2024EHA | Professor Huang He: Targeting CD7 Universal CAR-T Therapy Shows Significant Efficacy and Good Safety in Treating R/R CD7+ T-ALL/LBL Patients

**2024EHA | Professor Huang He: Targeting CD7 Universal CAR-T Therapy Shows Significant Efficacy and Good Safety in Treating R/R CD7+ T-ALL/LBL Patients**

The 29th Annual Meeting of the European Hematology Association (EHA) 2024 concluded successfully on June 16, 2024, in Madrid, Spain. As a premier event in the international hematology field, it showcased the latest advancements in foundational and clinical practices.

At this year’s EHA meeting, several studies from Professor Huang He’s team at the First Affiliated Hospital, Zhejiang University School of Medicine were selected. One of these studies, titled “Phase I Study of Targeting CD7 Universal CAR-T Therapy for Relapsed/Refractory CD7+ T-ALL/LBL Patients,” was featured in a poster presentation.

T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL) are aggressive malignancies originating from precursor T cells, often affecting the bone marrow (BM), central nervous system (CNS), and mediastinum. Despite multiple lines of chemotherapy or allogeneic hematopoietic stem cell transplantation, some patients progress to a relapsed/refractory stage with poor prognosis, posing a significant clinical challenge. Current CAR-T cell therapies primarily target B-cell hematologic malignancies and multiple myeloma, such as CD19 CAR-T and BCMA CAR-T, while mature targets for T-cell hematologic malignancies are lacking. Preliminary research data indicate that CD7 could be a potential therapeutic target for T-cell hematologic malignancies. Based on this, the team developed a universal CAR-T product targeting CD7, named RD13-02, characterized by CRISPR/Cas9 technology to modify T-cell receptors (TCR) and CD7, creating an innovative “off-the-shelf” CAR-T cell therapy product aimed at truly achieving shelf-ready cell therapy.

The objective of this study was to evaluate the safety and efficacy of RD13-02 in treating R/R T-ALL/LBL. A total of 12 eligible R/R T-ALL/LBL patients (7 ALL, 5 LBL) were enrolled in the study, all exhibiting CD7 antigen expression. Six patients had extramedullary disease; all had blast cells in the bone marrow, with a median proportion of 64% (range: 6% to 89%), indicating high-risk end-stage patients. The patients, aged 3 to 70 years, were enrolled in a “3+3” dose-escalation study. Based on the total dose of RD13-02, they were randomly divided into four dosage groups (DL-1: 0.5×10^8 CAR+T cells; DL1: 2×10^8 CAR+T cells; DL2: 4×10^8 CAR+T cells; DL3: 6×10^8 CAR+T cells). All patients received a standardized lymphodepletion regimen of fludarabine (30mg/m2/day) and cyclophosphamide (500mg/m2/day) for three consecutive days (Day -5 to Day -3) before CAR-T infusion. Preliminary disease assessment was conducted on Day 28. After determining the MTD and RP2D, dose expansion will be carried out.

The study results indicated that no dose-limiting toxicity (DLT), immune effector cell-associated neurotoxicity syndrome (ICANS), or graft-versus-host disease (GVHD) was observed at any dose level. Cytokine release syndrome (CRS) was manageable, mostly mild (G1, n=8; G2, n=2; G3, n=2). Due to the occurrence of Grade 3 CRS in one patient each in the DL2 and DL3 groups, the DL1 dose was set as RP2D, focusing on safety and efficacy. In the initial 28-day evaluation post-infusion, 9 out of 12 patients achieved CR/CRi. By the second month post-infusion, an additional 2 patients achieved CR/CRi, with an ORR of 92%. All patients showed expansion observed through qPCR, with the expansion occurring between Days 6 to 15 and peaking between Days 8 to 27, with a median duration of 33 days (15-79). The study preliminarily confirmed that the anti-CD7 universal CAR-T product RD13-02 is safe and effective for CD7+ R/R T-ALL/LBL. Long-term efficacy needs more patients and extended follow-up for validation. To date, this study has shown the best clinical results for universal CAR-T therapy for R/R T-ALL/LBL, attracting widespread attention from peers both domestically and internationally at this EHA meeting. Additionally, the Bone Marrow Transplantation Center at the First Affiliated Hospital, Zhejiang University School of Medicine is developing multiple targeted CAR-T cell therapy products for various hematologic malignancies, including B-cell, T-cell, and myeloid malignancies.

