Prof. Cheng Zhang: Application of CAR-T Therapy in HSCT The 16th National Leukemia and Lymphoma Conference

Sponsored by the Chinese Medical Association, Hematology Branch of Chinese Medical Association, Leukemia and Lymphoma Group of Hematology Branch of Chinese Medical Association, Hematology Hospital of Chinese Academy of Medical Sciences (Institute of Hematology, Chinese Academy of Medical Sciences), First Affiliated Hospital of University of Science and Technology of China The 16th National Leukemia and Lymphoma Academic Conference hosted by the Chinese Medical Association will be held in Hefei, Anhui Province on October 8-10, 2021
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At this conference, Professor Zhang Cheng from the Second Affiliated Hospital of the Army Military Medical University gave a theme report on "Chimeric Antigen Receptor T Cell (CAR-T) Therapy in Hematopoietic Stem Cell Transplantation (HSCT)".
The content is organized as follows
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CAR-T therapy has shown remarkable efficacy in acute leukemia and non-Hodgkin's lymphoma (NHL) in recent years, and is considered to be one of the most promising tumor treatments
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Among them, CAR-T therapy represented by CD19 CAR-T cells brings new hope for the treatment and survival of relapsed and refractory B-cell acute lymphoblastic leukemia (B-ALL)
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The combination of CAR-T therapy and HSCT is currently an important research direction, "Is it necessary to bridge HSCT after CAR-T therapy has reached complete remission (CR)", "Is it necessary to combine allogeneic CAR-T therapy to eliminate drug resistance during HSCT? Residual, reduce disease recurrence" and "whether CAR-T cell prophylactic infusion is needed after HSCT to improve long-term survival" are the current research hotspots of CAR-T therapy and HSCT
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The application of allogeneic CAR-T cells in HSCT pretreatment Professor Zhang Cheng first introduced a case on the application of allogeneic CAR-T cells in HSCT pretreatment
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The patient is a 12-year-old woman who was diagnosed with ALL for 1+ years.
She was re-admitted to the hospital due to recurrence of the disease and received chemotherapy and anti-infective treatment.

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Four weeks after the end of chemotherapy, the patient's blood routine indicators did not recover, and the spleen became progressively enlarged after a short period of time shrinking
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Due to the patient's low blood picture and high bone marrow tumor burden, sufficient T cells could not be collected, and the patient's autologous CAR-T cell culture failed
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 In the study of the graft-versus-host disease (GVHD) animal model of allogeneic hematopoietic stem cell transplantation (Allo-HSCT) in mice, it was found that CAR-T cells from the donor were returned to the recipient's body on day 01, which has enhanced transplantation.
It has anti-leukemia (GVL) effect without increasing the effect of GVHD
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Then the patient was pre-treated with allogeneic CAR-T cell therapy, followed by Allo-HSCT
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After allogeneic CAR-T cell pretreatment and Allo-HSCT, the patient's hematopoietic system was successfully reconstructed and reached CR.
No leukemia cells were found in bone marrow biopsy, and minimal residual disease (MRD) was negative
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Allo-HSCT pretreated with CAR-T therapy is safe in this patient.
During the treatment, this patient did not develop severe cytokine release syndrome (CRS), and no acute GVHD was observed
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 A domestic study explored the efficacy of microtransplantation combined with allogeneic CAR-T cells in an elderly patient with relapsed and refractory ALL.
In the study, donor CAR-T cells and donor low-dose granulocyte colony stimulating factor (G -CSF) mobilized peripheral blood stem cells (G-PBSC) were infused into the patient at the same time
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The patient received microtransplantation combined with allogeneic CAR-T treatment and the tumor burden decreased significantly.
At the same time, no severe acute GVHD was observed.
However, the patient died of severe infection 31 days after treatment
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 The application of allogeneic CAR-T cells for recurrence after HSCT Professor Zhang Cheng then introduced the application of allogeneic CAR-T cells for recurrence after HSCT
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A study published in 2019 explored the application of allogeneic CAR-T therapy in a B-ALL patient who relapsed after HSCT
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The patient first received CAR-T cell therapy from the donor after recurrence.
Although the patient subsequently turned negative in MRD, the MRD became positive only 1 month later
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The patient subsequently received the donor-derived CD19/CD22 bispecific CAR-T cell therapy.
The bispecific CAR-T cell obtained a better curative effect in this patient.
The patient reached CR, and the CR status has lasted for 12 More than months
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The study showed that the expansion advantage of bispecific CAR-T cells is more obvious, and the expansion of bispecific CAR-T cells can be detected in the bone marrow and peripheral blood of this patient
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Although the patients in this study developed CRS after receiving bispecific CAR-T treatment, CRS can be effectively controlled by conventional targeted therapy drugs
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 A systematic review published in 2017 explored the efficacy of CAR-T therapy in patients with recurrence after HSCT.
The results of the study showed that the application of CAR-T therapy after HSCT recurrence can bring patients with varying degrees of disease remission.
At the same time, it has not been observed.
To severe GVHD, the use of allogeneic CAR-T cells in patients with recurrence after HSCT is safe and effective.
