2022CSH Professor Jianxiang Wang: The CD19 CAR-T Herkirun race is poised in r/r ALL

Adult acute lymphoblastic leukemia (ALL) is one of the most common acute leukemias in adults, accounting for about 20% to 30%.

In recent years, the rapid development of chimeric antigen receptor T (CAR-T) cell therapy has improved the efficacy
of adult ALL to a certain extent.
In August 2017, the U.
S.
Food and Drug Administration (FDA) approved the world's first commercial CAR-T cell product, Kymriah (Tisagenlecleucel), for the treatment of recurrent or refractory acute B-lymphoblastic leukemia (r/r B-ALL), resulting in an 81% r/r B-ALL remission rate (CR+CRi) in children and young adults, and a 1-year OS rate and an EFS rate of 76% and 50%,
respectively.
* CR, complete remission; CRi, complete remission with incomplete recovery of hematology; OS, Total Survival; EFS, Event-free Survival
Recently, the much-anticipated "17th National Hematology Academic Conference of the Chinese Medical Association" was grandly held, and many domestic and foreign experts jointly discussed the cutting-edge progress
of blood diseases.
On this occasion, Yimaitong sincerely invited Professor Wang Jianxiang of the Hematology Hospital of the Chinese Academy of Medical Sciences to be interviewed to share the research progress in the field of ALL and the development prospects
of targeted CD19 CAR-T therapy.

As the corresponding author of the 2021 edition of the "Guidelines for the Diagnosis and Treatment of Acute Lymphoblastic Leukemia in Adults in China", can you please talk about the treatment status of ALL and the unmet clinical needs?

Professor
Wang Jianxiang As we all know, ALL is a common malignant disease of the blood system, which can occur in all ages, childhood is one of the high incidence ages, from childhood, adolescence, adulthood to old age, the incidence of ALL is gradually rising
.


At present, the main treatment measures for adult ALL are chemotherapy and hematopoietic stem cell transplantation, and patients with Philadelphia chromosome-positive (Ph+) ALL can also be combined with targeted drug therapy
。 In terms of overall efficacy, the treatment effect of ALL in children is better, and the efficacy of ALL from adolescents to adults gradually decreases with age, mainly manifested as poor survival, and the 5-year OS rate of ALL patients over 40 years old is less than 20%, so new drugs, technologies and treatment strategies are needed to solve the problem of poor efficacy and low survival rate of adult ALL
.

The rapid development of CAR-T cell therapy has improved the efficacy
of adult ALL to a certain extent.
As the principal investigator of Herculent Injection (CNCT19), the first Chinese proprietary intellectual property targeting CD19 CAR-T drug, could you please talk about the advantages of the drug in ALL treatment?

Professor
Wang Jianxiang After years of research, researchers at home and abroad have found that CAR-T cells have their own unique structure, including the recognition structure that is "navigation", a single chain of monoclonal antibodies and a T cell activation unit, which can navigate the modified T cells to leukemia cells and detonate "cannonballs", thereby killing leukemia cells
.


At present, the CAR-T therapy targeting CD19 has been approved internationally and is in the process of research and development in China
.
Hejirensai, a targeted CD19 CAR-T drug developed by Heyuan Biologics, is the first CAR-T cell product with China's independent intellectual property rights and the unique structure of antibody + T cell activation sequence 4-1BB molecule, and preclinical in vitro and in vivo tests have confirmed that it can effectively target and kill B-ALL tumor cells, and show preliminary efficacy
in the IIT study of patients with r/r B-ALL 。 Based on this Heyuan Biologics has initiated a number of registered clinical trials, in the phase I / II clinical trials, Herkilen race not only showed encouraging efficacy, but also has certain advantages over similar products in terms of safety, no level 5 CRS and ICANS events, and the incidence of level 3-4 CRS and ICANS is low
.
* IIT, a clinical study initiated by researchers; CRS, cytokine release syndrome; ICANS, immune effector cell-associated neurotoxicity syndrome
Considering the unmet clinical needs of domestic adult r/r B-ALL patients, as well as the domestic no targeted CD19 CAR-T cell product approved, Herkirensai was included in the "breakthrough therapeutic drug (BTD)" by the Drug Evaluation Center (CDE) of the State Drug Administration in 2021 due to its outstanding efficacy and safety in IIT and Phase I / II clinical trials, It is expected to receive accelerated review and marketing, providing new and effective treatment options
for the majority of r/r B-ALL patients.

Based on the innovations of Herkilens, how do you think this CD19 CAR-T targeted drug can benefit patients? What are your expectations for the clinical use of Herkilensaic?