**Current Clinical Treatment of T-ALL/LBL**

The treatment of T-ALL/LBL remains a significant clinical challenge. Current strategies involve achieving remission with existing frontline therapies followed by sequential allogeneic or autologous hematopoietic stem cell transplantation, with most patients achieving long-term survival. However, some patients face refractory or relapsed disease with poor prognosis. For these patients, clinical studies of new drugs or treatment strategies, such as innovative drugs based on disease targets and pathways, are actively being conducted but have not achieved significant progress. CAR-T cell therapy, with its excellent efficacy and safety, is currently the most promising innovative therapy. It is hoped that with further research, CAR-T cell therapy can bring more survival benefits to T-ALL/LBL patients.

**Challenges and Strategies in CAR-T Cell Therapy**

Cellular immunotherapy has been a milestone in the medical field over the past decade, showing breakthrough efficacy in hematologic malignancies, but it still faces several challenges that need to be addressed.

First, the discovery of new targets. Current mature CAR-T cell therapy products mainly focus on B-cell hematologic malignancies, and new targets are urgently needed for T-cell, myeloid, and solid tumors.

Second, improving efficacy. Existing CAR-T cell therapy for B-cell hematologic malignancies has an efficacy rate of about 50%, and continuous technological improvements are expected to develop more effective cell therapy products for clinical application.

Third, existing CAR-T products are autologous CAR-T, which are costly and have long treatment cycles, necessitating the development of universal CAR-T to improve patient compliance.

The team’s novel cell therapy research, including the study selected for this EHA meeting, addresses these clinical challenges. Additionally, last year, the team published results on “function-enhanced” CAR-T in the journal *Nature*, using PD-1 site-specific integration and non-viral delivery methods to successfully prepare CAR-T cells, significantly enhancing their therapeutic effects.

Furthermore, managing CAR-T cell therapy complications, such as ICANS and CRS, requires in-depth exploration. Progress has been made in understanding the mechanisms of complications, leading to gene functionalization of CAR-T cells and developing “smart” CAR-T products to achieve “efficacy enhancement and toxicity reduction.” Additionally, exploring CAR-T combinations with small molecule targeted drugs and immunotherapeutic drugs could achieve better efficacy. The team recently published in the *New England Journal of Medicine* on the sequential “integrated” regimen of CD7 CAR-T cell therapy and allogeneic hematopoietic stem cell transplantation (HSCT), showing excellent efficacy in relapsed/refractory hematologic malignancies.

**Future Prospects of Cellular Therapy**

It is well known that hematology has always been at the forefront of medical development, including the application of the first small molecule targeted drugs and the first antibodies. The remarkable efficacy of cellular therapy in hematologic diseases has demonstrated its great potential in clinical practice. In the future, it is believed that with the development and commercialization of more novel cellular immunotherapy products, their efficacy will continue to improve, side effects will gradually decrease, and indications will expand.

In the field of hematologic diseases, in addition to traditional chemotherapy, small molecule targeted drugs, antibody drugs, and hematopoietic stem cell transplantation, cellular therapy has improved the clinical treatment landscape of hematologic diseases and holds a significant position. It is anticipated that in the future, the treatment of hematologic diseases may enter a chemotherapy-free era, bringing higher cure rates and better quality of life for patients.

🎉🎉To assess whether the condition is suitable for CAR-T or clinic therapy, you can submit Advanced Medicine in China for preliminary evaluation!
WhatsApp: +8613717959070
Email: doctor.huang@globecancer.com

#CAR_T #TALL #LBL #EHA2024 #Immunotherapy #Hematology #CancerResearch #CD7 #CellTherapy #MedicalAdvancements

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4 months ago Myeloma

**2024 EHA | Breaking Through Multiple Myeloma Treatment Bottlenecks: Significant Advances of Equecabtagene Autoleucel in High-Risk NDMM Patients**

**2024 EHA | Breaking Through Multiple Myeloma Treatment Bottlenecks: Significant Advances of Equecabtagene Autoleucel in High-Risk NDMM Patients**

Multiple Myeloma

Multiple Myeloma (MM) is a malignant plasma cell disorder and one of the most common hematologic malignancies. In China, approximately 20,000 new cases of newly diagnosed multiple myeloma (NDMM) are reported annually, with a median age at diagnosis over 60 years. It is reported that Chinese MM patients generally exhibit higher rates of cytogenetic abnormalities, with an incidence rate exceeding 40%, which is significantly higher than in Western countries.

