The world's first PD1 knock-on virus-targeted integrated CART treatment for lymphoma has achieved breakthrough results

On September 25, 2020, Shanghai Bangyao Biotech Co., Ltd. ("Bangyao Bio"), a company focused on gene therapy and cell drug research and development, announced a breakthrough in the clinical trial of "PD1 Knockout Virus Point Integration CD19-CART Cell Therapy Recurring Non-Hodgkin's Lymphoma" in collaboration with the First Hospital affiliated with Zhejiang University Medical College. This is the world's first use of gene editing technology in PD1 locations to achieve fixed-point integration of CART treatment, but also the world's first non-viral fixed-point integration of CART cells to treat lymphoma clinical trials. At the same time, the latest research results were announced on September 23, 2020 on the preprinted platform medRxiv, by East China Normal University, Zhejiang University School of Medicine affiliated with the first hospital and Shanghai Bangyao Bio.PD1 fixed-point integrated CD19-CART is a STEP-by-step preparation of obtained CART products by Bangyao Bio using the Qukin CART™ platform technology with independent intellectual property rights. The product combined PD1 immuno-checkpoint suppression with CART tumor killing function, and played a role in the combined application of PD1 immunotherapy and CART therapy.2 patients were fully relieved after 3 months of treatment15 patients in the clinical study group were included, 4 patients who can now be evaluated have achieved partial remission (PR) at 1 month, and 2 patients who have reached 3 months of assessment time have received full remission (CR).The first patient to receive complete remission was diagnosed with diffuse large B lymphoma IVBE in 2018, and after multiple chemotherapy treatments, the condition was not effectively controlled. Pre-group imaging showed a lesions with a membrane gap of 3.6 x 3.5 cm in the left lower abdominal small intestine, with abnormally high radioactive intake. In May 2020, the group for PD1 knock-on unless the virus targeted integration CD19-CART cell refractation treatment, 28 days after treatment PET-CT imaging showed that FDG metabolism significantly decreased, reached PR, 90 days after treatment PET-CT imaging showed that the lesions all disappeared, FDG metabolism did not increase, reached CR.No adverse events associated with level 3 or more drugs, including cytokine storms and neurotoxicity, occurred throughout CART treatment. After the return loss, CART in vivo amplification is good, the duration is longer, D90 flow detection found that the cart cells in the outer blood is still maintained at a certain proportion. At present, 2 patients have recovered and been discharged from hospital and are still receiving long-term follow-up."Diffuse large B-cell lymphoma is the most common non-Hodgkin's lymphoma and currently lacks effective treatment for patients with relapses," said HuangHe, director of the First Hospital affiliated with Zhejiang University School of Medicine in the clinical study. This year we began exploring clinical studies of non-viral targeted integrated CART based on gene editing technology, and we are pleased to see patients rapidly reaching full remission after treatment, and we expect this new CART technology to bring more convenient, safe and accurate long-term treatment to patients with relapses. "BioCART Upgrade Version 2.0, more effective and safer!Bonyao Bio's non-viral fixed-point integrated CART technology (Quikin CART™) can use CRISPR/Cas9 gene editing technology to insert CAR components into specific site of the genome without using virus vectors, one step to achieve the stable integration of gene knock-out and CAR, belonging to Bonyao Bio 2.0 version of CART pipeline products.PD-L1/PD1 is an important immune checkpoint to inhibit T cell function, and the inhibitors for PD-L1/PD1 have achieved good results in many types of malignant tumors, and many studies have reported that PD1 knock-out can effectively enhance the function of CART cells. Non-Hodgkin's lymphoma is a malignant tumor of the blood system native to lymphatic tissue, accounting for 80%-90% of all lymphomas, and although the disease is alleviated after initial treatment, it often relapses later. Although CART products have been approved for clinical treatment of recurring recurring non-Hodgkin's lymphoma, the overall efficacy is still limited, and studies suggest that inhibiting the PD1 pathrapy may lead to better clinical outcomes.As a result, Bonyo Bio has developed non-viral PD1 fixed-point integrated CD19-CART cells using the Quiking CART™ platform for clinical treatment of recurring and incurable non-Hodgkin's lymphoma. The product has two advantages of CAR stability expression and PD1 gene knock-out, which is equivalent to the strong combination of PD1 inhibitors and CART cells. The CART product demonstrated excellent safety and effectiveness in several clinical trials that have been conducted