Editor's Note: From December 7–10, 2024, the 66th Annual Meeting of the American Society of Hematology (ASH) was held in San Diego, bringing together global experts and scholars in hematology for an in-depth exploration and exchange of the latest research progress in the field. Among the highlights of this year’s conference were three oral presentations (Oral 94, 238, 367) focusing on CAR-T cell therapy for lymphoma. These studies showcased the latest advancements in CAR-T therapy from three perspectives: enhancing accessibility, optimizing efficacy, and addressing resistance mechanisms. Hematology Frontier invited Dr. Wenbin Qian from The Second Affiliated Hospital of Zhejiang University School of Medicine to provide an in-depth analysis of these three studies, offering valuable guidance and insights for clinical practice.

Oral 94

Phase I Study Results of UF-Kure19, a CAR-T Product Manufactured in Less Than 1 Day, in Patients with Relapsed/Refractory Non-Hodgkin’s Lymphoma

Dr. Wenbin Qian：CD19 CAR-T cell therapy has achieved significant breakthroughs in treating large B-cell lymphoma. In China, two CD19 CAR-T products have been approved for patients with relapsed or refractory large B-cell lymphoma (LBCL) who have undergone at least three prior lines of therapy. However, as a highly personalized treatment, the high costs of CAR-T therapy have limited its widespread clinical application, resulting in inadequate accessibility. This economic burden prevents many eligible patients from accessing this potentially life-saving therapy.

At the recent ASH Annual Meeting, the results of Oral 94, a Phase I clinical trial of the ultra-fast CAR-T therapy UF-Kure19, were presented. This therapy is designed to treat relapsed/refractory non-Hodgkin lymphoma (NHL) with a production time of less than one day. In the United States, approximately 80% of LBCL patients eligible for CAR-T therapy are unable to access it, highlighting the significant challenge of high treatment costs. Addressing this issue through effective strategies to expand accessibility is both urgent and essential.

To overcome these challenges, two key research directions are being actively pursued:

1. Development of Universal CAR-T or CAR-NK Therapies This area of research holds great promise for making advanced therapies more widely available. At the Hematology Department of The Second Affiliated Hospital of Zhejiang University School of Medicine, our team is deeply involved in researching CAR-NK cell therapies, particularly for relapsed/refractory LBCL. Encouraging preliminary results have already been achieved, offering hope for more accessible treatment options.
2. Advancements in FAST CAR-T Therapy FAST CAR-T represents a novel and highly promising immunotherapy approach. In China, significant progress has been made in this area, with the successful development of corresponding FAST CAR-T products. Studies show that over 80% of patients achieved complete remission following FAST CAR-T therapy, demonstrating its remarkable efficacy. However, current research has limitations, including a small sample size and limited patient enrollment. Among the enrolled patients, only three had diffuse large B-cell lymphoma (DLBCL), while others had follicular lymphoma, mantle cell lymphoma, or plasmablastic lymphoma.

It is important to note that compared to LBCL, indolent lymphomas generally respond more favorably to CAR-T therapy. Additionally, the median number of prior treatment lines among enrolled patients was 1.5, indicating an earlier disease stage. Therefore, while FAST CAR-T therapy shows great potential, larger-scale clinical trials are necessary to comprehensively validate its efficacy.

One notable feature of FAST CAR-T therapy is its manufacturing process, which takes less than 24 hours. Once infused into the body, the peak expansion of CAR-T cells occurs at 21 days, compared to 7–14 days for conventional CAR-T cells. This delayed expansion contributes to its superior safety profile. The incidence of cytokine release syndrome (CRS) was only 30%, with all cases being Grade 2 or lower. Importantly, no severe Grade 3 or 4 CRS cases were observed. This safety advantage is likely associated with the slower in vivo expansion kinetics of FAST CAR-T cells, as CRS is closely linked to rapid and large-scale CAR-T cell proliferation within the body.

In summary, FAST CAR-T therapy offers a promising solution to the accessibility challenges of CAR-T therapy, with its rapid production process and favorable safety profile. However, further large-scale studies are necessary to fully establish its efficacy and optimize its use for broader patient populations.

Oral 238

Treatment Patterns and Outcomes Following Progression of Disease Post-CAR-T Therapy in Relapsed or Refractory Mantle Cell Lymphoma: A Multicenter Analysis

Dr. Wenbin Qian：This is a multicenter retrospective clinical study. Previously, Professor Michael Wang from the University of Texas MD Anderson Cancer Center published research findings in the New England Journal of Medicine, which fully demonstrated the significant efficacy of CD19 CAR-T therapy in the treatment of refractory mantle cell lymphoma. The core of this study presented at ASH is to delve into the efficacy of CD19 CAR-T therapy in treating relapsed/refractory mantle cell lymphoma (R/R MCL) and the key factors influencing prognosis. The study included a large sample of 306 R/R MCL patients from 9 medical centers, which holds significant reference value for clinical practice.

Notably, among all enrolled patients, as high as 97% had received BTK inhibitor (BTKi) treatment, with 36% of them being resistant to BTKi. For patients with BTKi-resistant mantle cell lymphoma, the prognosis is often not optimistic, and there is currently a lack of effective treatment options in clinical practice. Therefore, this study provides valuable clinical insights for exploring treatment strategies for patients with BTKi-resistant mantle cell lymphoma.

