In recent years, the rise of immunotherapy and targeted therapy has continuously updated the treatment strategies of hematological tumors, and cellular immunotherapy represented by CAR-T cell therapy is gradually changing the treatment pattern of hematological tumors, bringing new hope of cure to patients, especially in the field of lymphoma, and has achieved good results. However, due to the complexity and high cost of its preparation process, researchers from all over the world are exploring more "economical and applicable" CAR-T cell therapies to benefit more patients with hematological cancers.
The 50th Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT) (EBMT 2024) was held in Glasgow, UK, from April 14 to 17, 2024, to discuss cutting-edge research advances related to hematopoietic stem cell transplantation and cell therapy. Nearly 8,000 experts and scholars in the field of transplantation and cell therapy from 89 countries around the world attended the EBMT Annual Meeting, and the number of participants in China ranked eighth in the world, which fully reflects the increasing influence of the mainland in the field of transplantation and cell therapy. Professor Ma Jun from Harbin Institute of Hematology and Oncology went to the conference in Glasgow, UK, and shared with us two bedside manufactured studies of targeted CD19 CAR-T for the treatment of relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL).
01
Efficacy of Bedside Manufacturing, CD19-Targeted CAR-T Cell Therapy in R/R NHL: Phase I Atalanta-1 Trial Results
The Atalanta-1 trial is an ongoing Phase I/II, multicenter trial of an ongoing point-of-care (PoC)-manufactured CD19 CAR-T for the treatment of R/R NHL. GLPG5101 as a fresh product for patients with R/R diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), marginal zone lymphoma (MZL), mantle cell lymphoma (MCL), Burkitt lymphoma or primary central nervous system lymphoma (PCNSL). The primary objectives of Phase I (Ph1) are safety and to determine the recommended Phase II dose. The primary objective of Phase II (Ph2) is efficacy (objective response rate [ORR]), and secondary objectives include feasibility, safety, GLPG5101 pharmacokinetics, and other efficacy endpoints of PoC production.
Findings:
As shown in Table 1, as of September 1, 2023, 23 patients (R/R MCL [n=5], DLBCL [n=7], FL [n=9], or MZL [n=2]) were infused with fresh products with a median time of 7 days (range 7-8) and one patient received cryopreserved products with a vein-to-vein time of 13 days. In Ph1, three patients received dose level (DL) 1 instead of DL2 due to lower CAR+ T cell yields. Twenty-three patients were included in the safety group.
Table 1
Most treatment-emergent adverse events were grade 1 to 2, and most ≥ grade 3 adverse events were hematologic events. Cytokine release syndrome (CRS) occurred in 7 (50%) and 3 (33%) patients in Ph1 and Ph2, respectively (Table 2), and immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 6 (43%, all grade 1) and 1 (11%, grade 3), respectively (Table 3).
Table 2
Table 3
In Ph1, 2 patients developed grade ≥3 infection, and 4 patients reported dose-limiting toxicities (DL1, n=1; DL2, n=3). The latter included three cases of grade 4 neutropenia, which could be controlled by granulocyte colony-stimulating factor, but did not limit dose escalation, and one case of grade 5 intraperitoneal hemorrhage, which occurred 12 days after infusion (DL2), caused by grade 4 disseminated intravascular coagulation, and patients with multiple comorbidities. One patient with sustained complete remission (CR) was documented > 6 months after infusion, and one case of grade 5 urogenic sepsis was recorded. No grade ≥3 infection occurred with Ph2.
Of the 14 evaluable patients in Ph1, 12 responded to treatment (ORR 86%) and 11 achieved CR (CR rate 79%). Four patients progressed after initial remission: two with CD19-positive recurrence, one with CD19-negative recurrence, and one with undiagnosed diagnosis. The ORR and CR rates were 86% and 71% for DL1 and 86% for DL2, respectively. Of the 7 efficacy-evaluable patients in Ph2, 6 responded to treatment (ORR 86%), including 4 with CR (CR rate of 57%) (Figure 1). Assessed by exploratory flow cytometry, PoC manufacturing increases the early T cell phenotype of the final product. GLPG5101 exhibited strong amplification capacity at different doses.
Figure 1
Conclusions of the study
The ongoing Atalanta-1 study has shown that PoC-made CAR-T cell products with short vein-to-vein times (median 7 days) are feasible with fresh products. The safety profile of GLPG5101 is comparable to that of other CD19-targeted CAR-T cell therapies. CR rates were higher in both Ph1 and Ph2 in heavily pretreated patient populations.
02
Efficacy of Bedside Fabricated CD19-Targeted CAR-T Cell Therapies in R/R CLL (Including Richter Transformation): Results from the Phase I Euplagia-1 Study
The Euplagia-1 study is an ongoing Phase I/II study that explores the efficacy of PoC-prepared, CD19/4-1bb targeted CAR-T cell therapy (GLPG5201) in patients with R/R CLL/SLL, including Richter transformation [RT]). Patients with CD19+ R/R CLL/SLL who had received ≥ 2nd line of prior therapy, including BTK inhibitors, met the inclusion criteria, and the inclusion criteria for patients with RT were not related to prior lines. The primary objectives are safety and to determine the recommended Ph2 dose (RP2D, Ph1), objective response rate (ORR, Ph2).
