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Background Aims: Allogeneic hematopoietic stem cell transplant is a curative approach for many malignant and non-malignant hematologic conditions. Despite advances in its prevention and treatment, the morbidity and mortality related to graft-versus-host disease (GVHD) remains. The mechanisms by which currently used pharmacologic agents impair the activation and proliferation of potentially alloreactive T cells reveal pathways essential for the detrimental activities of these cell populations. Importantly, these same pathways can be important in mediating the graft-versus-leukemia effect in recipients transplanted for malignant disease. This knowledge informs potential roles for cellular therapies such as mesenchymal stromal cells and regulatory T cells in preventing or treating GVHD. This article reviews the current state of adoptive cellular therapies focused on GVHD treatment., Methods: We conducted a search for scientific literature in PubMed® and ongoing clinical trials in clinicaltrial.gov with the keywords "Graft-versus-Host Disease (GVHD)," "Cellular Therapies," "Regulatory T cells (Tregs)," "Mesenchymal Stromal (Stem) Cells (MSCs)," "Natural Killer (NK) Cells," "Myeloid-derived suppressor cells (MDSCs)," and "Regulatory B-Cells (B-regs)." All the published and available clinical studies were included., Results: Although most of the existing clinical data focus on cellular therapies for GVHD prevention, there are observational and interventional clinical studies that explore the potential for cellular therapies to be safe modalities for GVHD treatment while maintaining the graft-versus-leukemia effect in the context of malignant diseases. However, there are multiple challenges that limit the broader use of these approaches in the clinical scenario., Conclusions: There are many ongoing clinical trials to date with the promise to expand our actual knowledge on the role of cellular therapies for GVHD treatment in an attempt to improve GVHD-related outcomes in the near future., Competing Interests: Declaration of Competing Interest JJB: Consulting: Avrobio, BlueRock, Race Oncology, Advanced Clinical, Omeros, Sanofi, Medexus, Equillium, Sobi. AA: served on the safety monitoring committee for Sangamo Therapeutics and has no financial interest in the development of gene therapies. SP: Receives support for the conduct of clinical trials through MSK from AlloVir, Atara, and Jasper. Inventor of IP related to development of third-party viral-specific T cells program with all rights assigned to MSK. CB: Consulting: Zodiac, Amgen, Novartis. SC: ExCellThera: royalties, consulting, shares. DP: Novartis – honoraria, Gilead – honoraria, BMS-Celgene – honoraria, Jazz – honoraria, All honoraria were paid to the author's institution (Fiona Stanley Hospital), not the author. AS: Consultant: Spotlight Therapeutics (2020), Medexus Inc. (2021), Vertex Pharmaceuticals (2021). Research Funding: CRISPR Therapeutics (2021-2022). Honoraria: Vindico Medical Education (2020). Research Collaboration: Magenta Therapeutics (2021-Present). Clinical Trial site-PI: CRISPR Therapeutics (2018-Present), Vertex Pharmaceuticals (2018-Present), Novartis (2019-Present), Magenta Therapeutics (2021-Present). MP-D: Equity: GraphiteBio., (Published by Elsevier Inc.)

Ex vivo CD34 + -selected T cell depletion (TCD) has been developed as a strategy to reduce the incidence of graft-versus-host disease (GVHD) after allogeneic (allo) hematopoietic stem cell transplantation (HSCT). Clinical characteristics, treatment responses, and outcomes of patients developing acute (aGVHD) and chronic GVHD (cGVHD) after TCD allo-HSCT have not been well established. We evaluated 241 consecutive patients (median age, 57 years) with acute leukemia (n = 191, 79%) or myelodysplastic syndrome (MDS) (n = 50, 21%) undergoing CD34 + -selected TCD allo-HSCT without post-HCST immunosuppression in a single institution. Cumulative incidences of grades II-IV and III-IV aGVHD at 180 days were 16% (95% confidence interval [CI], 12 to 21) and 5% (95% CI, 3 to 9), respectively. The skin was the most frequent organ involved, followed by the gastrointestinal tract. Patients were treated with topical corticosteroids, poorly absorbed corticosteroids (budesonide), and/or systemic corticosteroids. The overall day 28 treatment response was high at 82%. The cumulative incidence of any cGVHD at 3 years was 5% (95% CI, 3 to 9), with a median time of onset of 256 days (range, 95 to 1645). The 3-year transplant-related mortality, relapse, overall survival, and disease-free survival were 24% (95% CI, 18 to 30), 22% (95% CI, 17 to 27), 57% (95% CI, 50 to 64), and 54% (95% CI, 47 to 61), respectively. The 1-year and 3-year probabilities of cGVHD-free/relapse-free survival were 65% (95% CI, 59 to 71) and 52% (95% CI, 45 to 59), respectively. Our findings support the use of ex vivo CD34 + -selected TCD allograft as a calcineurin inhibitor-free intervention for the prevention of GVHD in patients with acute leukemia and MDS., (Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Allogeneic hematopoietic cell transplants adequately depleted of T-cells can reduce or prevent acute and chronic GVHD in both HLA-matched and haplotype-disparate hosts, without post-transplant prophylaxis with immunosuppressive drugs. Recent trials indicate that high doses of CD34+ progenitors from G-CSF mobilized peripheral blood leukocytes isolated and T-cell depleted by immunoadsorption to paramagnetic beads, when administered after myeloablative conditioning with TBI and chemotherapy or chemotherapy alone can secure consistent engraftment and abrogate GVHD in patients with acute leukemia without incurring an increased risk of a recurrent leukemia. Early clinical trials also indicate that high doses of in vitro generated leukemia-reactive donor T-cells can be adoptively transferred and can induce remissions of leukemia relapse without GVHD. Similarly, virus-specific T-cells generated from the transplant donor or an HLA partially matched third party, have induced remissions of Rituxan-refractory EBV lymphomas and can clear CMV disease or viremia persisting despite antiviral therapy in a high proportion of cases. Analyses of treatment responses and failures illustrate both the advantages and limitations of donor or banked, third party-derived T-cells, but underscore the potential of adoptive T-cell therapy in the absence of ongoing immunosuppression.