High-risk MM patients often respond poorly to existing treatment regimens and face limited treatment options. Many elderly patients are frail and have multiple comorbidities, making them less tolerant of the adverse reactions associated with current therapies, particularly autologous stem cell transplantation (ASCT). Once the disease progresses to a refractory/relapsed state, the combination of advanced age, frailty, and high-risk cytogenetic abnormalities leads to limited salvage treatment options, worsening efficacy, and poor prognosis. Thus, selecting effective frontline therapy for NDMM patients, especially high-risk elderly patients unsuitable for transplantation, is a pressing clinical need, requiring innovative therapies to supplement existing treatments. The new generation of cell immunotherapies, exemplified by Equecabtagene Autoleucel, holds promise to fill this gap and potentially become a breakthrough for high-risk NDMM.

In the FUMANBA-1 study, which included 69.5% high-risk patients, Equecabtagene Autoleucel achieved an ORR of 96.1% and has been approved in China for treating third-line or later relapsed/refractory multiple myeloma (R/R MM) patients. This EHA meeting is the first to present oral data on the efficacy and safety of Equecabtagene Autoleucel in the FUMANBA-2 study for high-risk, newly diagnosed, transplant-ineligible MM patients.

### Study Introduction

FUMANBA-2 is a multicenter, open-label, single-arm Phase I study designed to evaluate the efficacy and safety of Equecabtagene Autoleucel in transplant-ineligible NDMM patients with 100% high-risk features (defined by mSMART 3.0: RISS Stage III, double-hit, or triple-hit). Patients received four cycles of induction therapy, including the VRd regimen (Bortezomib, Lenalidomide, Dexamethasone), the VCD regimen (Bortezomib, Cyclophosphamide, Dexamethasone), or the PAD regimen (Bortezomib, Doxorubicin, Dexamethasone). After the third cycle of induction therapy, T cells were collected from patients unsuitable for ASCT and Equecabtagene Autoleucel was prepared. After lymphodepletion, patients received a single infusion of Equecabtagene Autoleucel at a dose of 1.0 x 10^6 CAR-T cells/kg. The primary efficacy endpoints were the proportion of MRD-negative patients and progression-free survival (PFS). Secondary endpoints included objective response rate, duration of response, safety, pharmacokinetics, and pharmacodynamics.

### Study Results

As of January 25, 2024, 16 patients received Equecabtagene Autoleucel, with a median age of 58.5 years (51-69) and a median follow-up time of 13.1 months (7.9-24.3). All patients had high-risk cytogenetics, with 62.5% (10/16) being double-hit, 12.5% (2/16) being triple-hit, and 25% (4/16) having extramedullary disease. 37.5% (6/16) were R-ISS Stage III, with one patient each combining R-ISS Stage III with double-hit and triple-hit characteristics.

The median follow-up time after Equecabtagene Autoleucel infusion was 7.46 months (2.8-18.1). The median PFS was not reached, with a 12-month PFS rate of 84.4% (95% CI: 49.31-96.00). All subjects achieved MRD negativity, with 71.4% (95% CI: 25.8-92.0) maintaining MRD negativity for over 12 months. The objective response rate (ORR) was 100%, with 93.8% (15/16) achieving stringent complete response (sCR).

Grade 1-2 cytokine release syndrome (CRS) occurred in 68.8% (11/16) of patients, with no grade 3 or higher CRS, immune effector cell-associated neurotoxicity syndrome (ICANS), or neurotoxicity. The most common grade 3 or higher drug-related adverse events were hematologic, with a 25.0% (4/16) incidence of grade 3 or higher infectious disease adverse events.

The median peak CAR copy number in peripheral blood was reached on day 10 (7-21) post-infusion, with a median peak level of 79,681.299 copies/μg gDNA. 81.25% (13/16) of patients achieved free B cell maturation antigen (sBCMA) clearance within one month post-infusion. Median peak levels of inflammatory cytokines IL-6, CRP, and ferritin were 64.28 pg/mL (9.12-3017.83), 49.30 mg/L (3.66-117.30), and 553.35 ng/mL (68.10-2349.00), respectively. The median peak times for IL-6 and CRP were day 7 and day 10, respectively, with no significant change in serum ferritin levels compared to pre-infusion.

