The 17th National Hematology Academic Conference of the Chinese Medical Association was grandly opened in Shanghai from September 23 to 25, 2022. With the theme of "Respect, Inheritance, Collaboration and Innovation", famous experts at home and abroad specially invited famous domestic and foreign experts to discuss the latest progress in the field of blood diseases. At this conference, Professor Zhao Mingfeng, Tianjin First Central Hospital, , , , , gave an explanation on the current situation of CAR-T therapy in the field of acute myeloid leukemia (AML) and the development of various targets with the title "Current status of clinical application of CAR-T cells in the treatment of AML and the research on the new target CD312". Current status of application of
CAR-T therapy in AML
AML is the most common acute leukemia in adults, accounting for about 60% of all leukemia . Currently, the main measures of AML treatment include chemotherapy, targeted therapy and hematopoietic stem cell transplantation (HSCT). Patients with relapsed/refractory (R/R) AML have poor prognosis and high recurrence rates after transplantation, and new drugs and new regimens are needed to improve the long-term survival of such patients. The rapid development of CAR-T therapy provides new treatment options for AML patients, but compared with acute lymphocytic leukemia (ALL), non-Hodgkin's lymphoma (NHL) and multiple myeloma (MM), CAR-T therapy for AML is relatively slow, relatively immature, and is still in its infancy. Previously reported clinical targets include CD33, NKG2D, LeY, CD123, CLL-1, etc. Professor Zhao Mingfeng said that the current bottlenecks of CAR-T therapy include antigen escape, extratarget toxicity, lack of specific antigens and immunosuppression of microenvironment , etc. Therefore, the discovery of new targets, CAR-T combined targeted drugs, multi-target CAR-T therapy trials, etc. are all working hard to overcome the above problems. Research progress of
CAR-T therapy in AML
target CD123 CAR-T therapy
CD123 is a membrane-binding protein that is overexpressed in AML tumor cells and leukemia stem cells and other cells, and is involved in cell proliferation and differentiation. The 2018 American Annual Conference on Hematology (ASH) reported the efficacy results of a targeted CD123 CAR-T therapy. In the study, 4/6 AML patients achieved complete remission (CR) after receiving treatment; however, many researchers, including Professor Mingfeng's team, failed to repeat such good results in subsequent trials. Based on this, some researchers found in in vitro experiments that azacitidine or decitabine combined with targeting CD123 CAR-T therapy can enhance the lethality of CAR-T cells. Professor Zhao Mingfeng said that although the efficacy results of targeted CD123 CAR-T therapy in AML have not been repeated in many trials, because the high expression of CD123 by blastic plasmacytoid dendritic cell tumors (BPDCN) have achieved significant efficacy results in BPDCN treatment.
targeted CLL-1 CAR-T therapy
CLL-1 is a type II transmembrane glycoprotein and is present in most AML primitive cells, while normal hematopoietic stem cells (HSCs) do not express CLL-1. In 2021, Clinical Cancer Research published efficacy data on targeted CLL-1 CAR-T therapy for the first time in 4 R/R AML children. The results showed that 3 patients could achieve MRD-negative (MRD-) CR. Professor Mingfeng Zhao’s team reported the efficacy results of targeting CLL-1 CAR-T therapy combined with rituximab as a switch in adult patients with R/R AML in 2022 in the Journal of Hematology Oncology. In this study, 10 patients were included, with a median CLL-1 CAR-T cell transfection efficiency of 50.53% (23.98%-73.14%) and a median infusion dose of 1.5x106/kg (1~2x106); 7 of them achieved CR or hematologic incomplete recovery, but were not followed up for 173 days, and 6 patients survived; 6 patients were able to bridge HSCT after CAR-T, and 4 patients were still in MRD-CR at the last follow-up. For safety results, 9/10 patients developed grade 3/4 neutrophil deficiency, and all patients developed cytokine release syndrome (CRS). Professor Zhao Mingfeng concluded that targeted CLL-1 CAR-T therapy is relatively safe and effective in R/R AML patients, but due to the presence of CLL-1 on the surface of neutrophils, the incidence of granulocyte deficiency is higher after targeted CLL-1 CAR-T therapy; in addition, multiple specific cases show that bridging HSCT is an effective treatment method to save granulocyte deficiency caused by off-target toxicity and can benefit patients' long-term survival.
CAR-T therapy targeting other targets
siglecs family is a widely expressed cell surface receptor superfamily expressed in hematopoietic cells and is associated with the inhibitory signal of in human immune cells. Professor Zhao Mingfeng explained that siglecs-3 (CD33) is expressed on normal hematopoietic stem cells and progenitor cells, so targeted CD33 CAR-T therapy is relatively toxic, but the subsequent continuous optimization of targeted CD33 CAR-T products enables it to be used in the field of AML therapy. The results of a phase 1/1b clinical trial targeting CD33 CAR-T therapy for R/R AML patients were presented at the 2021 ASH conference. The study showed that among the 6 patients with evaluable condition, 3 achieved overall remission with an overall response rate (ORR) of 50%. In 2021, the Journal of Hematology Oncology published the efficacy results of a targeted CD38 CAR-T therapy in patients with relapsed AML after allo-HSCT. The study included 6 patients with AML who relapsed after transplantation, and 4 patients who received targeted CD38 CAR-T therapy to achieve CR or CRi. Professor Zhao Mingfeng said that there are targets such as CD7 and siglec-6 currently under research, and we look forward to better research data in the future. Individualized selection of CAR-T products is more important in AML therapy. For example, although CD19 is B cell expression antigen, AML patients with tumor cells expressing CD19 can successfully achieve MRD-CR and bridge HSCT after receiving targeted CD19 CAR-T therapy.
dual-target CAR-T therapy
Summary
AML CAR-T therapy is generally in the early stage of exploration, but breakthroughs have been made, such as targeted CLL-1 CAR-T therapy and dual-target CAR-T therapy. Regarding the exploration of new targets, Professor Zhao Mingfeng's team found that targeted CD312 CAR-T therapy has good efficacy in in vitro and intra-vitro trials. It is planned to further carry out relevant clinical trials, hoping to obtain better data results.
Zhao Mingfeng Professor
Doctor of Medicine, Chief Physician, Nankai University , Tianjin Medical University Doctoral Supervisor
Director of Hematology Department of Tianjin First Central Hospital
Member of the Red Cytocytology Group of the Chinese Hematology Society, Standing Committee Member of the Tianjin Branch
National Committee of the Hematology Committee of the Chinese Society of Integrated Traditional Chinese and Western Medicine, Vice Chairman of the Tianjin Branch
National Committee of the Hematology Society of China, Standing Committee Member of the Tianjin Branch
National Committee of the Hematology Society of China, Deputy Chairman of the Tianjin Branch
National Committee of the Hematology Society of China, Standing Committee Member of the Tianjin Branch
China Anti-cancer Association Tianjin Lymphoma Vice Chairman of the Professional Committee
National Committee of the Hematology Branch of the Chinese Geriatric Association
Member of the Expert Committee of the China MDS/MPN Collaboration Group
Member of the Hematology Professional Committee of the Cross-Strait Exchange Association
Member of the Hematology Committee of the Chinese Ethnic Medicine Association
Executive Director of the Hematology Committee of the Tianjin Medical and Health Society
Deputy Chairman of the Hematology Prevention and Control Professional Committee of the Tianjin Medical and Health Society
Review: Quinta
Typesetting: moly
Execution: moly
