Exploration and practice: New integration of cellular therapy and hematopoietic stem cell transplantation

Since the first hematopoietic stem cell transplantation (HSCT) in 1956, HSCT has served as a cellular-level transplantation treatment that has cured tens of thousands of patients with hematologic diseases.[1] HSCT primarily eradicates leukemia cells through myeloablative conditioning chemotherapy and the graft-versus-leukemia (GVL) effect, with subsequent developments such as donor lymphocyte infusion (DLI) and microtransplantation emerging as additional therapeutic methods.[2] However, traditional HSCT and related treatments still have certain limitations. First, the tumor-killing capacity of preconditioning regimens based on high-dose chemotherapy/total body irradiation is limited by safety concerns, especially regarding the eradication of leukemia stem cells, which is a major cause of patient relapse.[3] Second, traditional immunosuppressants, while preventing or treating graft-versus-host disease (GVHD), also inhibit the GVL effect. Managing GVHD, relapse, and infections solely through immunosuppressive drugs makes it difficult to achieve an ideal balance. Furthermore, there are currently no effective methods for addressing poor posttransplant engraftment and transplant-related endothelial injury complications.[4] The success of chimeric antigen receptor (CAR)-T cell therapy has ushered cellular therapy into a new era. The rapid development of gene editing technologies and the deepening understanding of immune mechanisms have endowed cellular therapy with stronger antitumor capabilities. In the treatment of hematologic diseases, CAR-T cell therapy, along with other immune cell therapies, plays a pivotal role in inducing remission and can even rescue patients who have not responded to HSCT under certain conditions. However, confirmatory clinical trials have revealed that immune cell therapy still faces challenges such as high relapse rates and off-target effects that require further treatment.[5] In addition to immune cell therapy, advancements in cell identification and sorting technologies have led to the development of stem cell therapies, represented by mesenchymal stem cells (MSCs), which are not limited by human leukocyte antigen (HLA) compatibility and can be used for a variety of autoimmune diseases.[6] Stem cell-based therapies involving MSCs also show promise in the treatment and prevention of complications such as poor engraftment and GVHD.[7] This article reviews the exploration and practice of new models that combine cellular therapy with HSCT [Figure 1].Figure 1: Integration of cell therapy with hematopoietic stem cell transplantation. CAR: Chimeric antigen receptor; EPC: Endothelial progenitor cell; GVHD: Graft-versus-host disease; HSCT: Hematopoietic stem cell transplantation; iPSC: Induced pluripotent stem cell; MSC: Mesenchymal stem cell; NK: Natural killer; TME: Tumor microenvironment.Role of immune cell therapy in transplantation Traditional autologous hematopoietic stem cell transplantation (ASCT) primarily achieves tumor cell killing through high-dose chemotherapy, and the reinfusion of autologous stem cells does not generate new antitumor effects. Early adoptive cell therapies aimed to enhance the antitumor effects of T cells or natural killer (NK) cells through cocultivation with tumor cells and cytokine stimulation in vitro, but their overall efficacy is limited. The advent of CAR-T cell therapy has changed this landscape, enabling autologous T cells to enhance their antitumor potency through specific antigen–antibody recognition. CAR-T cells have become a powerful force in the treatment of refractory and relapsed B cell hematologic malignancies.[5] In China, CAR-T cell therapy has been approved for the treatment of refractory and relapsed B cell non-Hodgkin lymphoma (B-NHL), acute B cell lymphoblastic leukemia (B-ALL), and multiple myeloma (MM).[8] Current clinical studies comparing second-line treatment options of ASCT vs. CAR-T cell therapy for B cell lymphomas have demonstrated certain advantages of CAR-T cell therapy. However, owing to target limitations, immune cell therapy also faces relapse issues, and combining immune cell therapy with HSCT represents a promising strategy for addressing refractory and relapsed hematologic tumors. Combining ASCT with CAR-T cell therapy can significantly improve outcomes in high-grade lymphomas and adverse prognoses associated with TP53 mutations.[9] While there is debate regarding the use of HSCT (allo-HSCT) after achieving complete remission, several studies have demonstrated an improvement in survival resulting from bridging to allo-HSCT for patients with relapsed/refractory (R/R) B-ALL.[10] Similarly, CAR-T cell therapy can achieve remission in hematologic malignancies that relapse post-HSCT.[11] Furthermore, universal cell therapies, such as CAR-NK and CAR-macrophages, which have relatively weaker antitumor effects and expansion capabilities than T cells do, can be combined with HSCT for effectiveness.