Heavyweight: breakthrough the traditional cell preparation process, the research team of Binda produced car-t cells in one day

The emergence of car-t cell therapy is a great innovation in the history of medicine, which has saved countless lives and provided the possibility for the cure of many diseases It is one of the most promising development directions in the field of tumor therapy However, high cost and highly variable manufacturing process are the key to its widespread application, so the production process of car-t cells has attracted great attention Recently, a research team of Penn University published a research summary at the American Society of Hematology (ash) meeting, announcing that it can produce functional CD19 specific car-t cells (cart19) in just 24 hours This is another technological innovation after Genxi biology announced to shorten the manufacturing time of car-t from two weeks to one day In the current development process of cell therapy, although the production of car-t cells is carried out by various manufacturing methods, all manufacturing methods include the same common steps First, the patient's white blood cells (WBC) were separated by leukocyte separation and washed Then, T cells are activated, transformed with car, and expanded to the required number of cells for treatment, preparation production and filling After quality control testing and preliminary lymphadenectomy chemotherapy, the product was injected into the patient At present, in all car-t research institutions, the University of Pennsylvania has accepted most patients; the cell target is usually CD19, and the origin product is mainly autogenous T cells; most car-t cell products are manufactured within 20 days; car-t cell therapy is mainly used to treat malignant tumors of blood system The efficacy of car-t cell therapy depends on the implantation and persistence of T cells after adoptive transfer The potential for implantation and persistence is related to the state of T-cell differentiation, and the team of Penn University has previously demonstrated that reducing the duration of in vitro culture will limit T-cell differentiation and improve the efficacy of car-t cell therapy However, most of the experimental programs usually activate T cells through the combination of TCR and costimulatory receptor, and then expand T cells in vitro for 9 to 14 days, which has a certain impact on the efficacy of car-t cell therapy In a research summary recently published at the ash annual meeting, the team of Penn University described that the use of lentivirus vectors can generate functional CD19 specific car-t cells (cart19) in one day without activating T cells in advance, This abstract shows that using a non optimized process, a lentivirus vector expressing IRFP can be used to transduce freshly isolated static T cells with an average of 6.5% (ranging from 2% to 10%) and the expression kinetics is slower than that of activated T cells (static and living T cells peak at 96 hours and 48 hours, respectively) Although the efficiency is much lower than that of activated T cells, the central memory T cells showed the highest transduction efficiency in all T cell subsets; compared with untreated T cells, the average transduction rate was 4 times higher The Penn team demonstrated that car expression can occur in static T cells even without reverse transcription or integrase function, so-called "pseudo transduction" Importantly, the Penn team demonstrated that the car-t cells produced by this expression have cytolytic activity and effector cytokines, and the response to antigens is similar to that of activated and transduced car-t cells The team tested the nalm6 model of acute lymphoblastic leukemia, and found that cart19 cells produced by washing and removing the carrier after 16 hours of static T cell transduction showed dose-dependent ANTI LEUKEMIA activity, which could last for 2x10 ^ 5 T cells as long as a small dose was injected Michael Milone, co-author of the study, is an associate professor of pathology and laboratory medicine at the University of Pennsylvania Hospital and School of medicine He received his doctor's degree in medicine from the University of medicine and Dentistry of New Jersey in 1999; he continued to receive postgraduate medical training in internal medicine, laboratory medicine and transfusion medicine at the University of Pennsylvania; he continued his scientific research during his postdoctoral research; he had worked with Carl of Penn University Dr June worked together on cancer immunotherapy, which led to an open-ended phase I study of artificial antigen receptors in patients with B-cell leukemia and lymphoma Previously, immunocytotherapy company Genxi Biotechnology Group Co., Ltd ("Genxi biology") announced the successful development of a new fast car-t production platform, which can shorten the manufacturing time of car-t from two weeks to one day At the same time, in vivo and in vitro studies show that CD19 targeting fast car-t ("cd19-f-car-t") has a higher therapeutic effect on B-cell acute lymphoblastic leukemia (B-ALL) and non Hodgkin's lymphoma (NHL) Compared with traditional car-t therapy (c-car-t), fast car-t greatly reduces manufacturing time and cost Fast car-t only needs 1 day of production time (but according to regulatory requirements, quality release testing needs 7 days), while c-car-t generally needs about two weeks of production time, plus 7 days of testing time, so fast car-t can be returned to patients about 12 days in advance This is critical for patients who are progressing rapidly Genxi biology will also release research data on the treatment of relapsed and refractory multiple myeloma and relapsed / refractory acute lymphoblastic leukemia with car-t cells produced by the production platform at the ash meeting The team's ability to transfer genes to static T cells using lentivirus vectors, and the highly simplified manufacturing methods described have the potential to enhance therapeutic effectiveness while significantly reducing costs In addition, this manufacturing method may increase the number of patients receiving treatment The research team will release more data at the ash meeting on December 9, and we are looking forward to more exciting data Reference source: 1.https://ash.confex.com/ash/2019/webprogram/Paper131147.html