Novartis CAR-T therapy CTL-019 has been approved by FDA oncologists, which means that this revolutionary cancer treatment method has been basically recognized by the most stringent drug regulatory agencies in the world, and is only one step away from the official approval of the market. At present, CAR-T is sweeping the world with unprecedented popularity, causing widespread concern among pharmaceutical companies, investors, clinicians and patients.
There is no doubt that the success of CTL-019 will make the names of Novartis, University of Pennsylvania, Carl June, and Emily Whitehead in the medical history. But at the same time, it's important to remember that CAR-T, like other major scientific discoveries or medical breakthroughs, is based on teamwork and the unremitting exploration of predecessors. Many scientists have made silent contributions behind the scenes. Excellent scientists from China, Russia, Canada and other countries.
Professor Xu Zhongwei is the representative of Chinese scientists in the Carl June team. Professor Xu graduated from the First Military Medical University (now Southern Medical University) and Beijing Medical University. As early as the early 1990s, he began pioneering the use of retrovirus-based "suicidal" gene therapy and LAK in the Third Hospital of Beijing Medical University. Cell therapy. In 1996, he started studying related to CAR-T-CEA technology in Japan, and was one of the scientists who carried out CAR-T research in the world.
It was because of the scarcity of the people who had the background of CAR-T technology development and cell therapy at that time. Professor Xu Zhongwei received a special invitation from Professor Carl June of Penn in 2005. He was invited to join the CAR-T R&D team as the project leader, with a focus on CAR. Development and quality control of upstream technologies such as -T vector design and construction, improvement of chronic disease vector production and transfection process. Thanks to Professor Xu's solid molecular biology and viral vector production and preparation, in a few months, a variety of different signal domains combined CAR-T structure and high titer, high stability and high transfection rate The CAR-T cell production process plan came into being. This series of technical problems was overcome to screen out the most effective CAR-T structure and overcome the technical bottleneck of CAR-T cell production and make CAR-T therapy finally go to clinical application. The successful cure of the little girl Emily Whitehead and other patients made important contributions.
After seeing the huge clinical application potential of immune cell therapy technologies such as CAR-T, Professor Xu Zhongwei returned to China to start a full-time business in 2015, leading the establishment of Mesert Biotechnology Co., Ltd., and determined to establish China's own national immune cell therapy business. For the benefit of domestic patients. In 2016, in cooperation with the Institute of Hematology, Peking University People's Hospital, the haploid semi-coherent allogeneic CAR-T therapy was pioneered internationally, which solved the practical problem of the heterogeneous CAR-T donor. The “Beijing Programâ€, called the allogeneic CAR-T treatment in the industry, has made China's all-in-one CAR-T technology at the forefront of the international market. Currently, the 3-year-old leukemia patient who received a one-time treatment with CAR-T has survived for 12 months without cancer recurrence.
Allogeneic CAR-T is an opportunity for China to lead the world
The CAR-T treatment that is mentioned is usually referred to as autologous CAR-T cell therapy. The basic process is to collect the patient's own peripheral blood, isolate T cells, and complete the preparation and reinfusion of CAR-T cells. This is a very personalized treatment for cancer. The advantage is that autologous cells have no immune rejection. The disadvantages are in special cases, such as infants or elderly patients or elderly patients over 70 years old, or patients after chemotherapy or radiotherapy. The quantity and quality of T cells may not meet the requirements and effects of CAR-T cell therapy, thus losing treatment opportunities. Therefore, allogeneic CAR-T treatment can solve such problems.
At present, France's Cellectis is at the forefront of the development of the general-purpose CAR-T. Two children with leukemia, 11 months and 16 months, respectively, had only mild rejection after treatment, and the final duration of remission was 18 and 12 months, respectively. In March of this year, Cellectis's universal CAR-T therapy UCART123 was approved by the US FDA for clinical trials, indicating the possibility of clinical application of allogeneic CAR-T technology.
The technical feature of Cellectis is to edit the T cell of healthy donors by TALEN gene editing technology, knock out the expression of TCR-α chain, reduce or eliminate the allogeneic rejection caused by allogeneic cell infusion and only exert anti-tumor effect. . At present, more is the preparation of allogeneic CAR-T cells using a new generation of gene editing technology-CRISPR technology. CRISPR technology is simple and convenient to operate, can knock out multiple targets at the same time (such as TCR chain and HLA-1), and has relatively low cost. It is the main technical direction of future general-purpose CAR-T cells.
General-purpose CAR-T cells are also not perfect and flawless, such as: 1) the safety of donor occult infection; 2) the mechanism of GVHD or GVD production is complicated, and knocking out one or two genes does not completely eliminate this two-way Rejection; 3) The number, recovery and generation of uCAR-T cell bank will have a certain impact on clinical application and therapeutic effects. 4) A series of potential safety issues that may arise from the “off-target†effect of gene editing.
In addition, allogeneic CAR-T treatment of HLA all-in-one donors has been conducted internationally. However, as with a fully-matched bone marrow transplant, the probability of a suitable ligand is only one in 100,000, which is difficult for the donor, and it is difficult for the critically ill patient to wait.
Professor Xu Zhongwei and the director of the Peking University People's Hospital Blood Institute Huang Xiaojun jointly developed the "Beijing Program" in the treatment of allogeneic CAR-T, no need for genetic editing, no need for cell cryopreservation and resuscitation, as long as patients can provide T cells Healthy parents, children, or siblings can perform CAR-T treatment without having to pump their own blood to prepare cells. In addition, the presence of moderate GVL can also enhance the effect of killing tumor cells.