[12] In addition to the additive antitumor effects, combining HSCT and CAR-T cell therapy can further reduce the side effects of each treatment. For acute myeloid leukemia (AML)-targeted CAR-T cell therapy, since most effective targets are expressed on hematopoietic stem cells (HSCs), HSCT is an effective approach to address severe bone marrow suppression following related treatments.[13] CAR-T cells targeting B cells have also been proven effective in treating autoimmune diseases, and preclinical trials are investigating CAR-T and T cell receptor (TCR)-T cell therapies for GVHD post-HSCT.[14] Additionally, owing to the high infection rates in patients post-HSCT, virus-specific T cell (VST) therapies targeting cytomegalovirus (CMV) and Epstein–Barr virus (EBV) have been clinically validated.[15] CAR-T cell therapies with higher specificity for viral and fungal infections are also in development, ensuring better protection for HSCT patients.[16,17] Integration of stem-cell based with HSCT GVHD The primary challenge in managing complications of allogeneic HSCT, particularly haploidentical HSCT (haplo-HSCT), lies in balancing GVHD with GVL effects when immunosuppressants are used. Conventional immunosuppressive agents, while suppressing GVHD, simultaneously increase the risks of relapse and infection. Given the variability among patients, the dosage of immunosuppressants for prevention and treatment is difficult to control, making the imbalance between GVHD and GVL challenging to resolve. In the context of HSCT, completely removing donor T cells significantly reduces the risk of acute and chronic GVHD. However, this also significantly increases the risk of relapse. Currently, the exploration of transplant components is a key defense in enhancing transplant efficacy. Cell therapy has also played an important role in managing GVHD. Multiple clinical studies have demonstrated that MSCs can reduce and treat GVHD while preserving GVL effects without significant toxic side effects.[18–21] MSCs have been approved as a second-line treatment for acute GVHD. Our center pioneered the use of MSCs for the prevention of chronic GVHD, demonstrating that the infusion of MSCs 100 days post-transplant effectively prevents chronic GVHD, particularly in the case of pulmonary chronic GVHD with a poor prognosis.[22] Recent studies have also shown that early infusion of MSCs (45 days post-transplant) can significantly reduce the incidence of severe chronic GVHD without impacting relapse rates, thereby improving GVHD-free relapse-free survival (GRFS). However, several meta-analyses have suggested that the efficacy of MSC treatment is inconsistent, and factors such as the MSC source, infusion dosage, and timing significantly affect outcomes due to MSC heterogeneity.[7] This variability is a major point of contention in stem cell-based therapy. The pluripotency of stem cells results in a complex mechanism of action, making outcomes less consistent than those of traditional drugs. Nonetheless, current clinical research suggests that MSCs are beneficial for reducing the incidence of GVHD without increasing the risk of relapse. Professor Liu’s team at Nanfang Hospital has enhanced the efficacy of MSC treatment by combining MSCs with monoclonal antibody drugs. In addition to preventing and treating GVHD, MSCs play crucial supportive roles in the normal hematopoietic microenvironment.[23] Amniotic sac stem cells have also been shown to have therapeutic effects on acute GVHD.[24] Graft failure (GF) occurs when the transplanted stem cells do not successfully establish themselves in the recipient’s body, leading to a lack of sustained hematopoietic function. Research has demonstrated that co-infusion of MSCs with HSCs can promote hematopoietic reconstruction and assist in platelet recovery.[25,26] Clinical studies have shown that the use of MSCs in combination with HSCs significantly increases the engraftment rate in patients who experience GF. Endothelial progenitor cells (EPCs), precursors to endothelial cells, are also crucial components of the hematopoietic microenvironment. In patients with poor HSC engraftment, the quantity and function of bone marrow EPCs are severely compromised, making EPC impairment an independent risk factor for poor engraftment. Repairing EPCs can facilitate hematopoietic reconstruction posttransplant and reduce transplant complications such as poor engraftment. Hepatic sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) is another early, high-mortality complication linked to endothelial damage. EPCs can effectively repair the endothelium, reducing the incidence of SOS/VOD, and clinical trials are ongoing.[27] Additionally, advancements in the editing and development of HSCs have made gene-level treatment of hematologic genetic disorders possible. Gene editing therapies for single-gene hereditary diseases such as thalassemia and sickle cell anemia have been reported in clinical settings.[28,29] Reinfusion of edited HSCs can restore normal hematopoiesis, and transplanting edited HSCs may represent a new direction for treating genetic blood disorders.