Editor’s Note: Hematopoietic stem cell transplantation (HSCT) is an effective, and often the only, curative treatment for malignant hematological diseases such as leukemia. Key steps that impact the success of the transplantation include stem cell engraftment and the reconstitution of immune functions. From April 14 to 17, 2024, the 50th European Society for Blood and Marrow Transplantation (EBMT) annual meeting was grandly held in Glasgow, UK. The conference focused on the latest advancements in stem cell transplantation and cell therapy, driving better clinical outcomes for patients with hematological diseases. At this conference, a team led by Professor Xianmin Song from Shanghai First People’s Hospital presented an oral report titled “VLA-4 Agonists Promote Engraftment and Cellular Immune Reconstitution in Allogeneic Hematopoietic Stem Cell Transplantation,” which garnered widespread attention. Professor Song was specially invited to our live interview room to share the main findings of his research and provide a detailed explanation of the latest developments in the critical steps of allogeneic stem cell transplantation: graft engraftment and immune reconstitution.
“Oncology Frontier – Hematology Frontier”: Engraftment of hematopoietic stem cells is a key step for the success of bone marrow transplantation. Could you discuss the critical factors that influence hematopoietic stem cell engraftment?
Professor Xianmin Song: Hematopoietic stem cell transplantation, particularly allogeneic transplantation, is influenced mainly by three factors: the degree of recipient immune suppression, the dosage of cell infusion, and the extent of recipient bone marrow clearance.
1. Extent of recipient bone marrow clearance: The traditional view holds that the pre-transplant preparatory treatments mainly serve to vacate the bone marrow microenvironment for stem cell engraftment, allowing more space for the donor cells and thus promoting engraftment. The more intense the preparatory treatment, the higher the success rate of allogeneic hematopoietic stem cell engraftment. Compared to reduced intensity or non-myeloablative preparatory treatments, myeloablative treatments lead to higher success rates. Currently, for older transplant patients or those with comorbidities who cannot tolerate intense preparatory treatments, reduced dosage or even non-myeloablative preparatory treatments are used. With non-myeloablative treatments, we observe a decrease in the proportion of patients achieving complete donor chimerism and an increase in partial donor chimerism, with many reports indicating about 40% partial chimerism. This is one aspect of hematopoietic stem cell engraftment that we focus on.
2. Dosage of cell infusion: The greater the dose of infused hematopoietic stem cells, the more it promotes engraftment. However, more is not always better. For example, umbilical cord blood is one source of hematopoietic stem cells for transplantation, and its limited quantity restricts its use in adult patients, thereby affecting engraftment.
3. Degree of recipient immune suppression: The stronger the immune suppression of the recipient, the more it facilitates the engraftment of hematopoietic stem cells. Therefore, the pre-transplant preparatory phase includes immunosuppressive drugs, such as anti-thymocyte globulin (ATG). ATG promotes stem cell engraftment by suppressing recipient immunity. However, if donor T lymphocytes are removed ex vivo, the success rate of engraftment significantly decreases. The reason is that the removal of donor T lymphocytes weakens the immunosuppression against the recipient’s cells, leading to an increased rate of engraftment failure.
“Oncology Frontier – Hematology Frontier”: Could you elaborate on the significance of immune reconstitution after transplantation in bone marrow transplants, and what are the main advancements in early immune reconstitution research?
Professor Xianmin Song: The essence of allogeneic hematopoietic stem cell transplantation lies in its immunotherapy aspect, as the engraftment of hematopoietic stem cells is key to the treatment. After engraftment, the recipient’s immune system must be reconstructed, which is crucial for its anti-tumor effects, especially against malignant tumors. One of the primary reasons transplant patients can survive long-term is that post-transplant immune reconstitution effectively reduces tumor relapse and improves overall survival.
The reconstitution of immunity, especially cellular immunity, after transplantation is a time-consuming process. Haploidentical transplant recipients might experience slower immune reconstitution compared to recipients from matched sibling donors (MSDT), often taking up to a year, and many patients may need two years
or more. Before complete restoration of cellular immunity, patients are in an immunodeficient state, making them susceptible to infections, particularly from viruses and fungi, which can lead to transplantation failure.
From this perspective, how to accelerate post-transplant immune reconstitution, especially cellular immunity, is crucial for improving overall patient survival. However, there is currently a significant lack of safe and effective methods and medications that can promote early immune reconstitution. The clinical approach to accelerating post-transplant immune reconstitution has involved earlier reduction or cessation of immunosuppressants, but this carries a risk of graft-versus-host disease (GVHD). Other strategies, including the use of cytokines, also pose safety concerns. There is a need for more attention and research on early immune reconstitution.
