Cellular Therapies for the Prevention and Treatment of Acute Graft-versus-Host Disease

Rheumatology and Immunology Hematology Immunology Cell Biology Oncology Life Sciences Medicine
acute graft-versus-host disease allogeneic hematopoietic cell transplantation cellular therapy T-cell depletion mesenchymal stem cells regulatory T cells immunomodulation

Advances in Cellular Therapies for the Prevention and Treatment of Acute Graft-versus-Host Disease (aGVHD) — An Authoritative Review on the Paper “Cellular therapies for the prevention and treatment of acute graft-versus-host disease”

1. Academic Background and Motivation

Acute graft-versus-host disease (aGVHD) is one of the most severe complications following allogeneic hematopoietic cell transplantation (allo-HCT), particularly highlighted in the curative treatment of high-risk hematologic malignancies and certain non-malignant blood disorders. The essence of aGVHD lies in donor immune cells mistakenly attacking patient tissues as “non-self” in the new environment, leading to severe tissue damage, with the most common and dangerous target organs being the gastrointestinal tract, liver, and skin.

Even with the widespread clinical use of various immunosuppressive drugs for prevention and treatment of aGVHD, their efficacy remains limited. About 20%—60% of transplant recipients develop aGVHD, and even after conventional first-line corticosteroid therapy, nearly half will progress to steroid-refractory aGVHD (SR-aGVHD), which has a poor prognosis and significantly increases the subsequent risk of chronic GVHD (cGVHD), severely affecting patient survival and quality of life. This predicament has driven the scientific community to urgently seek newer, more effective, mechanism-based, and less toxic preventive and therapeutic strategies.

Against this background, cellular therapy has drawn widespread attention as an emerging approach for treatment and prevention. Traditional drugs suppress donor T cells in a non-specific manner, but this leads to slow immune reconstitution, diminished anti-infective and anti-leukemia ability, and increased risks of infection and leukemia relapse. The new generation of cellular therapies aims to optimize the composition of donor grafts, precisely remove pro-GVHD cellular subsets, enrich immunomodulatory cells, and even “adoptively transfer” exogenous immunoregulatory cells, thereby achieving both GVHD control and maximal preservation of anti-leukemia and anti-infection capability — an approach termed “precision immune modulation.”

2. Source of the Paper and Authors

This is a review article titled “Cellular therapies for the prevention and treatment of acute graft-versus-host disease,” authored by experts Daniel Peltier (Indiana University, USA), Van Anh Do-Thi, Timothy Devos (KU Leuven, Belgium), Bruce R. Blazar (University of Minnesota, USA), and Tomomi Toubai (Yamagata University and Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Japan), among others. The paper was published March 21, 2025, in the authoritative journal Stem Cells, volume 43, issue 6, 2025. This invited review systematically examines recent progress in cellular therapy for aGVHD prevention and treatment.

3. Key Contents and Core Viewpoints of the Paper

(1) Review Structure and Focus

  1. Review of aGVHD pathogenesis and latest mechanistic discoveries
  2. Summary of traditional and emerging cellular therapies/graft optimization methods
  3. Detailed assessment of research and clinical advances on multiple cellular therapies (mesenchymal stem cells, regulatory T cells, myeloid-derived suppressor cells, etc.)
  4. Indication of future directions and challenges

Below, each core viewpoint and its scientific evidence is explained in detail by topic.

(2) New Advances in the Pathogenesis of aGVHD

1. Classical Three-Stage Model

The occurrence of aGVHD can be generally divided into a “three-stage model”: Stage one involves tissue damage caused by pre-transplant sequential chemotherapy or radiotherapy, releasing damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs), activating the host’s innate immunity; Stage two is where donor T cells are recognized by host or donor antigen-presenting cells (APCs), get activated, and massively proliferate/differentiate into cytotoxic and inflammatory effector T cells (Teffs); Stage three sees these Teffs migrate and attack the recipient’s GI tract, liver, skin, and other target organs.