The research team conducted a comprehensive analysis of the clinical characteristics of patients with post-CAR-T treatment disease progression (POD). The results showed that high-risk MCL features at POD mainly included: a blastoid/pleomorphic subtype accounting for 55%, 75% of patients with Ki67 expression levels of ≥50%, and 60% of patients with TP53 mutations. These findings reveal that blastoid/pleomorphic subtype, high Ki67 expression, and TP53 mutations are the main factors for poor prognosis in CAR-T treated MCL.

Furthermore, in exploring mechanisms of drug resistance, this retrospective clinical study also found that the proportion of drug resistance due to CD19 antigen escape was only 12%. This result indicates that antigen escape is not the main cause of drug resistance. Compared to previous studies that pointed out that about one-third of drug-resistant patients in diffuse large B-cell lymphoma were due to CD19 antigen negativity, the large-sample, multicenter data in this study reveal the important role of MCL tumor biological characteristics in the mechanisms of drug resistance.

For patients after POD24, the study also provided beneficial treatment suggestions. The median survival time for patients after POD24 is only about 5.4 months, with a very poor prognosis. For patients who fail CAR-T treatment, whether it is diffuse large B-cell lymphoma or the mantle cell lymphoma in this study, salvage treatment outcomes are not satisfactory. The study results show that bispecific antibodies offer new therapeutic hope for patients who have failed CD19 CAR-T treatment in mantle cell lymphoma, demonstrating a promising application prospect.

Oral 367

Targeting Lymphoma Associated Myeloid-Monocytic Cells through CSF1R Blockade Enhances CAR-T Cell Response in Aggressive B Cell Lymphoma

Dr. Wenbin Qian：The Oral 367 study builds on the foundational ZUMA-1 trial demonstrating a complete remission (CR) rate of 58% for CD19 CAR-T therapy in large B-cell lymphoma. Although five-year follow-up data revealed an overall survival (OS) rate of 42.6%, challenges such as resistance, non-response, and relapse remain substantial hurdles for most patients.

A landmark study published in Nature Medicine last year had already shed light on the role of the lymphoma microenvironment (LME) in mediating CD19 CAR-T resistance in large B-cell lymphoma, offering a fresh perspective on therapeutic failure.

At the 2024 ASH meeting, Oral 367 further delved into these resistance mechanisms through multi-omics analyses, comparing outcomes between patients with durable responses (defined as complete remission sustained for six months) and those with poor outcomes following CAR-T therapy.

Key findings include:

1. The presence of CSF1R+CD14+CD68+ LAMM cells correlating with poor outcomes.
2. Reduced CD8+ T-cell infiltration in tumor tissues among non-durable responders.
3. A clear demonstration of how LAMMs suppress CAR-T cell functionality.

The study’s most innovative contribution is the introduction of CSF1R blockade as a strategy to overcome resistance and enhance CAR-T efficacy. This breakthrough not only provides a deeper understanding of the mechanisms underlying CAR-T therapy failure but also establishes a robust foundation for developing novel CAR-T approaches.

Dr. Qian emphasized that the insights from this study offer valuable guidance for future research and clinical application, holding promise for optimizing CAR-T therapies and improving outcomes for patients with aggressive B-cell lymphomas.

Dr. Wenbin Qian

Zhejiang University School of Medicine Second Affiliated Hospital

• Director of the Hematology Department, Zhejiang University School of Medicine Second Affiliated Hospital
• Director of the Biotherapy Center, Zhejiang University School of Medicine Second Affiliated Hospital
• Chief Scientist, National Key Research and Development Program for Technological Innovation 2030
• Member, Hematology Physician Branch, Chinese Medical Doctor Association
• Standing Committee Member, Tumor Hematology/Hematological Oncology Professional Committee, Chinese Anti-Cancer Association
• Member, Lymphoma Professional Committee, Chinese Anti-Cancer Association
• Vice Chairman, Lymphoma Professional Committee, Chinese Association of Geriatric Health Care
• Member, Lymphocytic Disease and Infection Groups, Chinese Society of Hematology
• Chairman, Hematology Branch, Zhejiang Medical Association

Academic Achievements

Dr. Qian has published over 90 papers as the first or corresponding author in prestigious international journals, including Cell Discovery, eClinical Medicine, Clinical Cancer Research, Leukemia (2), Haematologica, Blood Cancer Journal, Cancer Communication, Journal of Hematology & Oncology (2), Signal Transduction and Targeted Therapy, Cellular & Molecular Immunology, and The Lancet Hematology.

Editorial Work

• Co-editor of “Clinical Management Guidelines for Adverse Effects of CAR-T Cell Therapy for NHL” and “Expert Consensus on Multidisciplinary Management of CAR-T Cell Therapy for Lymphoma”, published by Tsinghua University Press, 2021.
• Associate Editor of “CAR-T Cell Immunotherapy”, published by People’s Medical Publishing House, 2021.
• Associate Editor of “Case Studies in Tumor Cell Therapy”, published by Shanghai Scientific & Technical Literature Publishing House, 2024.

Research Contributions

Dr. Qian has led or participated in seven national key research projects, including the National Natural Science Foundation’s major and exploratory projects, and key projects under Zhejiang Province’s Research and Development Program.

• Recipient of two National Science and Technology Progress Second Prizes
• Recipient of nearly ten Zhejiang Province Science and Technology Progress First and Second Prizes

Dr. Qian’s distinguished career has firmly established him as a leader in hematology and CAR-T cell therapy, advancing both scientific research and clinical practice in the field.