[30] Furthermore, mRNA editing therapies can achieve short-term in vivo expression, affecting stem cell antigens such as CD33 to protect HSCs during targeted tumor antigen killing. This method does not alter genetic material and could be further applied in the clinical treatment of autoimmune diseases and human immunodeficiency virus (HIV). Prospects Previous studies have focused primarily on improving the antitumor and reparative functions of HSCT through cellular therapies. A notable example is Professor Huang’s research[14] on CD7 CAR-T cells for the treatment of CD7+ malignancies, which simultaneously addresses GVHD prevention. The hematologic origin of these malignancies makes immune cell therapy versatile, but further exploration is needed to fully elucidate immune cell functions post-transfusion. While immunology has advanced significantly in understanding immune cell behavior, deeper investigations into their mechanisms post-HSCT remain essential. With the increasing understanding of tumor-associated antigens, targeted interventions with reduced toxicity are becoming increasingly feasible.[31,32] The functional role of tumor cell targets plays a crucial role in the success of immune therapies. However, when these therapies are integrated with HSCT, careful attention must be given to targeting cancer cells without affecting normal physiological functions. Further research into cell behavior, gene editing, and the characteristics of target cells will provide the foundation for future innovations. A comprehensive understanding of immune (stem) cell interactions and their regulatory pathways is necessary for optimizing therapeutic strategies. CAR-T cell therapy has demonstrated great potential, but its efficacy and range of viable targets remain limited, with few alternatives matching the success of CD19 and B cell maturation antigen (BCMA) therapies. Continuous efforts are needed to identify, screen, and validate new cell therapy targets. While studies have shown the benefits of combining immune and stem cells, further work is needed to enhance the synergy between these therapies. Current research often focuses on single cell types, but understanding the systemic regulatory roles of multiple cell types is crucial for developing more effective treatments. Immune and stem cell therapies offer solutions to the limitations of HSCT, such as insufficient antitumor effects and a high incidence of complications. However, challenges such as HLA matching persist. Advances in universal immune cells, such as gene-edited universal CAR-T and CAR-NK cells, have made progress, but these therapies still require further optimization. HSCT can serve as a bridge to mitigate the side effects of immune therapies. Future development should emphasize the creation of clinical-grade cell banks and off-the-shelf availability to facilitate rapid, combined transplantation strategies. Tailoring therapies to individual patient needs, including the use of MSCs and EPCs, could further reduce relapse rates and the incidence of GVHD. Since its inception, HSCT has been a cornerstone for treating both benign and malignant hematologic diseases. Recent advancements in CAR-T cell therapy, stem cell therapy, and gene editing have enabled more precise interventions, filling gaps in the transplantation framework. These therapies show promise in enhancing immune and hematopoietic functions and restoring the hematopoietic microenvironment. However, like HSCT, immune cell therapies still face challenges related to HLA matching, which contribute to high costs. Universal immune cell therapies, such as NK cells or macrophages as CAR carriers, are under investigation, although they often lack sustained efficacy and require bridging transplants. Gene editing of T cells also holds promise but requires further safety validation in clinical settings.[31] In the context of infectious diseases, antiviral T cell and CAR-T cell therapies have demonstrated clinical effectiveness, but other treatments are still in preclinical stages.[15] Gene-edited HSCs have shown potential in treating single-gene hereditary diseases, but their long-term safety and efficacy require more data. The safety of MSCs and EPCs has been established, although their efficacy remains inconsistent. Advances in primary cell subgroups and culture methods, as well as the use of induced pluripotent stem cell (iPSC)-derived MSCs, offer a path toward more consistent and clinically applicable treatments. Advances in gene editing technologies for HSCs and iPSCs offer promising solutions for treating genetic disorders and targeting tumor-associated antigens. For patients with refractory or relapsed disease, therapies such as CAR-T, CAR-NK, and TCR-T cells can induce complete remission, enabling subsequent HSCT. In cases of post-HSCT relapse, DLI and tumor microenvironment-specific CAR-T cells can support immune reconstitution. Additionally, virus-specific T cells and antifungal CAR-T cells can prevent and treat infections. To address GF and GVHD, MSCs and EPCs promote recovery. Emerging CAR-T cell therapies also show potential for preventing GVHD and relapse simultaneously. Funding This work was supported by grants from the National Natural Science Foundation of China (No. 82341201), the National Key R&D Program of China (Nos. 2022YFA1103300, 2022YFA1103304), the Chongqing Municipal Natural Science Foundation General Project (No. 2024NSCQ-MSX3299), and the Special Project for Talent Construction in Xinqiao Hospital (No. 2022XKRC001). Conflicts of interest None.