Editor’s Note: Chronic graft-versus-host disease (cGVHD) is a clinical syndrome occurring after allogeneic hematopoietic stem cell transplantation (allo-HSCT), where the recipient’s organs are attacked by donor-derived lymphocytes during the reconstitution of the donor’s immune system. This includes both classic cGVHD and overlapping syndromes and is one of the main complications of transplantation, with an incidence rate of 30% to 70%. The mechanisms behind cGVHD are complex, its clinical manifestations diverse, and the individual differences significant. The course of the disease can be prolonged and persistent; if not properly diagnosed and treated, it can severely affect the patient’s quality of life and long-term survival. With the introduction of guidelines, there are now standardized diagnostic criteria and first-line treatment protocols for cGVHD, but there is still no consensus on second-line treatments. PI3Kδ inhibitors, which interfere with the proliferation and survival of lymphocytes by inhibiting the activity of the PI3Kδ enzyme and thus suppress tumor growth, have not only introduced new drugs and strategies for non-Hodgkin’s lymphoma but have also shown therapeutic potential in the treatment of GVHD. At the recent 50th European Society for Blood and Marrow Transplantation (EBMT) annual meeting, a basic study from the Second Affiliated Hospital of Army Medical University was selected for an oral presentation (Abstract No: OS7-05) [1], showcasing the activity of PI3Kδ inhibitors in the treatment of cGVHD. “Oncology Frontier – Hematology Frontier” has invited Professor Qingxiao Song from The Second Affiliated Hospital of Army Medical University (Xinqiao Hospital) to interpret and comment on this research for our readers.there is still no consensus on second-line treatments. PI3Kδ inhibitors, which interfere with the proliferation and survival of lymphocytes by inhibiting the activity of the PI3Kδ enzyme and thus suppress tumor growth, have not only introduced new drugs and strategies for non-Hodgkin’s lymphoma but have also shown therapeutic potential in the treatment of GVHD. At the recent 50th European Society for Blood and Marrow Transplantation (EBMT) annual meeting, a basic study from the Second Affiliated Hospital of Army Medical University was selected for an oral presentation (Abstract No: OS7-05) [1], showcasing the activity of PI3Kδ inhibitors in the treatment of cGVHD. “Oncology Frontier – Hematology Frontier” has invited Professor Qingxiao Song from The Second Affiliated Hospital of Army Medical University (Xinqiao Hospital) to interpret and comment on this research for our readers.
Professor Qingxiao Song at EBMT: Limited Benefits from Traditional Steroid Treatment, Urgent Need for New Breakthroughs in cGVHD Treatment
cGVHD is a significant challenge for patients following allo-HSCT, severely impacting their quality of life and being a major cause of non-relapse mortality. Currently, first-line treatment for cGVHD primarily relies on corticosteroids. However, a significant portion of patients are either insensitive to steroid treatment or develop resistance, necessitating the development of second-line or more advanced treatments to improve outcomes and extend patient survival. Recent advancements in second-line treatments for cGVHD have been notable. For example, the development and exploration of new drugs such as BTK inhibitors and ROCK2 inhibitors, especially the newly approved ROCK2 inhibitor Besudil Mesylate in China, have proven effective and safe for patients who fail steroid therapy and are now recommended as a second-line treatment option for cGVHD. Additionally, innovative treatments like mesenchymal stem cell (MSC) therapy, due to their multi-dimensional and multi-target effects on immune modulation, also show potential in the prevention and treatment of cGVHD. When devising treatment plans for cGVHD, clinicians must consider both efficacy and safety, striving to control the disease effectively while minimizing side effects. For patients resistant to steroids, personalized treatment plans are particularly crucial. Currently, there is no international consensus on second-line treatments for steroid-resistant cGVHD, requiring clinicians to weigh the pros and cons based on individual patient circumstances to devise the most appropriate treatment strategy.
The Mechanistic Basis of PI3Kδ Inhibitors in cGVHD Treatment
The primary pathophysiological process of cGVHD involves an immune-inflammatory response, with complex immune regulatory mechanisms at play, where the activation and proliferation of T cells and B cells play a central role. As a critical signaling molecule, PI3Kδ plays an important role in the signaling pathways of T cells and B cells, making PI3Kδ inhibitors potentially valuable in treating cGVHD. These inhibitors primarily work by blocking the activity of PI3Kδ, thereby affecting the activation, proliferation, and function of T and B cells. PI3Kδ signaling mediates the abnormal activation of T and B cells in cGVHD, and these inhibitors could modulate the pathological immune responses associated with cGVHD without significantly affecting the overall immune response.
Currently, research on PI3Kδ inhibitors is primarily at the basic stage, with several preclinical model studies reporting their impact on immune cell function. Additionally, clinical research on PI3Kδ inhibitors is underway, focusing mainly on other diseases, such as non-Hodgkin’s lymphoma, autoimmune hemolytic anemia, and in combination with ruxolitinib for treating myelofibrosis. These studies could provide important references and experiences for the future application of PI3Kδ inhibitors in the treatment of cGVHD.
Significant Activity of PI3Kδ Inhibitors in Treating Mouse cGVHD
The basic research presented at this EBMT conference aimed to explore the potential therapeutic effects of PI3Kδ inhibitors in treating cGVHD. In previous work, our research team extensively studied various cGVHD animal models, including those primarily exhibiting skin lesions. In these models, we observed significant effects of PI3Kδ inhibitors in alleviating chronic GVHD symptoms in the skin. Specifically, PI3Kδ inhibitors not only reduced hair loss in the animals but also significantly alleviated immune cell infiltration at the pathological level. Furthermore, as treatment progressed, the overall condition of the mice was well maintained. Besides the specific skin cGVHD model, we also studied models resembling systemic autoimmune diseases. In these models, we found that PI3Kδ inhibitors significantly extended the survival of the mice, suggesting that PI3Kδ inhibitors may play an active role in modulating the systemic pathological processes of cGVHD.
