Ash is the world's first BCMA-CD19 composite CAR for autoantibodies-mediated diseases.

December 14, 2019 / emmed club / - - the 61st annual meeting of American Society of Hematology (ash) was held in Orlando, USA from December 7 to 10, 2019. Dozens of Chinese scholars attended the ash stage to give oral reports and share academic achievements.in this meeting, Professor Liu Fang's team (Abstract No.: 38) of Western Theater General Hospital (former Chengdu Military Region General Hospital) reported the results of the first phase I clinical trial of bcma-cd19 CCAR significantly reducing autoimmune antibodies.& lt; & lt; swipe left to view the picture & gt; & gt; conference video background research background allogeneic hematopoietic stem cell transplantation (allo HSCT) is an effective method to cure many hematological malignancies and some benign diseases.however, only 40% of patients can find HLA matched donors at the right time.therefore, HLA mismatched donors are more and more widely used.donor specific anti HLA antibodies (DSAs) are antibodies found in recipients against donor HLA antigens, and their production is related to multiple blood transfusion and multiple pregnancies.the presence of high titer DSA significantly increased the risk of primary implantation failure (PGF).it is reported that the incidence of PGF caused by DSA is 24% - 83%, with the highest incidence in haploid transplantation and umbilical cord blood transplantation.therefore, the European Association for bone marrow transplantation (EBMT) recommends that DSA reduction should be performed in the presence of high titer DSA (MFI & gt; 5000).at present, there is no specific specification on how to reduce DSA. Some methods such as immunosuppressive agents, high-dose immunoglobulin, plasma exchange, rituximab and proteasome inhibitors such as bortezomib may be effective, but they are time-consuming and easy to rebound due to the persistence of long-lived plasma cells.therefore, it is very important to find a feasible method to reduce DSA in recipients.systemic lupus erythematosus (SLE) is a kind of immune disease which is mediated by autoimmune antibodies and involves multiple organs and systems of the whole body.under the existing treatment system, some patients suffer from repeated diseases and have certain lethality. B cells play an important role in the pathogenesis of the disease.a recent study in the authoritative journal Nature showed that in mouse model, using CD19 car-t to remove B cells in the treatment of SLE, the effect of significantly reducing antibody was observed, and the clinical symptoms were reversed.however, this study only targets CD19 alone, and the long-lived plasma cells do not express CD19, which is likely to exist for a long time in vivo and produce antibodies continuously, which may affect the therapeutic effect.therefore, anti DNA IgG and IgM autoantibodies in some peripheral circulation of the treated mice were increased.we know that B cells and plasma cells are the "roots" of antibody production.therefore, the researchers hypothesized that targeting CD19 and BCMA at the same time could remove B cells and plasma cells at the same time, thus removing the "root" of antibody production, achieving a more significant and lasting effect.therefore, the researchers constructed a bcma-cd19 complex car, which is a car with two independent units. A complete bcma-car was fused with a complete cd19-car through a self-cleaved P2a peptide. Thus, the two car receptors were independently expressed on the surface of T cells, and a rituximab safety switch was installed in the hinge region.in the preclinical study, the antigen targeting of the car was confirmed by the co culture test with BCMA / CD19 expressing target cells, and the killing effect on the target cells was confirmed in the mouse model constructed by multiple BCMA + / CD19 + cells.Clinical Research Professor Liu Fang accepted the video Journal of hematological Interview with oncology, two patients were introduced in the phase I clinical trial. The first patient was a 48 year old female who was diagnosed with acute B-lymphocytic leukemia (B-ALL). After multiple chemotherapy, there was still a small residual leukemia (MRD) in the body. If the patient was directly transplanted, the risk of recurrence would be higher.at the same time, it was found that the patient had DSA for HLA mismatched sites of the donor, and the antibody titer was as high as 7800, and the risk of implantation failure would increase. Therefore, we were enrolled in the clinical trial.after conventional pretreatment, the patient received 2x106 / kg car-t cells. On the 14th day after infusion, MRD of bone marrow turned negative, B cells and plasma cells in bone marrow and peripheral blood were 0, and DSA gradually decreased to low level. He received haploidentical transplantation 103 days after car-t cell infusion.during car-t treatment, no cytokine storm (CRS) and neurotoxicity were observed.after 8 weeks of car-t treatment, DSA MFI decreased from 7800 to 1400, and other HLA antibodies also decreased significantly, with a decrease rate of 80% at the 8th week.in addition to HLA antibodies, the common antibodies including IgG, IgA and IgM also decreased significantly. The patients were successfully transplanted 12 days after transplantation. The chimerism test was 100% donor type, and multiple DSA tests were negative.the second case was from Shenzhen Hospital of Peking University, with a 20-year history of SLE, combined with recurrent fever and joint pain. It was necessary to take long-term hormone control. High titer of ANA was detected in peripheral blood (& gt; 1:1000).recently, diffuse large B-cell lymphoma (DLBCL) with bone marrow involvement was diagnosed, and the lymphoma progressed after conventional chemotherapy.the patient received 5.5x106/kg car-t cell infusion. After 28 days of treatment, the lymphoma was relieved, bone marrow was negative, and there was no fever without taking hormone, and joint pain improved significantly.only grade 1 CRS occurred during car-t treatment, and no neurotoxicity occurred.laboratory tests found that complement C3 / C4 gradually increased in the normal range without hormone use. What's more, Ana decreased gradually from the high titer (< Gt; 1:1000) before treatment, especially the nuclear and cytoplasmic types turned negative on the 64th day after treatment.in conclusion, this preliminary study on bcma-cd19 composite car showed that it showed strong, lasting and specific killing power on BCMA + / CD19 + cells in vitro and in vivo.this study demonstrated for the first time in human clinical trials that bcma-cd19 CCAR can clear the "root" of antigen production, B cells and plasma cells, and has a significant effect in reducing the level of autoantibodies. in the future, we will continue to complete the dose escalation test and explore when to activate the safety switch, so that new B cells and plasma cells can be regenerated from bone marrow hematopoietic stem cells. this study further suggests that bcma-cd19 CCAR has potential applications outside the field of blood diseases. It can be used in the treatment of DSA in patients undergoing solid organ transplantation, or autoimmune diseases including SLE, such as multiple sclerosis and ANCA related autoimmune diseases, including microscopic multiple vasculitis (MPA), granuloma with polyangitis (GPA), or eosinophilic granuloma with polyangitis (egpa). - end - [source of report] [References] doi.org/10 .1038/s41409-017-0062-8 doi.org/10 .1126/ scitranslmed.aav1648 Liu Fang, M.D., graduated from Peking University Medical Department, is a doctoral student under academician Lu Daopei, the father of Asian bone marrow transplantation. She has done postdoctoral research at the Nevada Cancer Institute. engaged in basic and clinical research of hematology for more than 20 years, and is now the director of hematopoietic stem cell transplantation center of Western Theater general hospital. exclusive disclosure: the world's first IPS corneal transplantation operation, the world's first in vivo CRISPR clinical trial, zynteglo, approved by EU, zolgensma approved by FDA, ASCO, decitabine and PD-1, China's largest license in Japan car-t was approved, car-t cells were manufactured in one day, CRISPR was the first human trial in the United States, TAC therapy was horizontal China's first dry cargo dry cargo package is approved by CAR-T, PD-L1/TGF- PD-1:K, O, T, B and I. Stem cell policies and regulations bispecific antibody gift pack 2.29g! 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