBSC; b) CD34+-selected PBSC; c) PBSC with post-HSCT cyclophosphamide; d) PBSC with tacrolimus and methotrexate
Bleakley also describes trials on TN-depleted donor lymphocyte infusions (DLI). For example, a phase I trial of CD8+ TN-depleted DLI in patients with relapsed hematological malignancy (NCT01523223); although this is a small trial, of only 15 participants, two patients who achieved complete remission prior to DLI, maintained their remission for a long period, and only one patient developed asymptomatic liver GvHD. Furthermore, another group, at the Duke University Medical Center, Durham, US, published results of a phase I/II trial with 16 patients, where CD45RA-depleted DLI was administered (at a median 113 days) after T cell-depleted hematopoietic cell transplantation (HCT), with reduced conditioning including alemtuzumab or thymoglobulin, which led to acute GvHD in one patient and chronic GvHD in another patient; thus, supporting the potential of TN-depleted DLI as a safe and feasible strategy (NCT00914940).
Clinical trials of TN-depleted HSCT are showing effective engraftment, and low rates of chronic and serious acute GvHD in the HLA-matched setting, and no increased frequency of opportunistic infections. While acute GvHD remains common, it is rarely severe, responsive to steroids, and typically does not evolve into chronic GvHD.
Further randomised controlled trials comparing TN-depleted PBSCT with standard unselected HCT, and with other promising approaches to GvHD reduction, are essential to further define efficacy, safety long-term outcomes, and relapse risk. Work is needed to understand the GvL responses that are retained in TN-depleted HCT with a view to further augmenting GvL in patients at a high-risk of relapse.