Specific experimental results found that in a minor histocompatibility antigen mismatched mouse model (B10.D2→BALB/c), both skin cGVHD and systemic inflammatory responses were observed. PI3Kδ inhibitor treatment significantly reduced the cGVHD score in the skin of the recipients and extended their overall survival. On day 30 post-transplant, compared to the non-GVHD (syngeneic transplant) group, recipients treated with solvent (control group) exhibited immune cell infiltration, collagen deposition, and severe fat atrophy in the skin. In contrast, recipients treated with PI3Kδ inhibitors showed significantly reduced cell infiltration and collagen deposition in the skin. Moreover, PI3Kδ inhibitor treatment significantly reduced the presence of CD69+ and CD103+ tissue-resident memory T cells (TRM) in the skin, lungs, and liver. More importantly, PI3Kδ inhibitor treatment upregulated the expression of Foxo1 and Foxo3α, promoted the expression of Foxp3, and expanded a stable and highly suppressive regulatory T cell population in the skin, which may help suppress skin cGV
HD. Compared to the control group, the recipients treated with PI3Kδ inhibitors showed a significant reduction in the proportion and number of CD19+, B220+ B cells, and CD11b+, F4/80+ macrophages in the skin, liver, and lungs; the therapeutic effects of PI3Kδ inhibitors were validated in a major histocompatibility antigen mismatched GVHD model (C57BL/6→BALB/c).
These findings demonstrate that PI3Kδ inhibitors can regulate the tissue microenvironment by enriching Treg cells while simultaneously suppressing TRM cells, B cells, and macrophages in the tissues, effectively alleviating cGVHD. These data provide a basis for the use of PI3Kδ inhibitors in treating cGVHD patients and can serve as reference data for future clinical research exploration.
The Prospects of PI3Kδ Inhibitors in the Treatment of Blood Diseases
Currently, the development of new drugs is at the core of global medical innovation, particularly the development of targeted therapeutic drugs for specific molecular targets, which has become a cutting-edge strategy for treating various diseases. In this field, new targeted drugs such as BTK inhibitors and ROCK inhibitors have attracted widespread attention from the medical community due to their significant effects in treating related diseases.
The PI3K signaling pathway, as an important intracellular signaling route, plays a key role in regulating the activation, proliferation, and survival of immune cells, especially the PI3Kδ subtype, due to its specific role in B and T cell signaling, has become an important target for drug development.
PI3Kδ inhibitors have high target selectivity, effectively blocking the mediated signaling transmission, which theoretically reduces the adverse effects on other PI3K subtypes and their related physiological processes, potentially resulting in fewer side effects and increasing the safety of the treatment. Also, PI3Kδ plays a key role in various immune-mediated diseases, including some hematological tumors, autoimmune diseases, and cGVHD, hence, PI3Kδ inhibitors might have a broad range of therapeutic indications, providing new strategies for the treatment of various diseases.
PI3Kδ plays a significant role in the development, activation, and function of T and B cells, making PI3Kδ inhibitors potentially particularly effective in treatments requiring fine-tuned immune responses, such as cGVHD. By modulating immune cell signaling, PI3Kδ inhibitors may help control pathological immune responses, alleviate symptoms, and improve patient survival quality. Moreover, based on positive preclinical research results, PI3Kδ inhibitors show great potential for clinical translation. Currently, several clinical trials are assessing the therapeutic effects of PI3Kδ inhibitors in various diseases, and the results of these studies will provide important evidence for the clinical application of PI3Kδ inhibitors.
With the development of personalized medicine, future treatment strategies will increasingly focus on customizing personalized treatment plans based on the patient’s genetic background, disease characteristics, and treatment response. The development and application of PI3Kδ inhibitors are expected to align with this trend, providing more precise treatment options for patients.
Although PI3Kδ inhibitors have shown great potential in new drug development, their clinical application still requires a series of rigorous clinical trials to verify their safety, efficacy, pharmacokinetics, and optimal medication regimen in humans. Further research into the role of PI3Kδ in different diseases and exploring combination strategies with other drugs will expand the clinical application scope of PI3Kδ inhibitors and bring more effective treatment options to patients. As research continues to deepen, we have reason to expect that PI3Kδ inhibitors will play an important role in the future of the pharmaceutical field, providing safer and more effective treatment options for patients.
Overall, preclinical research results provide strong experimental evidence for the application of PI3Kδ inhibitors in the treatment of cGVHD. However, to translate these research findings into clinical practice, further in-depth mechanism studies and clinical trials are needed to verify the safety, efficacy, and optimal medication strategies of PI3Kδ inhibitors in human cGVHD patients. In the future, we look forward to providing more effective and safe treatment options for cGVHD patients through continued research efforts.
Expert Profile
Researcher, Hematology Center, the Second Affiliated Hospital of Army Medical University (Xinqiao Hospital)
Member, Hematology Physicians Branch of Chongqing Medical Association
Member, American Society of Hematology
Editorial Board Member, Blood & Genomics Journal
Primary research focus on the basic and clinical translational research of hematopoietic stem cell transplantation.
Recipient of the “New Chongqing Talent Recruitment Program Innovation Base Special Project”
Principal investigator of one National Natural Science Foundation project, one Chongqing Innovation Development Joint Fund project, and one Chongqing Science and Health Joint Key Project. The main research findings have been published in authoritative journals in the field, such as Blood, Journal of Clinical Investigation, Nature Communications, PNAS, and American Journal of Transplantation, with 7 first-author papers and 2 corresponding author papers.
