From April 14 to 17, 2024, the 50th Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT) was held in Glasgow, marking the 50th anniversary of EBMT. This event gathered leaders in hematopoietic stem cell transplantation and over 6,000 hematology experts worldwide to reflect on the extraordinary achievements in the field over the past half-century and to explore future patient management strategies. At the conference, Professor He Huang from the First Affiliated Hospital of Zhejiang University College of Medicine shared significant advancements in novel cellular immunotherapies, capturing the attention of many. This publication has invited Professor Huang for an in-depth interview to discuss the innovations in the field of cellular immunotherapy.
Celebrating Unity: CAR-T Cell Immunotherapy as a Central Theme at This Conference
Professor He Huang: This year marks the 50th anniversary of EBMT, and this year’s conference is a landmark event in the field of hematopoietic stem cell transplantation. We have witnessed another milestone in the global development of hematology and stem cell transplantation. At this conference, hematopoietic stem cell transplantation and cellular immunotherapy have emerged as the most critical topics.
Over the past decade, cellular immunotherapy has seen rapid advances. From CAR-T cells targeting CD19 to those targeting B-cell maturation antigen (BCMA) and other new targets, CAR-T cell therapy has made significant progress in treating hematological diseases, including lymphomas, myelomas, and leukemias.
To date, there are 11 commercial CAR-T cell products globally, with six approved in China, targeting CD19 and BCMA, and covering diseases such as acute lymphoblastic leukemia (ALL), multiple myeloma (MM), and non-Hodgkin lymphoma (NHL). CAR-T cell therapy has achieved breakthrough efficacy in these areas, offering promising application prospects.
However, we still face many challenges. As highlighted at this year’s EBMT conference, particularly at the “Global CAR-T Cell Therapy Symposium,” about 50% of lymphoma treatments using CAR-T cells achieve complete remission, and approximately 60% of patients with acute lymphoblastic leukemia may relapse. Addressing these issues, which may require more potent CAR-T cells, is a significant challenge we face. In response, our team has been exploring innovative cellular immunotherapy, which I presented at this year’s symposium.
Exploring Enhanced CAR-T Cell Immunotherapy
Professor He Huang: In recent years, our team has undertaken various innovative projects in cellular immunotherapy, from initial single-target CAR-T cells to dual-target and other new target CAR-T cells. In 2022, we published a study in the prestigious journal Nature, developing a non-viral, PD-1 integrative targeting CAR-T therapy aimed at CD19. This new CAR-T cell therapy achieved an 87.5% complete remission rate and a 100% objective response rate in clinical trials for relapsed/refractory B-cell non-Hodgkin’s lymphoma (r/r B-NHL), with the longest disease-free survival now exceeding two years. This research underscores the leading role of Chinese scholars in the development and clinical application of CAR-T cell therapies.
Subsequently, in 2023, we published a cohort expansion study in EClinicalMedicine (impact factor: 14.49). This Phase I single-arm dose-escalation clinical trial further assessed the efficacy and safety of the non-viral PD-1 integrative CAR-T in adult patients with r/r B-NHL, showing a complete remission rate of 80%, a significant improvement in the treatment of r/r B-NHL.
Additionally, our team conducted a more cutting-edge exploration published in the top-tier journal Cell Metabolism (impact factor: 27.287), exploring how to enhance CAR-T function through immune metabolic pathways. Our research found that isocitrate dehydrogenase 2 (IDH2) inhibits glucose utilization via the pentose phosphate pathway, hindering the metabolic adaptability of CAR-T cells, especially under nutrient-limited conditions. IDH2 also limits cytoplasmic acetyl-CoA levels, inhibiting histone acetylation crucial for memory cell formation. Based on this, preclinical models showed that the IDH2 inhibitor enasidenib enhances the formation of memory CAR-T cells and maintains anti-leukemic cytotoxicity in vivo, thus improving the efficacy of CAR-T cell therapy.
In addition, we are conducting a clinical study aimed at maintaining mitochondrial structure and function within CAR-T cells in the tumor microenvironment through autocrine IL10, enhancing oxidative phosphorylation metabolism dependent on the mitochondrial pyruvate carrier (MPC), and promoting proliferation and effector functions of CAR-T cells. To date, this work has shown excellent efficacy, achieving a 100% complete remission rate in lymphoma patients and significant effects in ALL patients.
CAR-NK Cells: The Next Frontier in Cell Therapy?
Professor He Huang: One of the strategic directions for developing universal cell therapy involves transitioning the “chassis cells” from T cells to NK cells. Given the limited in vivo persistence and expansion potential of autologous NK cells, we are exploring the directed differentiation of CAR-induced pluripotent stem cells (iPSCs) into CAR-NK cells. The challenge lies in directing the differentiation of anti-tumor cells while maintaining their functionality and addressing the limited persistence and expansion capabilities of NK cells. Hence, we are continuously editing and correcting genes to achieve ideal clinical efficacy.
Our clinical studies are ongoing. Overall, iPSC-directed differentiation into CAR-NK cell therapy promises to provide a low-cost, off-the-shelf supply of CAR-T cells, although the research is still in its early stages, and its safety and efficacy remain to be further verified. There is still a long road ahead.
Summary
Professor He Huang: This year’s EBMT conference focused on the latest clinical research and cutting-edge technologies in cellular immunotherapy and hematopoietic stem cell transplantation. We are thrilled to see the increasing widespread application of new technologies. As life sciences continue to evolve, the fields of cellular immunotherapy and stem cell transplantation will likely introduce a plethora of new technological systems and cell therapy products, such as CAR-T cells targeting various antigens and potentially universal CAR-NK cells. Additionally, the integration of cellular immunotherapy with stem cell transplantation presents a promising avenue. Through the continuous development and integration of these new technologies, we hope to provide better treatment options and medical services for patients globally.