The use of donor CAR-T cells after HSCT is expected to separate GVHD and GVL
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 Subsequently, a multi-center retrospective study conducted in China also explored the application of CAR-T therapy in patients with relapse after HSCT
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The study included 43 patients from 9 centers across the country.
Among them, 34 patients received CAR-T cell therapy after HSCT recurrence to achieve CR.
The CR rate was as high as 79.
1%, and the 1-year event-free survival (EFS) rate reached 43%
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Among the 34 patients who achieved CR, 32 patients did not receive Allo-HSCT again, and the 1-year EFS rate of these patients reached 59%
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The subgroup analysis of the study showed that the therapeutic benefits of CAR-T therapy for patients with relapse after HSCT are not affected by leukemia load, CAR-T cell costimulatory molecules, and CAR-T cell dose
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In addition, the CAR-T therapy in this study has good safety in patients with relapse after HSCT.
Although the incidence of CRS is high (88%), no patients died due to complications
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The results of the study show that CAR-T therapy can bring better efficacy and long-term survival for patients who relapse after HSCT, and is a treatment option worthy of further exploration
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 A retrospective study was announced at the 2020 ASH conference to explore the application of CAR-T therapy combined with HSCT in NHL patients
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The results of the study show that CAR-T therapy combined with HSCT can improve the EFS of NHL patients, and the advancement of the application timing of CAR-T therapy can further improve the efficacy of NHL patients
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In addition, the application of CAR-T therapy after HSCT can further extend the overall survival (OS) of NHL patients compared with other therapies after CAR-T therapy
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 Professor Zhou Jianfeng's team from Tongji Hospital of Huazhong University of Science and Technology conducted a study to explore the efficacy of sequential CD19/CD22 CAR-T therapy after HSCT in the treatment of relapsed and refractory high-risk B-cell lymphoma
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The results of the study announced at the 2020 ASH Conference showed that the overall response rate (ORR) of HSCT sequential CD19/CD22 CAR-T treatment of relapsed and refractory B-cell lymphoma reached 90.
5%, and the 1-year progression-free survival (PFS) rate reached 85.
7%, the 1-year OS rate reaches 90.
5%
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Prophylactic infusion of allogeneic CAR-T cells after HSCT Professor Zhang Cheng said that the preventive infusion of allogeneic CAR-T cells after HSCT is also worthy of attention
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A phase I clinical study published in 2016 explored the efficacy of CD19 CAR-T cell infusion to prevent recurrence after HSCT
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A total of 26 patients were enrolled in the study, of which 7 patients received autologous hematopoietic stem cell transplantation, and 19 patients received Allo-HSCT
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Three patients developed GVHD after Allo-HSCT, of which two patients were controlled by hormones, and one patient with a history of liver disease developed liver GVHD one month after CAR-T cell infusion, and eventually died of liver failure
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A total of 5 patients died of recurrence of the disease after Allo-HSCT
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The 30-month OS rate of patients in the autologous hematopoietic stem cell transplantation group reached 100%, and the 30-month PFS rate reached 83.
3%; the 1-year OS rate of the Allo-HSCT group was 63%, and the 1-year PFS rate was 53%.
The 1-year OS rate of patients with ploidy Allo-HSCT reaches 100%, and the 1-year PFS rate reaches 75%
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For patients receiving haplotype Allo-HSCT, prophylactic infusion of CAR-T cells can bring more clinical benefits
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Summary Professor Zhang Cheng concluded: The combination of CAR-T therapy and HSCT has a good application prospect
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The application of CAR-T therapy during HSCT can effectively eliminate residual disease, the application of CAR-T therapy after HSCT can prevent disease recurrence, and the application of CAR-T therapy after HSCT recurrence can bring remission of disease to patients
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However, there are still many contents worth exploring in the combination of CAR-T therapy and HSCT, including the construction of CAR-T vector, the number of infused cells, the management of CRS, and the application of immunosuppressants.
Follow-up research is required for CAR-T The combination of T therapy and HSCT provides more clinical guidance
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Professor Zhang Cheng Deputy Director, Chief Physician, Associate Professor, Doctoral Supervisor Member of the Infection Group of the Hematology Committee of the Chinese Medical Association Member of the Lymphoid Oncology Group of the Hematology Committee of the Chinese Anti-Cancer Association Vice Chairman, Chongqing Labor Ability Appraisal Medical and Health Expert, Secretary of Chongqing Hematology Medical Quality Control Center, is mainly engaged in basic and clinical research on leukemia and cellular immunotherapy
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Presided over a number of sub-projects of major military logistics topics, national aspects, Chongqing natural science key, clinical key, etc.
, published 45 SCI papers in Blood, leukemia, JHO, etc.
as the first or corresponding author, and won the second prize of National Science and Technology Progress 1 prize, 1 first prize of the Chinese Medical Science and Technology Award, 2 first prizes of Chongqing Science and Technology Progress, 1 second prize, 3 second prizes of military medical achievements, and 3rd prize of Science and Technology Award of China Anti-Cancer Association 1 Item
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Served as an editorial board member and reviewer of journals such as "Biomaterial", "JHO", "China Pharmacy" and "Laboratory Medicine and Clinical"
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