Introduction: Director Chunrong TONG from Beijing Boren Hospital shared the achievements and experience in the CART therapies for refractory/relapsed hematological malignancies in Beijing Boren Hospital.
In November 2018, the “2018 (4th) Seminar on Next-generation CAR&TCR-T” sponsored by the Bio Valley and supported by Zhangjiang Hi-Tech Park was held in Shanghai, and the scientists, doctors and scholars in the field of scientific research and medical treatment gathered to discuss the topics on next-generation CAR&TCR-T.
Director Chunrong TONG from Beijing Boren Hospital gave a keynote report on “Clinical outcome and experience of CART therapy for refractory/relapsed (rr) hematological malignancies” to share the achievements and experience in CART therapies for refractory/relapsed hematological malignancies in Beijing Boren Hospital, and this was the fourth time Director Tong shared the achievements in clinical practice of cellular immunotherapy at the conference.
After the conference, Director Tong accepted an exclusive interview by MedSci. Director Tong’s wonderful report and interview are as follows.
Director Chunrong TONG
CART is by far the most powerful method for refractory/relapsed B-cell hematological malignancies
The medical team led by Director Chunrong TONG in Beijing Boren Hospital has made remarkable achievements, its therapeutic effect has reached the internationally advanced level, and the research achievements of the team have been exhibited and reported in large-scale conferences at home and abroad for many times.
In this report, Director Tong gave a wonderful and concentrated summary of the clinical studies on immunotherapy in Beijing Boren Hospital: including the achievements in CART cell immunotherapy for five major diseases and conditions, i.e., CD19-CART therapy for refractory/relapsed B-cell acute lymphoblastic leukemia (rrB-ALL); CD22-CAR-T therapy for rrB-ALL; CD19 and CD22-CAR-T therapy for relapsed B-ALL after allogeneic hematopoietic stem cell transplantation (allo-HCT); CD19, CD20 and CD22-CART therapy for advanced diffuse large B-cell lymphoma (DLBCL); CD19 or CD22-CART therapy for CD19 or CD22-positive acute myeloid leukemia (AML) / blastic crisis of chronic myeloid leukemia (CML).
CART is actually a targeted immunotherapy. CART combines the advantages of both B cells and T lymphocytes: taking the advantage of strong binding of monoclonal antibodies and antigens and the advantage of strong tumor killing after T lymphocyte activation, thus CART cells can better specifically kill tumor cells, unlike traditional chemotherapy and radiotherapy that non-specifically kill normal and tumor cells.
For example, CD19-CART therapy can only be used for CD19-positive tumors, but has no effect on other cells; the higher the proportion of expression of CD19 antigen in tumor cells and the higher the expression intensity, the better the efficacy of CD19-CART therapy is; it is also true for CART therapy at other targets. Therefore, when selecting a targeted CART therapy, it is necessary to analyze and compare the proportion and intensity of antigen expression in tumor cells.
However, due to the heterogeneity of tumor cells (different tumor cells in a same patient may have different levels of cell surface markers, genes, etc.), and although target-positive tumor cells are killed after single-target CART therapy, target-negative cells may proliferate, leading to relapse.
Therefore, if transplantation or other treatments cannot be undergone after CART cell therapy at a target, other targets on the tumor cells are often selected for CART therapy, thus increasing the cure rate.
Patients who have previously received murine CART therapy may produce antibodies against murine antigens, and the efficacy of reuse of murine CART therapy is not good, so humanized CART therapy is used as second and subsequent CART therapy.
It is worth noting that in recently one year, the achievements in various clinical studies of Beijing Boren Hospital have been continuously reported at international and domestic conferences.
In June 2018, at the 23rd EHA (European Hematology Association) held in Sweden, Director Pan Jing in Department of Hematology in Beijing Boren Hospital made an oral presentation of the clinical findings on CD22-CART therapy that humanized CD22-CART therapy was used to treat 15 children with rrB-ALL, 14 of whom had no response or relapsed after previous treatment with 19-CART therapy, and one’s leukemia cells did not express CD19, so CD22-CART therapy was selected. After CD22-CART therapy, 86.7% of patients had response, 80% achieved complete remission (CR), and after median 109 days of observation, 91% of patients with response achieved progression-free survival; no deaths and serious complications occurred during the CD22-CART therapy.
The report was discussed and praised by the participating experts. After the conference, Director Pan Jing accepted an interview by international media and received wide attention and praise.
In November 2018, at the 23rd Asia-Pacific Blood and Marrow Transplantation (APBMT) held in Taipei, Director Zhang Yan in the Department of Transplantation reported the results of bridging allo-HCT after CART cell therapy in Beijing Boren Hospital.
From August 2017 to August 2018, 36 patients with refractory/relapsed B-ALL underwent bridging Allo-HSCT after CART therapy achieved CR or CRi, of whom 30 received CD19-CART therapy and 6 received CD22-CART therapy. After these patients underwent Allo-HCT again, the 6-month overall survival rate was 96.9%, and the relapse-free survival rate was 91.7%.
These patients had little hope of cure, and if they did not undergo salvage allo-HCT after CR or CRi was achieved, the cure rate would be very low. The efficacy of bridging allo-HCT after CART therapy is outstanding. Such excellent efficacy on refractory/relapsed B-ALL is achieved mainly by rapid bridging Allo-HSCT and appropriate transplantation after CART therapy achieves CR.