so far.The preparation of traditional CART products mainly uses virus vectors, which places high demands on the virus preparation process, which greatly increases the manufacturing cost and difficulty of CART cells, hinders the large-scale clinical application of CART treatment, and is very expensive, such as the current listed CART products, Novartis Ky Mriah is priced at $475,000 and Kite's Yescarta is priced at $373,000, and because the virus integrates CAR components into the cell genome using random insertion, it can alter the expression of normal genes, potentially caused by cancer. Quikin CART™ technology eliminates the need for cell preparation using viral vectors, greatly reducing the cost of producing CART products while avoiding the risk of cancer from random insertion.Quikin CART™ technology enables both the regulation of T-cell endotgens and the continuous expression of CAR in one step. Compared with other CART technology, it has the advantages of simple process, few production links, short preparation time and high product ism. The technology platform can be used for the preparation of multiple immune checkpoint knock-out enhanced CART cells, can quickly produce universal CART cells, can develop dynamically regulated safe CART products, etc., and provides strong technical support for the diversification of CART cells in the future.Professor Mingyao Liu, chief scientist of Bangyao Biology and professor of life sciences at East China Normal University, said: "Compared to traditional in-body CART technology, Quikin CART™ technology can achieve the fixed-point integration of CAR components in the genome and the regulation of T-cell endogenes without the use of viruses. This means that the preparation process, production process and preparation time of CART cells are greatly simplified and shortened, thus greatly reducing the production cost of CART cells, while reducing the risk of tumor caused by random insertion of viruses, and improving the erration of CART products. The current results show that the non-viral PD1 fixed-point integrated CD19-CART cells we have great therapeutic potential and show good safety and mitigation rate in clinical trials. "In recent years, the growing maturity and development of CRISPR/Cas9 gene editing technology has led us to the idea of applying it to CART therapy," said Dr. Zhang Yanqin, lead author of theproject and lead author of the paper, Director of Research and Development of Bangyao Bioinnovatical CART, and Associate Researcher, School of Life Sciences, East China Normal University. Through an in-depth analysis of the problems with existing CART technologies, we realize that the use of gene editing techniques to prepare non-viral fixed-point integrated CART cells is a promising direction. Through a large number of methods and conditions exploration, we have established a mature Qukin CART ™ technology platform. The technology does not require the use of any viruses, only one step to prepare CART cells, with existing CART technology incomparable many advantages. Looking forward to using this technology platform in the future to develop more successful CART products, in clinical treatment to achieve greater breakthroughs.it is understood that in addition to the ongoing clinical study of non-viral PD1 fixed-point integration CD19-CART, Bangyao Bio is also layout other non-viral fixed-point integrated CART products for solid tumors, with a view to making a greater breakthrough in CART therapy.About Bangyao Bio Shanghai Bangyao Biotech Co., Ltd. is committed to becoming the world's leading gene cell pharmaceutical company, Bangyao Bio to "lead innovation with gene editing, the development of breakthrough therapies for the benefit of all mankind" as its mission, relying on independent research and development center and the "Shanghai Gene Editing and Cell Therapy Research Center" jointly established with East China Normal University, in the past five years has produced 108 patent results, 5 projects in 8 well-known hospitals to carry out IIT trials, including 3 projects into the IND filing stage, 12 high-level academic papers have been published in internationally renowned journals such as Nature Medicine. Bangyao Bio has built three major technology platforms for gene editing, cell therapy and gene therapy, and has a pilot base of 6000 square meters of GMP and an operation team of nearly 100 people, which can effectively guarantee the rapid transformation and application of innovative research results. Bang Yew Bio continues to drive rapid product update iterations through patient needs and clinical feedback. Driven by the new era of commercial civilization, Bangyao Bio upholds an open, shared and win-win attitude, and together with the global innovative biopharmaceutical ecological chain enterprises, accelerate the transformation and landing of innovative drugs for the benefit of global genetic diseases and malignant tumor patients! (Biological exploration)