On September 25, 2020 Shanghai Bangyao Biotechnology Co., Ltd. (BIORAY LABORATORIES Inc. "BIORAY LABORATORIES Inc."), a company focused on gene therapy and cell drug research and development, reported for the first time its cooperation with the First Affiliated Hospital of Zhejiang University School of Medicine The "PD1 knockout non-viral targeted integration of CD19-CART cells for the treatment of relapsed and refractory non-Hodgkin’s lymphoma clinical trials" achieved breakthrough results (Press release, Shanghai Bioray Laboratory, SEP 25, 2020, View Source [SID1234567717]). This is the world’s first use of gene editing technology to achieve targeted integration of CART therapy at the PD1 site, and it is also the world’s first clinical trial of non-viral targeted integration of CART cells to treat lymphoma. At the same time, the latest research results were announced on the preprint platform medRxiv on September 23, 2020, jointly completed by East China Normal University, the First Affiliated Hospital of Zhejiang University School of Medicine, and Shanghai Bangyao Biotechnology.
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The CD19-CART integrated by PD1 is a CART product obtained by Bangyao Biologics using the Quikin CART platform technology of independent intellectual property rights without using viral vectors. This product combines PD1 immune checkpoint suppression and CART tumor killing functions into one, which has the effect of combined application of PD1 immunotherapy and CART therapy.
2 patients in complete remission after 3 months of treatment
The clinical research plan enrolled 15 patients. The 4 patients that have been evaluated have achieved partial remission (PR) at 1 month, and 2 patients who have reached the evaluation time of 3 months have achieved complete remission (CR). ).
The first patient who achieved complete remission was diagnosed with diffuse large B lymphoma stage IVBE in 2018. After multiple radiotherapy and chemotherapy, the condition has not been effectively controlled. Before enrollment, imaging showed that the size of the mesangial space of the left lower abdominal small intestine was 3.6*3.5cm, and the radioactive uptake was abnormally increased. In May 2020, he was enrolled in the group for PD1 knockout non-viral targeted integration of CD19-CART cells for reinfusion therapy. PET-CT imaging showed that FDG metabolism was significantly lower than before 28 days after treatment, reaching PR. PET-CT after 90 days of treatment Imaging revealed that all the lesions disappeared, and FDG metabolism did not increase, reaching CR.
During the entire CART treatment process, no adverse events above grade 3 occurred, including cytokine storm and neurotoxicity. After reinfusion, CART expanded well in the body and lasted for a long time. The d90 flow cytometry showed that the CART cells in the peripheral blood remained at a certain proportion. At present, 2 patients have recovered and been discharged and are still undergoing long-term follow-up.
Comparison of imaging examinations before and after treatment
The principal investigator (PI) of the clinical study (PI), Dean of Huanghe, the First Affiliated Hospital of Zhejiang University School of Medicine, said : "Diffuse large B-cell lymphoma is the most common type of non-Hodgkin’s lymphoma. Lack of effective treatment. This year we began to explore the clinical research of non-viral targeted integrated CART based on gene editing technology. We are very pleased to see that patients quickly achieve complete remission after treatment. We expect this new CART technology will be difficult Treating relapsed patients will bring more convenient, safe and accurate long-term treatment effects."
Bangyao Bio-CART is upgraded to version 2.0, which is more effective and safer!
Bangyao Biotech’s non-viral targeted integration CART technology (Quikin CART) can use CRISPR/Cas9 gene editing technology to insert CAR elements into specific locations in the genome without using viral vectors, achieving gene knockout in one step Stable integration with CAR is a pipeline product of Bangyao Biology 2.0 version of CART.
PD-L1/PD1 is an important immune checkpoint for inhibiting T cell function. At present, PD-L1/PD1 inhibitors have achieved good efficacy in many types of malignant tumors, and many studies have reported PD1 knockout Can effectively enhance the function of CART cells. Non-Hodgkin’s lymphoma is a hematological malignant tumor that originates in the lymphatic tissues, accounting for 80%-90% of all lymphomas. Although the disease is relieved after the initial treatment, the patient often relapses afterwards. Although CART products have been approved for the clinical treatment of relapsed and refractory non-Hodgkin’s lymphoma, the overall efficacy is still limited, and studies have suggested that inhibiting the PD1 pathway may bring better clinical results.
Therefore, Bangyao Biosciences developed non-viral PD1 targeted integration of CD19-CART cells using Quikin CART platform to carry out clinical treatment of relapsed and refractory non-Hodgkin’s lymphoma. This product has the two major advantages of uniform and stable expression of CAR and PD1 gene knockout, which is equivalent to the combination of PD1 inhibitor and CART cells. In many clinical trials that have been carried out so far, the CART product has demonstrated excellent safety and effectiveness.
The preparation of traditional CART products mainly uses viral vectors, which puts forward high requirements on the virus preparation process, which greatly increases the manufacturing cost and difficulty of CART cells, and hinders the large-scale clinical application of CART treatment; and the price is very expensive, as currently For CART products on the market, Novartis’ Kymriah is priced at US$475,000, and Kite’s Yescarta is priced at US$373,000. In addition, because the virus uses random insertion to integrate CAR elements into the cell genome, it may change the expression of normal genes. The safety hazards of cancer. Quikin CART technology does not require the use of viral vectors for cell preparation, which greatly reduces the production cost of CART products and avoids the risk of cancer by random insertion.
Quikin CART technology can simultaneously realize the regulation of T cell endogenous genes and the continuous expression of CAR in one step. Compared with other CART technology, it has the advantages of simple process, fewer production links, short preparation time, and high product uniformity. This technology platform can be used for the preparation of multiple immune checkpoint knockout enhanced CART cells, rapid production of universal CART cells, and the development of dynamically regulated safe CART products, etc., providing a strong foundation for the diversified transformation of CART cells in the future. Strong technical support.
Professor Liu Mingyao, Chief Scientist of Bangyao Biosciences , East China Normal University, said : "Compared with traditional autologous CART technology, Quikin CART technology can achieve the targeted integration of CAR elements in the genome in one step without the use of viruses. Regulation and intervention of endogenous genes in T cells. This means that the preparation process, production links, and preparation time of CART cells will be greatly simplified and shortened, thus greatly reducing the production cost of CART cells and reducing tumorigenicity caused by random insertion of viruses Risks have also improved the uniformity of CART products. The current results show that the non-viral PD1 site-specific integration of CD19-CART cells prepared by us has great therapeutic potential and has shown good safety and remission rates in clinical trials."
Dr. Zhang Jiqin, the main person in charge of the project, the first author of the paper, the R&D director of Bangyao Bio-Innovation CART, and the associate researcher of the School of Life Sciences of East China Normal University, said: "In recent years, the continuous maturity and development of CRISPR/Cas9 gene editing technology has given us birth. Applying it to the idea of CART therapy. Through an in-depth analysis of the existing CART technology problems, we realized that the use of gene editing technology to prepare non-viral targeted integration of CART cells is a very promising direction. Through a large number of methods to try and After exploring the conditions, we have established a mature Quikin CART technology platform. This technology does not require the use of any virus, and can produce CART cells in one step. It has many advantages that cannot be compared with the existing CART technology. Looking forward to using this technology platform in the future We can develop more successful CART products and make greater breakthroughs in clinical treatment."
It is reported that in addition to the ongoing non-viral PD1 targeted integration of CD19-CART clinical research, Bangyao Biosciences is also deploying other non-viral targeted integration of CART products for solid tumors in order to achieve greater breakthroughs in CART therapy.