At the just-ended 2018 Annual Conference of American Society of Hematology (ASH), Dr. Liu Shuangyou, director of the Department of Hematology, on behalf of Beijing Boren Hospital, presented a clinical study on the poster: "Sequential CA19- and CD22-CART Cell Therapies for Relapsed B-Cell Acute Lymphoblastic Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation".
From June 30, 2017 to May 31, 2018, a total of 24 patients who relapsed after transplantation were included in the study. Their leukemia cells were confirmed by flow cytometry to simultaneously express CD19 and CD22 antigens; the median age of the patients was 24 years old (range: 2.3-55 years old); 17 patients had bone marrow relapse, 6 had intramedullary and extramedullary relapse, and 1 had only extramedullary relapse; 14 patients received other treatments, such as chemotherapy, donor lymphocyte infusion and interferons, or received CD19-CART therapy in other hospitals after relapse.
The results showed that for relapsed B-ALL after transplantation, after a single CD19 or CD22-CART therapy, 83.3% of patients achieved CR; after sequential CD19- and CD22-CART therapies and median 6.5 (4-10) months of follow-up, the 6-month overall survival (OS), leukemia-free survival (LFS) and minimal residual disease (MRD)-negative LFS was 100%, 81.3% and 68.8%, respectively.
“CART is by far the most powerful method for refractory/relapsed hematological malignancies, can achieve CR in most patients, and saves time for further cure. For patients with refractory/relapsed B-ALL, CART is currently a better cure. It is difficult to cure patients with a single CART therapy, and further bridging transplantation and combination with multiple-target CART therapy and other treatments can cure most patients.”
The success of Director Tong's team in the treatment of various hematological malignancies with CART therapy has three main factors:
Firstly, design of CAR. CAR mainly includes antibodies that binds to antigens, a signal system that activates T cells after binding to antigens, and a vector that packs these together, and after being loaded to T cells, CAR does not cause secondary tumors and other side effects. Director Tong’s team has been working with Professor Zhang Hongsheng's team, and its designed CAR has the characteristics of high affinity and good safety.
Secondly, culture of CAR-T cells. The laboratory team in Beijing Boren Hospital has done a good job in cell culture, the number and quality of CART provided are guaranteed, and clinical treatment using a very small number of CART cells can achieve good outcome, which greatly reduces the cost of CART preparation and increase the safety of preparation.
Furthermore, clinical aspects. The team will train all teams involved in the CART study, as well as family members, to ensure that each link is properly handled in a timely manner, including early assessment of whether serious cytokine release syndrome (CRS), neurotoxicity, decreased blood cell count, etc. may occur. Once it happens, it can be treated in time.
Early immunotherapy and targeted therapy + individualized treatment can improve the cure rate and quality of life of patients with hematological malignancies
In addition to CART therapy, more and more immunotherapies (such as monoclonal antibodies, bispecific antibodies, vaccines, cellular immunotherapy and cytokines), targeted drug therapies have greatly improved the cure rate of hematological malignancies. Such as CD20, CD30, CD38, CD70, CD3/CD19, CD3/CD20 bispecific antibodies, PD1 monoclonal antibody, CTLA4 monoclonal antibody, new antigen vaccines prepared according to patient’s tumor gene mutations, tumor antigen-specific cytotoxic T cell therapy, targeted therapeutic drugs designed according to tumor gene mutations and their involved signaling pathways, etc.
Previous therapies for hematological malignancies mainly include chemotherapy, radiotherapy and hematopoietic stem cell transplantation. Chemotherapy and radiotherapy are not targeted to tumor cells, killing tumor cells while damaging patient's immunity, and they may cause new chromosome and gene mutations, leading to new tumors. Actually, some so-called relapses are secondary tumors caused by chemotherapy and/or radiotherapy.
Immunotherapy and targeted therapy are mainly for malignant cells and have little damage to normal cells, so after CR is achieved by chemotherapy, immunotherapy and/or targeted therapy with confirmed efficacy and less toxic side effects can avoid the long-term toxic side effects of chemotherapy and improve the cure rate.
Director Tong believes that if patients receive immunotherapy after long-term chemotherapy causes more chromosome and gene abnormalities and leads to advanced disease, then CART and other therapies can only prepare for bridging allo-HCT, it is difficult to achieve the purpose of cure, and allo-HCT has greater risks. Therefore, it is recommended to give early immunotherapy and targeted therapy with less toxicity to prevent patients from entering the advanced stage.
In addition, because hematological malignancies are heterogeneous diseases and have a large individual difference, patients with different types of hematological malignancies should choose different treatment routes and regimens, different individuals with a same type have different responses to a same treatment route and regimen, and a same individual responds differently to a same treatment regimen at different stages of disease, indicating the importance of individualization in the treatment of hematological malignancies. Director Tong believes that each patient is an individual case and should follow the principle of individualized treatment.
Finally, Director Tong appealed that the era of immunotherapy and targeted therapy is coming, hoping to draw everyone's attention.
The international community has long proposed the "Cancer Moonshot", the core of which is to reduce the use of chemotherapy and radiotherapy and increase the use of immunotherapy or targeted therapy with less side effects to further improve the cure rate and quality of life in patients with cancer.
CART is only one kind of immunotherapy, and there are still many new methods to be developed. I hope that everyone will open their eyes and integrate various methods to treat hematological malignancies to bring new hope of cure for patients!