2. Protective Mechanisms Within/Outside Target Organs

  • Gastrointestinal “tissue tolerance” mechanisms — Intrinsic processes within intestinal epithelial cells (IECs) such as inhibition of apoptosis, autophagy, inflammasomes (e.g., NLRP6/NLRP3), β-catenin signaling, mitochondrial metabolism, and secretion of local protective factors (e.g., IL-22, IFN-λ, antimicrobial peptides, mucus, etc.), all participate in regulating the severity of target organ injury during aGVHD.
  • Crucial role of the gut microbiome — Pre-transplant dysbiosis increases the risk of GVHD; multiple post-transplant factors (antibiotic use, immune reactions, etc.) further exacerbate “loss of microbial diversity,” thereby mediating GVHD progression. Different microbial metabolites (short-chain fatty acids, bile acids, indoles) also have positive or negative regulatory effects on GVHD.

3. Cellular Pathogenic Factors

  • Donor naïve T cells are most likely to induce aGVHD, while memory T cells, regulatory T cells (Tregs), and certain NK cells are actually protective.
  • γδ T cells, myeloid-derived suppressor cells (MDSCs), specific dendritic cell (DC) subtypes, and macrophages also play key roles in initiation or mitigation of GVHD.

(3) Evolution and New Advances in Cellular Therapies

1. Ex Vivo Donor Graft Engineering

  • Since the 1980s, global T-cell depletion (TCD) has been utilized to prevent GVHD, but due to delayed immune reconstitution and high infection/relapse rates, the method has been gradually optimized.
  • Currently, clinical strategies tend to “selectively remove pro-GVHD cell subsets and preserve or enrich beneficial populations.” Major approaches include:
    • CD45RA+ (naïve T cell) depletion: Using immunomagnetic beads to first enrich CD34+ hematopoietic stem cells, followed by selective depletion of CD45RA+ T cells, which maximally reduces GVHD-inducing sources while retaining memory and some Treg/other beneficial cells. Bleakley et al., with three phase II trials, confirmed extremely low rates of GVHD (grade III 4%, grade IV 0%, chronic GVHD only 7%), with overall survival and relapse not inferior to traditional approaches, and antitumor/anti-infection capacity preserved.
    • Combined removal of TCRαβ T cells/CD19+ B cells: This removes the major “culprit” αβT cells for GVHD, and reduces EBV-related lymphoproliferative risk (via CD19+ depletion), especially suited for high-risk matched/haploidentical transplants, though relapse risk needs attention.
    • “Orca-T” and “Orca-Q” precision engineered grafts: By precisely controlling the ratio of donor Tregs, conventional T cells, and hematopoietic stem cells, early clinical trials show effective reduction in GVHD and improved survival/quality of life, representing a trend toward individualized and precise donor graft engineering.

2. Emerging Adoptive Cellular Therapies

  • There is an urgent need for new therapies for steroid-refractory GVHD. The following summarizes clinical advances in mesenchymal stem cells (MSCs), regulatory T cells (Tregs), etc.:

    • Mesenchymal stem cell (MSC) therapy: Derived from bone marrow, adipose, umbilical cord, placenta, etc., these possess multipotency, self-renewal, and immunosuppressive properties. Their main mechanisms include being phagocytosed by macrophages to generate IDO (indoleamine 2,3-dioxygenase) resulting in immunosuppressive metabolites; directly suppressing donor T cells, inhibiting APCs, inducing M2 macrophage polarization, promoting Treg differentiation and releasing immunoregulatory factors (IL-10, TGF-β, PGE2, etc.). Multicenter studies show efficacy for SR-aGVHD but with variable results, due to lack of standardized manufacturing, source differences, and dosing. Meta-analysis reveals overall response rate of about 67%, CR 39% (response closely related to MSC dose), and more pronounced effect for GI SR-aGVHD. Recent iPSC-derived MSC products have shown feasibility and safety in clinical trials.
    • Regulatory T cell (Treg) adoptive therapy: Tregs (CD4+Foxp3+CD25hi) are natural inhibitors of aGVHD; their deficiency or dysfunction promotes GVHD. Early clinical studies of Treg infusion show it is safe, feasible, and effective for aGVHD prevention, with no apparent increase in tumor relapse. Future challenges include large-scale production of Tregs, maintaining purity and preventing non-Treg contamination, determining rational dosing, and avoiding post-infusion Treg death or dysfunction.
    • Type 2 innate lymphoid cell (ILC2) therapy attempts: Still at the animal experiment stage, but shown to mitigate aGVHD by activating MDSCs and secreting IL-13.