“Oncology Frontier – Hematology Frontier”: Your team presented an oral report at this EBMT meeting. Could you briefly introduce the findings of this study?
Professor Xianmin Song: As discussed, a key aspect of allogeneic stem cell transplantation is the complete engraftment and full immune reconstitution. Our research focuses on these unmet clinical needs, spanning 6-7 years.
We collected samples from some patients and conducted a series of experiments in a mouse model using single-cell transcriptomics. We identified a critical regulatory target that promotes hematopoietic stem cell engraftment—VLA-4. We also discovered a small molecule compound, a VLA-4 agonist, that enhances the engraftment of donor hematopoietic stem cells. Additionally, this agonist accelerates post-transplant cellular immune reconstitution by influencing the differentiation of hematopoietic stem cells into T cells. Moreover, from a biological functional perspective, this reconstructed cellular immunity has antiviral and antitumor effects and does not increase the incidence of graft-versus-host disease.
Our research confirms the significant clinical translational value of VLA-4 agonists. We also look forward to this new drug being applied clinically to address the current challenges of slow post-transplant immune reconstitution and reduced engraftment rates, thereby enhancing the success rate of patient treatments.
Oral Presentation by Professor Xianmin Song’s Team, Dr. He
“Oncology Frontier – Hematology Frontier”: What are the adverse effects of cytomegalovirus (CMV) infection on patients undergoing bone marrow transplantation, and what are the mechanisms?
Professor Xianmin Song: CMV infection is a common post-transplant viral reactivation and infection, related to the incomplete recovery of immune reconstitution after transplantation. CMV reactivation and infection rarely occur in the later stages of immune reconstitution. CMV infection can lead to several adverse outcomes, such as hematopoietic suppression, CMV pneumonia, and CMV retinitis. Currently, there are limited options for antiviral drugs, mainly ganciclovir and foscarnet. Both drugs have different side effects; ganciclovir may cause hematopoietic suppression, while foscarnet may lead to renal damage, limiting their safety. Letermovir, a preventive medication for CMV, effectively reduces the rate of post-transplant CMV infections and activation but also poses a risk of resistance. All these factors can affect patient survival, hence the need for the development of new treatment methods.
“Oncology Frontier – Hematology Frontier”: What are the current methods to combat CMV infection? Circular mRNA (circRNA) technology, referred to as the mRNA 2.0 era, has been receiving significant attention. What are the characteristics and advantages of circRNA-based TCR-T technology compared to traditional anti-infection drugs and other novel anti-infection treatments?
Professor Xianmin Song: The application of novel cell therapies like TCR-T is still in the early stages of research, with a primary focus on post-transplant viral infections, particularly CMV. For CMV treatment, we have explored a new therapy — TCR-T. Post-transplant viral infections are benign diseases, and we use mRNA technology to reduce safety concerns associated with viral transduction. From our technical system, the high safety and transduction efficiency of mRNA are crucial for clinical application.
The advantages of TCR-T in treatment mainly lie in its high specificity and lower required cell dosage, allowing for more efficient control of CMV infection with fewer cells. However, there are limitations, as TCR-T is a cell therapy with high treatment costs (such as manufacturing processes and time), which is an area needing improvement. We plan to research generic TCR-T cell therapies to reduce treatment costs, aiming to address the problem of refractory post-transplant CMV infections. We believe that with the refinement of technology, these issues can be adequately resolved, bringing greater benefits to patients.
Expert Profile
Professor, Chief Physician, PhD Supervisor
Director of the Hematology Department at Shanghai Jiao Tong University Affiliated First People’s Hospital
President of the Hematology Branch of the Shanghai Medical Association
Vice Chair of the Hematological Immunology Committee of the Shanghai Immunology Society
Chairman of the Shanghai Alliance for Hematopoietic Stem Cell Transplantation (ASCT-SH) – First Term
Member of the Hematopoietic Stem Cell Transplantation Group of the Chinese Medical Association Hematology Branch
Member of the Experimental Diagnosis Group of the Chinese Medical Association Hematology Branch
Lead Expert for the National Key Research and Development Program (Stem Cell and Translational Research Key Projects)
Academic Focus: Hematopoietic Stem Cell Transplantation