A 3-year-old acute lymphoblastic leukemia (ALL) was treated by Professor Xu Zhongwei's “Beijing Program†program. The patient had already had a stem cell transplant at that time. The source of stem cells was also his father. The prognosis of bone marrow transplantation was not good, and he received multiple chemotherapy before surgery. The number of T cells was very small and his autoimmunity was weak. In order to save the patient, Professor Xu Zhongwei and Director Huang Xiaojun carefully studied and developed a treatment plan, and decided to extract the peripheral blood T cells of the patient's father for cell preparation. After the return, the adverse reactions of CAR-T treatment itself were The graft-versus-host response (GVHD) should be fully and timely, and it will be successful. There has been no recurrence in 12 months.
Although this allogeneic CAR-T approach is still similar to autologous and does not meet the individualized needs of CAR-T treatment, this small step is also a bold attempt and innovation. Professor Xu Zhongwei pointed out that "in the history of drug development, the gap between the development of small molecule drugs and the United States is about 90 years. The difference between macromolecular drugs is 20-30 years, but in the third form of genes and cells like CAR-T. On drugs, we have the potential to catch up with the US. We are almost in sync with R&D in the US, and even better in the development of allogeneic CAR-T and solid tumor indications."
When is the domestic CAR-T policy coming?
In Professor Xu Zhongwei's view, China has many advantages in CAR-T development, no shortage of technology, no shortage of funds, because many outstanding scientists who have received advanced technology training and research and development concepts abroad return to China, which is equivalent to directly reducing the West. National technology gap. However, what is urgently needed in China is a scientific system of cell therapy supervision.
Referring to this, it is necessary to review the changes in cell regulation in domestic regulatory policies:
In the early 1990s, some hospitals in China began the early exploration of immune cell therapy such as LAK and TIL cells.
In 2003, SFDA (formerly CFDA) issued the "Guidelines for Human Cell Therapy Research and Preparation Quality Control Technology", which included the first time the regulation of immune cell therapy;
Beginning in 2005, the SFDA stopped accepting the approval of cell therapy and suspended the regulation of cell therapy;
At the end of 2005, the General Office of the Ministry of Health (formerly the Health Planning Commission) issued a document to Document No. 263 of the Heilongjiang Provincial Department: In vitro cell culture such as tumor immunorehabilitation therapy is a clinical technique, and the Ministry of Health has begun part of the supervision of cell therapy. ;
In 2009, the Ministry of Health issued the “Administrative Measures for the Clinical Application of Medical Technologyâ€. The autoimmune cell therapy technology was listed as the first third-class medical technology that allows clinical application. The cell treatment supervision seems to have regulations, but only a department. ;
In 2015, the Wei Zexi incident occurred;
In May 2015, the Health and Family Planning Commission canceled the third type of technical access approval, called the clinical application of stop cell therapy, and stipulated that cell therapy can only be used in clinical research;
In December 2016, the CFDA issued the "Guidelines for the Research and Evaluation of Cellular Products" (Draft for Comment), pointing out that the reference to the "Scope" of cell products complies with the management of pharmaceuticals, and the regulatory power is also returning to the CFDA.
Due to the discontinuity and uncertainty of this regulatory policy, CAR-T therapy has always been in the country for “consistency according to whether the drug is administered by the drug administration or the management of the technology.â€
We can also look at how the FDA regulates cellular products. The US FDA currently implements a risk-based hierarchical management model for cell products: according to two basic principles of minimally manipulated and homologous use, cell products are classified into high-risk and low-risk class. According to the US Public Health Service Act (PHS), the high-risk group is regulated according to Article 351. At this time, the cell product is a drug and needs to apply for IND; the low-risk group is in compliance with the conditions of minimization of preparation process and homology only. Cell preparations are regulated in accordance with Section 361 and no IND application is required. PHS 351 products are uniformly approved by the FDA Center for Biological Product Evaluation (CBER), and PHS 361 products can be directly used in hospitals for clinical applications. CAR-T treatment is a high-risk group and is accepted and approved by CBER.
In the organization, CBER has a cell, tissue and gene therapy office. The office consists of three departments: human tissue management, clinical evaluation and pharmacology, and cell and gene therapy. The cell and gene therapy department is responsible for receiving approvals for cell therapy products. Admission, fast approval process time is 6 ~ 10 months.
In addition to regulations, the FDA continues to communicate with companies and research organizations in the field of cell therapy to develop more than 15 guidelines and specifications for cell therapy. These guidelines are instructive in product development and quality control, and provide a reference for expert evaluation.
“Even if the FDA is the most advanced and perfect in the regulatory system, it has established a scientific regulatory path for cell therapy. From the regulations to the different levels of the industry guidelines, the full-time task force and hierarchical classification management model constitute a relatively complete Regulatory system. We can learn from the advanced experience of the United States and combine the domestic situation to establish a set of “dual track system†policies that are beneficial to the safe and healthy development of gene-cell drugs, and benefit the patients in the latest. Scientific and technological achievements, Professor Xu Zhongwei suggested.
Although CAR-T is a brand new drug form, domestic CAR-T companies are already ready to go. Once the regulatory policies and approval paths become clear, China will not be listed on the first CAR-T product. Far
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