Elsevier

Blood Reviews

Volume 43, September 2020, 100669
Blood Reviews

Review
Can we prevent or treat graft-versus-host disease with cellular-therapy?

https://doi.org/10.1016/j.blre.2020.100669Get rights and content

Abstract

Acute and chronic graft-versus-host disease (GvHD) are the most important causes of treatment-related morbidity and mortality after allogeneic hematopoietic cell transplants for various diseases. Corticosteroids are an effective therapy in only about one-half of affected individuals and new therapy options are needed. We discuss novel strategies to treat GvHD using cellular-therapy including adoptive transfer of regulatory T-cells (Tregs), mesenchymal stromal cells (MSCs), cells derived from placental tissues, invariant natural killer T-cells (iNKTs), and myeloid-derived suppressor cells (MDSCs).These strategies may be more selective than drugs in modulating GvHD pathophysiology, and may be safer and more effective than conventional pharmacologic therapies. Additionally, these therapies have not been observed to substantially compromise the graft-versus-tumor effect associated with allotransplants. Many of these strategies are effective in animal models but substantial data in humans are lacking.

Introduction

Acute and chronic graft-versus-host disease (GvHD) account for 15–20% of transplant-related deaths and substantial morbidity after allogeneic hematopoietic cell transplantation (allotransplant) for various diseases [[1], [2], [3], [4]]. Therapeutic options are limited. Initial therapy for acute and chronic GvHD is usually corticosteroids [4]. Response rates are only about 50% and response durations are typically brief. Several drugs are reported to be effective in patients not responding to corticosteroids but most data are unconvincing [2,[5], [6], [7]].

We discuss novel strategies to treat acute and chronic GvHD using cellular-therapies which influence immune function and GvHD biology. Our review is based on a comprehensive electronic search from several databases to evaluate cellular-therapy products used to prevent or treat GvHD. We address adoptive cellular-therapies including mesenchymal stromal cells (MSCs), regulatory T-cells (Tregs), cells derived from placental tissues, myeloid-derived suppressor cells (MDSCs) and invariant natural killer T-cells (iNKTs).

Section snippets

Literature search

The PubMed database was searched for English language articles. Medical subject headings (MeSH) including ‘cell-’, ‘cellular-’, ‘tissue-based therapy’ and ‘graft-versus-host disease’ were cross-referenced in the search which was supplemented with a manual search of PubMed, Ovid Medline, Google Scholar, and Cochrane databases. Further manual searching was carried out by reviewing the articles listed in the references of the articles obtained from the primary search.

Results

Our electronic search yielded many cellular- and tissue-based therapies used to prevent and treat acute and chronic GvHD. Proposed mechanisms of action of these therapies vary and are complex. The general aspects of these modalities are depicted in Table 1.

Discussion and future considerations

Preventive and therapeutic interventions for acute and chronic GvHD are rapidly changing with many new approaches being tested [81,82]. So far no pharmacologic approach is convincingly better than current drugs [83,84]. Ruxolitinib is reported active in corticosteroid-refractory acute and chronic GvHD in a retrospective, uncontrolled multi-center study [85]. Based on findings from the phase II REACH1 trial, ruxolitinib gained US FDA approval for corticosteroid-refractory acute GvHD in 2019 [86,

Practice points

  • MSCs are the most extensively studied cellular-therapy for GvHD and can easily be harvested from multiple tissue sources and expand easily in vitro. Currently, MSCs are not FDA-approved for GvHD treatment in the US, but are routinely used in other regions such as Europe and Canada. MSCs show encouraging findings in the therapeutic and prophylactic settings, and their safety is well established, though published randomized trial data are still very limited.

  • MAPCs are another class of adult

Research agenda

  • Although encouraging results are reported with the cellular-therapies, these data are from small, uncontrolled, single-center studies thus future research should focus on randomized studies comparing these novel therapies with standard of care.

  • Approval of cellular-therapy products is subject to regulatory requirements of different country specific regulatory organizations. Registration procedures differ tremendously in different countries. Trials need to be designed with advice from the

Acknowledgments

None.

Decloration of Competing Interest

RPG is a part-time employee of Celgene Corp.

SKH has received an honorarium from Mallinckrodt, Janssen, Pfizer, and Novartis for educational presentations.

HML is a consultant at Pluristem Therapeutics, Inc.

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