2022CSH Prof. Mingfeng Zhao: Research progress of CAR-T cells in the treatment of acute myeloid leukemia

The 17th National Hematology Academic Conference of the Chinese Medical Association was grandly opened in Shanghai on September 23-25, 2022, with the theme of "respect, inheritance, collaboration and innovation", and invited well-known experts at home and abroad to talk about the latest progress
in the field of blood diseases.
At the conference, Professor Zhao Mingfeng of Tianjin First Central Hospital gave a lecture
on the current situation of CAR-T cell therapy in the field of acute myeloid leukemia (AML) and the development of various targets with the title of "Clinical Application Status of CAR-T Cell Therapy in AML and Research on New Target CD312".

AML is the most common acute leukemia in adults, accounting for about 60% of all leukemias, and the main measures currently treated by AML include chemotherapy, targeted therapy, and hematopoietic stem cell transplantation (HSCT
).
Patients with relapse/refractory (R/R) AML have a poor prognosis and high post-transplant recurrence rates, requiring new drugs and new protocols to improve long-term survival
in such patients.
The rapid development of CAR-T therapy has provided new treatment options for AML patients, but compared with acute lymphoblastic leukemia (ALL), non-Hodgkin lymphoma (NHL) and multiple myeloma (MM), AML's CAR-T therapy has progressed relatively slowly, relatively immature, and is still in its infancy, and 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, extra-target toxicity, lack of specific antigens and immunosuppression of the microenvironment, etc.
, so the discovery of new targets, CAR-T combined targeted drugs, multi-target CAR-T therapy trials, etc.
, are trying to overcome the above problems
.

CD123 is a membrane-binding protein that is overexpressed in cells such as AML tumor cells and leukemia stem cells, and is involved in the proliferation and differentiation
of cells.
The 2018 American Hematology Annual Meeting (ASH) reported efficacy results in a targeted CD123 CAR-T therapy in which 4/6 patients with AML achieved complete remission (CR) after treatment; However, many researchers, including Professor Zhao Mingfeng's team, have not been able to repeat such good results in subsequent trials
.
Based on this, researchers have found in in vitro trials that the combination of azacitidine or decitabine 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 replicated in many trials, due to the high expression of CD123 in mother-cytocytic plasmacytic dendritic cell tumors (BPDCN), targeted CD123 CAR-T therapy has achieved significant efficacy in
BPDCN therapy.

CLL-1 is a type II transmembrane glycoprotein found in most AML blast cells, while normal hematopoietic stem cells (HSCs) do not express CLL-1
.
In 2021, Clinical Cancer Research published the efficacy data of targeted CLL-1 CAR-T therapy for the first time in 4 children with R/R AML, and the results showed that 3 patients could achieve MRD-negative (MRD^-)CR
.
Professor Mingfeng Zhao's team reported in the Journal of Hematology Oncology in 2022 the efficacy of
targeted CLL-1 CAR-T therapy combined with rituximab as a switch in adult patients with R/R AML.
The study included 10 patients 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).
Among them, 7 patients achieved CR or hematological incomplete recovery of CR (CRi), with median follow-up of 173 days, and 6 patients survived; Six patients were able to bridge HSCTs after CAR-T, and four patients were still in MRD-CR
at the time of their last ^follow-up.
For safety results, grade 3/4 neutrophil deficiency occurred in 9/10 patients, and cytokine release syndrome (CRS)
occurred in all patients.
Professor Mingfeng Zhao concluded that targeted CLL-1 CAR-T therapy is relatively safe and effective in patients with R/R AML, but due to the presence of CLL-1 on the surface of neutrophils, the incidence of agranulocyte deficiency after targeted CLL-1 CAR-T therapy is high; In addition, several specific cases have shown that bridging HSCT is an effective treatment to save agranulocyte deficiency due to off-target toxicity and can benefit
patients for long-term survival.

The siglecs family is a superfamily of cell surface receptors that are widely expressed in hematopoietic cells and are associated
with inhibitory signals in human immune cells.
Professor Zhao Mingfeng explained that siglecs-3 (CD33) is expressed on normal hematopoietic stem cells and progenitor cells, so the targeting of CD33 CAR-T therapy is relatively toxic, but the 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 patients with R/R AML were presented at ASH 2021.
The study showed that of the 6 patients whose condition was assessable, 3 achieved an overall remission with an overall response rate (ORR) of 50%.

The 2021 Journal of Hematology Oncology published the results
of a targeted CD38 CAR-T therapy in patients with recurrent AML after allo-HSCT.
The study included six patients with AML who relapsed after transplantation and four who achieved CR or CRi after receiving targeted CD38 CAR-T
therapy.
Professor Zhao Mingfeng said that there are still CD7, siglec-6 and other targets under study, and it is expected that there will be better research data
in the future.
The individualized selection of CAR-T products is more important in AML therapy, for example, although CD19 is a B-cell surface antigen, patients with AML whose tumor cells express CD19 can successfully achieve MRD-CR and bridge HSCT
after receiving targeted CD19 ^CAR-T therapy.

The efficacy results of a double-target CAR-T therapy targeting CLL-1 and CD33 in AML were announced at the 2020 EHA conference, and 7 of the 9 patients included in the study achieved ^MRD-CR; Six cases can successfully bridge HSCT.

Professor Zhao Mingfeng said that dual-target CAR-T therapy is expected to bring further improvement to the efficacy of AML patients, and Professor Zhao Mingfeng's team is currently exploring the efficacy and safety of CD123 and NKG2D dual-target CAR-T therapy in AML, and looks forward to better data results
.

AML's CAR-T therapy is generally in the early exploration stage, but there have been breakthroughs, such as targeted CLL-1 CAR-T therapy and dual-target CAR-T therapy
.
For the exploration of new targets, Professor Zhao Mingfeng's team found that targeted CD312 CAR-T therapy has a good efficacy in in vitro and in vivo trials, and plans to further carry out relevant clinical trials in the hope of achieving better data results
.

Professor Zhao Mingfeng

• Doctor of Medicine, Chief Physician, Doctoral Supervisor of Nankai University and Tianjin Medical University

• Director of the Department of Hematology, Tianjin First Central Hospital

• He is a member of the Red Blood Cell Group of the Chinese Society of Hematology and a member of the Standing Committee of the Tianjin Branch

• He is a member of the Hematology Committee of the Chinese Association of Integrative Traditional Chinese and Western Medicine, and a vice chairman of the Tianjin Branch

• He is a member of the National Committee of the Hematology Society of the Chinese Medical Doctor Association and a member of the Standing Committee of the Tianjin Branch

• Vice Chairman of Tianjin Lymphoma Professional Committee of China Anti-Cancer Association

• He is a member of the Hematology Branch of the Chinese Geriatrics Association

• Member of the Expert Committee of the China MDS/MPN Collaboration Group

• He is a member of the Hematology Professional Committee of the Cross-Strait Exchange Association

• Standing Director of Hematology Committee of Chinese Society of Ethnic Medicine

• Vice Chairman of the Blood Disease Prevention and Treatment Professional Committee of Tianjin Medical and Health Society

Reviewer: Quinta

Typography : moly

Execution: moly

Poke "Read the original article" and go to the micro-official website to get more meeting information