Findings:
The baseline characteristics of patients are shown in Table 4, and as of September 6, 2023, all 15 patients planned to receive Ph1 treatment were enrolled with DL1 (35×106 CAR+ T cells, n=6) or DL2 (100×106 CAR+ T cells, n=9). All enrolled patients received fresh products after successful PoC preparation. Thirteen of 15 patients (80%) were infused, and the median time to vein-to-vein was 7 days (range 7-14 days). All patients were diagnosed with R/R CLL, and 9/15 patients had RT. 14/15 patients had been previously treated with BTK inhibitors and/or venetoclax. High-risk features were prevalent in this population, and 3 cases (23%) were found to be 17p deletion, 6 cases (46%) were TP53 mutations, 3 cases (50%) were complex karyotypes, and 13 cases (100%) were not mutated in the variable region of immunoglobulin heavy chain.
Table 4
Most treatment-emergent adverse events were grade 1 to 2, and most ≥ grade 3 adverse events were hematologic events. Seven patients (47%) developed grade 1 to 2 CRS, no CRS≥ grade 3 cases, and no ICANS cases. One dose-limiting toxicity (grade 4 neutropenia) occurred, but it was manageable. No GLPG5201-related unintended toxicities were observed, and no patients died during the study (Table 5).
Table 5
Among patients with evaluable efficacy (n=14), 13 patients had remission (ORR 93%). Eight patients had radiographically confirmed CR (CR rate of 57%). The ORR and CR rates were 83% and 50% at DL1 and 100% and 63% at DL2, respectively. All but one patient with RT had a response (ORR of 89%), and 6 of the 9 patients with RT achieved CR (CR rate of 67%). One patient with RT was refractory to CD19 negative. All six RT patients treated with DL2 responded (ORR 100%, CR rate 67%). Select DL2 as the RP2D. At the time of analysis, 10/13 patients (77%) were still in remission. Median duration of response was not achieved (median follow-up of studies was 6 months, range 1-15 months). Three patients progressed after initial remission.
Figure 2
Conclusions of the study
Data from 15 patients enrolled in the Phase I Euplagia-1 trial suggest that a CAR-T cell therapy prepared with a vein-to-vein time of only 7 days is feasible and effective. No accidental safety signals, no CRS ≥ level 3 or ICANS occurring. Efficacy data were encouraging, with a best ORR of 93% and a CR of 57%, with all patients achieving RP2D responding (ORR of 100%). Follow-up is ongoing and the Ph2 expansion cohort will be open.
Expert commentary
As a new type of cellular immunotherapy, CAR-T cell therapy has direct, synergistic and persistent, which can mobilize the body's immune system, specifically kill tumor cells, and continue to play an immune surveillance role. However, due to the complexity and length of the preparation process and the high price, many patients are discouraged, so how to optimize the CAR-T production process, shorten the preparation time, and reduce the price and cost has always been the key to update and iterate in this field. The two studies explored the efficacy of point-of-care, manufactured CD19-targeted CAR-T therapy for R/R NHL and CLL/SLL with encouraging efficacy data and manageable safety, and the process shortened the vein-to-vein time to 7 days without the need for cryopreservation, which is expected to address the key limitations of traditional CAR-T cell therapy and may bring new opportunities for patients with hematological cancers.
In addition to the high price and complex preparation process, CAR-T cell therapy is still facing problems such as balancing efficacy and safety, relatively concentrated indications, and target clustering, so there are still a lot of gaps in the CAR-T field that need to be broken through and innovated. I believe that in the future, these problems can be overcome one by one, and CAR-T cell therapy will eventually be able to break the game, cover more tumor types and benefit more patients.
Prof. Jun Ma
- Chief Physician, Professor, Doctoral Supervisor
- Director of Harbin Institute of Hematology and Oncology
- Chairman of the Board of Supervisors of the Chinese Society of Clinical Oncology (CSCO).
- Vice Chairman of the Asian Society of Clinical Oncology
- Chairman of the Leukemia Expert Committee of the Chinese Society of Clinical Oncology
- Leader of the expert group of the lymphoma specialty construction project of the Capacity Building and Continuing Education Center of the National Health Commission
- Editor-in-Chief of the Journal of Leukemia and Lymphoma
- Former Chairman of the Chinese Society of Clinical Oncology (CSCO).
- Former vice chairman of the Hematology Branch of the Chinese Medical Association
Bibliography:
1.Marie José Kersten, Kirsten Saevels, Sophie Servais, et al. SEVEN-DAY VEIN-TO-VEIN POINT-OF-CARE–MANUFACTURED CD19 CAR T-CELL THERAPY (GLPG5101) IN RELAPSED/REFRACTORY NON-HODGKIN LYMPHOMA (NHL): RESULTS FROM THE PHASE 1 ATALANTA-1 TRIAL. 2024 EBMT. Abstract # OS16-04.
2.Valentín Ortiz-Maldonado, Nuria Martinez-Cibrian, Julio Delgado, et al. SEVEN-DAY VEIN-TO-VEIN POINT-OF-CARE–MANUFACTURED CD19 CAR T-CELL THERAPY (GLPG5201) IN RELAPSED/REFRACTORY CHRONIC LYMPHOCYTIC LEUKEMIA INCLUDING RICHTER TRANSFORMATION: RESULTS FROM THE PHASE 1 EUPLAGIA-1 STUDY. 2024 EBMT. Abstract # OS16-05.
Editor: Moly Review: Professor Ma Jun Typesetting: Moly Execution: Cherry
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