2022CSH Prof. Dehui Zou: Application Status of CAR-T Cell Therapy

Listening to the sound of blood and perceiving the rhythm of life, the much-anticipated "17th National Hematology Academic Conference of the Chinese Medical Association" was grandly opened
at the National Convention and Exhibition Center in Shanghai on September 23-25, 2022.
The conference was hosted by the Chinese Medical Association and the Hematology Branch of the Chinese Medical Association, hosted by the Shanghai Medical Association, co-organized by Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, the First Affiliated Hospital of Soochow University, and the Union Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology, with the theme of "respect, inheritance, collaboration and innovation", specially invited famous experts at home and abroad to talk about the latest progress
in the field of blood diseases.
On this occasion, Yimaitong specially invited Professor Zou Dehui of the Blood Disease Hospital of the Chinese Academy of Medical Sciences to be interviewed, combined with clinical experience, to introduce the application status of
CAR-T cell therapy for us.

As a leader in immunotherapy, CAR-T cell therapy has brought new hope
to many patients with blood malignancies.
Could you please briefly talk about the current application of CAR-T cell therapy in hematological malignancies worldwide?

Professor Zou Dehui

In the past ten years, cell therapy drugs represented by CAR-T have developed rapidly, and commercial CAR-T products have been listed
at home and abroad.
At present, CAR-T cell therapy has made great breakthroughs in the field of hematological tumors, while the progress in the field of solid tumors is relatively slow
.
In hematologic tumors, CAR-T cell therapy is more mature in B-cell tumors, such as relapsed/refractory acute B-lymphoblastic leukemia (B-ALL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantular cell lymphoma (MCL), marginal area lymphoma (MZL), and multiple myeloma (MM
).
Both clinical research and commercially available CAR-T cell therapies are mainly focused on the field of
B-cell tumors.
After a large number of clinical trials and large-scale real-world studies after marketing, CAR-T cell therapy is becoming increasingly mature
.
Recent clinical trials/findings support that the timing of CAR-T cell therapy in large B-cell lymphoma can be moved from >2-line therapy to 2-line therapy in high-risk relapsed/refractory patients; At the same time, the application of CAR-T cell therapy in the 1.
5-line treatment of high-risk patients is also being explored, and good results have been achieved
.

Compared with the development of other new drugs, the gap between the development of CAR-T cell therapy in China and the international leading level is small
.
China and the United States are currently the two countries with the largest number of registered CAR-T clinical trials, accounting for 80% or more
of the world's registered CAR-T clinical trials.
In addition, the number of registered CAR-T clinical trials in China has increased
significantly in recent years.
In 2021, two CAR-T cell therapies (Achillense and Ricky Ollense) will be available in China with indications for relapse/refractory large B-cell lymphoma
.
After a year of development and practice, CAR-T cell therapy has been well applied
in the real world.
In addition, BCMA CAR-T will be available at the end of this year or the first half of next year, and CD19 CAR-T cell therapy will also be approved in China for relapse/refractory adult B-ALL patients
.

Although CAR-T cell therapy has made great progress, the development of CAR-T cell therapy has only been around for more than ten years, and it is still in the early and early stages of development, and there is still huge room for
development in the future.
In the future, more indications should be further developed, more CAR-T cell therapy targets should be explored, and CAR-T cell therapy technology should be improved to further improve the efficacy and safety of CAR-T cell therapy, so that more patients can benefit
from CAR-T cell therapy.

In recent years, CAR-T cell therapy has blossomed
everywhere in blood malignancies.
Research on myeloid tumors has progressed slowly
compared to lymphoma.
Could you please briefly talk about the development status and development trend of CAR-T in myeloid hematologic malignancies?

Professor
Zou Dehui At present, CAR-T cell therapy is relatively mature
in B cell tumors.
CAR-T cell therapy has also made initial progress in T-cell lymphoma, and further clinical trials and even marketing
may be carried out in the future.
Myeloid tumors account for a relatively large proportion of hematologic malignancies, but the development of CAR-T cell therapy in myeloid tumors is slower than lymphoma, the main reason is that although there are multiple possible CAR-T cell therapy targets in myeloid tumors, CAR-T cells will also produce relatively large toxicity to normal hematopoietic cells and hematopoietic stem/group cells while killing tumor cells, that is, obvious "off-target" bone marrow/hematopoietic toxicity
.


There are multiple antigenic targets in myeloid tumors that may be used in CAR-T cell therapy, such as CD33, CD123, LeY, CD44v6, CLL1, etc
.
Taking the common target CD123 as an example, CD123 is overexpressed in myeloid blasts and is low
on normal myeloid cells and hematopoietic stem/group cells.
ADC drugs targeting CD123 have shown certain efficacy in clinical trials and have relatively low toxicity to hematopoietic stem cells; However, in studies related to CD123 CAR-T cell therapy, there is significant bone marrow/hematopoietic toxicity
.

Professor Wang Jianxiang's team from the Blood Disease Hospital of the Chinese Academy of Medical Sciences reported a preclinical study on CD123-CD33 complex CAR-T cells with novel single-stranded antibody variable region fragment (scFvs) antigen binding domain in acute myeloid leukemia at EHA, and the results showed that the composite CD123-CD33 CAR-T cells have good anti-tumor activity while also greatly reducing the toxicity of CAR-T cell therapy to hematopoietic stem cells, better retaining hematopoietic function, and is expected to enter the next clinical trial
.
It is believed that with the continuous progress of CAR-T cell therapy, the number of clinical trials related to CAR-T cell therapy for myeloid tumors will increase, and even one day there will be CAR-T cell therapy for myeloid tumors on the market
.

Professor Zou Dehui

• Chief Physician, Hematology Hospital, Chinese Academy of Medical Sciences

• Standing Committee Member of Lymphoma Professional Committee of Chinese Anti-Cancer Association

• Chairman of the Lymphoma Professional Committee of Tianjin Anti-Cancer Association

• Deputy Leader of the CSCO Autologous Hematopoietic Stem Cell Transplantation Working Group

• Deputy leader of the lymphoma group of the Hematology and Oncology Professional Committee of the Chinese Anti-Cancer Association

• Member of the Standing Committee of the Hematology Branch of the Chinese Geriatrics Association

• Editorial Board Member, Chinese Journal of Hematology

Editor: Wenting Reviewer: Professor Zou Dehui Typesetting: Wenting Execution: moly

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