In order to verify the efficacy of CD19 CAR-T therapy, Professor
Wang Jianxiang initiated an IIT clinical study of Hekylenrace for adult r/r B-ALL as the lead investigator
.
The study included a total of 30 adult patients with B-ALL who received Herculense cell therapy between July 2017 and September 2020, and evaluated the effectiveness of
27 patients within 3 months.


The results of the study showed that 14 of the 15 patients with bone marrow relapse (including 11 patients with refractory) obtained CR/CRi, with an ORR of 93.
3%, of which the CR rate was 80.
0%, and 92.
9% of the remission patients (13/14) achieved MRD negative, and the MRD negative rate was 90.
9%, indicating that the patient's residual disease level after treatment was very low and achieved very good deep remission
。 In addition, patient survival was also significantly improved, with a median OS of 19.
3 months in 30 patients and 11.
5 months in 14 patients with relapse or refractory in remission, and the efficacy of Herkirensai was positive
compared with the previous poor survival data of these patients (2-6 months).
* ORR, total response rate; MRD, minimal residual disease
In subsequent Phase I clinical studies, Herkirensai also showed a high remission, with an ORR of 88.
9% within 3 months and an ORR of 56%
at 3 months.
Based on its considerable efficacy, Herkilen Race is expected to become the first targeted CD19 CAR-T product with independent intellectual property rights in China, which can benefit Chinese r/r B-ALL patients and other B-cell tumor patients
.

What do you think is the prospect of targeted CD19 CAR-T cell therapy in the ALL field, and what other research directions are worth exploring in the future ALL field?

Professor Wang Jianxiang

At present, ALL has a short remission period and a high recurrence rate after traditional treatment, and some patients are not easy to achieve remission, or it is difficult to achieve remission after recurrence and become refractory patients
.
Therefore, the primary goal at this stage is to solve the problem that r/r ALL patients are not easy to alleviate and the depth of remission is not enough, and the next step is to improve the treatment plan according to the individual patient's situation, optimize the treatment dose and carry out patient management, not only so that r/r ALL patients can achieve remission, but also to extend the duration of remission as much as possible, so as to achieve the purpose of improving the long-term survival of
patients.

It is worth noting that CAR-T cell therapy has also produced a series of clinical problems in the new era of cellular immunotherapy, which need to be continuously explored and improved by researchers, such as improving the efficacy of CAR-T therapy while minimizing its adverse reactions as much as possible to ensure the safety of treatment and maximize the benefits of
patients from treatment 。 For example, when CD19 CAR-T cell products are treated with ALL, T cells will be activated in the process of identifying and killing tumors, bringing corresponding adverse reactions; Since some of the target antigens are expressed not only in leukemia cells or tumor cells, but also in other tissues and even normal tissues, CAR-T therapy may have a targeted detumor effect
.
How to identify and manage these adverse reactions as early as possible is a matter of clinical concern
.

In addition, how CAR-T therapy can be effectively combined with existing therapies such as targeted therapy, immunotherapy and other therapies to maintain the viability of T cells and strengthen the activity of CAR-T cells, effectively control adverse reactions in related treatments while improving efficacy, optimizing treatment processes, promoting rational drug use and realizing whole-process management of diseases need to be further explored
in the future.

Professor Wang Jianxiang

• Vice President of the Hematology Hospital of the Chinese Academy of Medical Sciences and Director of the Leukemia Diagnosis and Treatment Center

• Director of the National Research Center for Clinical Medicine of Hematology

• Former Chairman of the Hematology Branch of the Chinese Medical Association

• Vice President of Internal Medicine Branch of Chinese Medical Doctor Association

• Vice President of the Hematology Branch of the Chinese Medical Doctor Association

• Chairman of Hematology and Oncology Committee of Chinese Anti-Cancer Association (2012-2015)

• J Hematol & Oncol Associate Editor, Blood Editorial Board, Chinese Journal of Hematology Editor-in-Chief (2012-2016)

• "Jie Qing", "New Century Millions of Talents Project" national candidates, the Ministry of Health Tugong experts, the State Council special experts

• CD19 and CD33 CAR-T are the main developers and leaders of leukemia treatment, and the prognostic stratification, intensive induction and full management have significantly improved the efficacy of acute leukemia

• Led the development of multiple diagnosis and treatment guidelines for acute myeloid leukemia, acute lymphoblastic leukemia and chronic myeloid leukemia

• NIH Postdoctoral Outstanding Research Award, First Prize of the 10th Wu Jieping Medical Research Award - Paul Janssen Pharmaceutical Research Award, First Prize of Tianjin Science and Technology Progress Award (First Finisher)

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