  • Additionally, the article briefly discusses prospects and challenges for new-generation gene-modified cell therapies, such as CAR-T/TCR-engineered cells and CAR-Treg/NK/macrophages, in GVHD prevention and treatment.

(4) Scientific Value and Practical Significance of Cellular Therapies and Engineering Approaches

1. Scientific Significance

aGVHD pathogenesis is complex; traditional prevention/treatment strategies rely on “broad immunosuppression,” but face loss of anti-infection/antitumor function and raised relapse rates. Cellular therapies and precision graft engineering are innovative for their “immune-selective regulation”—precisely targeting pathogenic T cell subsets plus enrichment of regulatory cells, so as to maximally lower GVHD while retaining graft-versus-leukemia (GvL) and immune defense, fitting with the trend toward personalized and precision medicine. The article’s systematization of mechanisms and clinical data provides a theoretical foundation for future innovations and new therapy development.

2. Clinical and Applied Value

The article details the gradual realization of large-scale manufacturing of engineered donor grafts, and the fact that adoptive cell therapies (especially MSCs) have become a standard second-line choice in many countries, bringing new hope to patients with refractory/high-risk aGVHD. In the future, gene-edited CAR cells and combinatorial engineered cell transplants may completely reshape the clinical landscape of allo-HCT.

(5) Highlights and Innovations of the Review

  • Comprehensive summary of aGVHD immunopathogenesis and new insights, emphasizing non-classical factors such as the microenvironment, microbiome, and host tissue tolerance
  • Systematic review of current mainstream graft engineering and adoptive cellular therapy clinical workflows, key milestones, and landmark results at home and abroad, covering next-generation precision engineering (e.g., CD45RA/TCRαβ targeted depletion, Orca-T/Q, etc.)
  • Robust demonstration of efficacy and limitations of these methods, drawing on recent international multicenter/prospective trial data
  • Prospective outlook on how gene-edited cell therapies may revolutionize future aGVHD prevention and treatment

4. Value and Impact of the Paper

This review stands as an authoritative guide in the current field of aGVHD cellular therapy, providing clinicians, scientists, pharmaceutical and biotech companies with theoretical and empirical support for novel prevention, treatment, and research innovation. Its arguments are well-linked, from pathogenesis and target selection to cell product engineering and real-world clinical application, offering important references for promoting collaboration across industry, academia, and research, accelerating translational research, facilitating multidisciplinary integration, and advancing international cooperation and standardized practice in the future.

In addition, the article reminds readers to pay attention to current limitations (such as dependence on high-intensity conditioning, insufficient long-term follow-up data, etc.), calls for larger samples, standardized protocols, and collaborative mechanism exploration, and emphasizes that only the organic integration of engineered cells and molecular new drugs can eventually bring significant long-term improvements in outcomes for allo-HCT recipients.

“Cellular therapies for the prevention and treatment of acute graft-versus-host disease” provides a comprehensive, in-depth, and forward-looking scientific analysis for mechanism research, cellular therapy innovation, and future clinical translation, and is one of the most important academic papers in the field of aGVHD and allogeneic transplantation clinical practice.