### Study Outlook

The FUMANBA-2 study of Equecabtagene Autoleucel demonstrates the efficacy and safety of a novel fully human BCMA CAR-T therapy in high-risk, transplant-ineligible, newly diagnosed multiple myeloma patients. This is the first international report of CAR-T therapy as frontline treatment in this specific population. The study highlights the potential application of cell immunotherapy in the MM field. Compared to traditional chemotherapy and new drug treatments, frontline CAR-T therapy for NDMM has the potential to further improve response rates, extend survival, and improve prognosis, particularly for high-risk cytogenetic abnormalities and high tumor burden. For elderly and frail patients who are unsuitable for hematopoietic stem cell transplantation, CAR-T therapy may fill the treatment gap to some extent. The one-time treatment approach, as opposed to continuous chemotherapy or multiple transplants, offers patients better quality of life and treatment convenience. Although CAR-T therapy carries risks such as CRS and neurotoxicity, these side effects are manageable in many studies, and safety improves with treatment experience and management strategies. Bringing CAR-T therapy to the frontline provides patients with more diverse and promising treatment options. However, large-scale, long-term follow-up studies are needed to validate its long-term efficacy and survival benefits, and further exploration and optimization are required for the best administration timing, regimen, and duration.

In summary, the FUMANBA-2 study of Equecabtagene Autoleucel shows significant treatment potential in newly diagnosed, transplant-ineligible multiple myeloma patients. With accumulating research evidence and advances in CAR-T technology, we anticipate CAR-T therapy will benefit more patients in the future.

🎉🎉To assess whether the condition is suitable for CAR-T or clinic therapy, you can submit Advanced Medicine in China  for preliminary evaluation!

WhatsApp: +8613717959070

Email: doctor.huang@globecancer.com

#EquecabtageneAutoleucel #MultipleMyeloma #MMTreatment #HighRiskMM #NDMM #CAR_Therapy #Immunotherapy #BloodCancer #OncologyResearch #EHA2024 #CancerBreakthrough #CellTherapy #MyelomaTreatment #ClinicalTrials #InnovativeMedicine #HealthcareAdvancements

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4 months ago CAR-T

#EBMT / #EHA Leading the Frontiers of Medicine: China’s Top Medical Expert Explains the Groundbreaking CAR-T Cell Therapy

#EBMT / #EHA Leading the Frontiers of Medicine: China’s Top Medical Expert Explains the Groundbreaking CAR-T Cell Therapy

Expert:**Huang He**

Chief Physician and Doctoral Supervisor.

Currently serves as the Director of the Hematology Institute at Zhejiang University, Director of the Zhejiang Provincial Engineering Research Center for Stem Cell and Cellular Immunotherapy, Chief Scientist for the “Hematology and Immunology Diseases” division at the Liangzhu Laboratory, and Director of the Bone Marrow Transplantation Center at the First Affiliated Hospital of Zhejiang University School of Medicine.

He is the Vice Chairman of the Asia Cell Therapy Organization and Deputy Leader of the Hematopoietic Stem Cell Application Group of the Hematology Branch of the Chinese Medical Association.

He has published over 300 papers (including over 200 as corresponding author) in journals such as The New England Journal of Medicine, Nature, Cell Metabolism, Lancet Haematology, Blood, and Leukemia.

He has received 17 provincial and ministerial-level awards and holds 23 authorized invention patents.

In the past five years, he has served as chairperson, invited speaker, and oral presenter at over 60 international conferences. As the conference chair, he organized the Asia-Pacific International Bone Marrow and Hematopoietic Stem Cell Transplantation Conference in Hangzhou in 2005 and 2014.

He is the chief editor of “CAR-T Cell Immunotherapy” and “Hematology” published by People’s Medical Publishing House.

He serves on the editorial boards and committees of multiple international journals and organizations.

To assess whether the condition is suitable for CAR-T or clinic therapy, you can submit Advanced Medicine in Chinafor preliminary evaluation!

WhatsApp:+8613717959070
Email: doctor.huang@globecancer.com

#MedicalInnovation #CAR_Therapy #Hematology #MedicalBreakthrough #ExpertTalks #CuttingEdgeMedicine #cart #EHA2024