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Universal CAR-T cell therapy refers to a therapy that extracts T cells from healthy donors, transforms them through gene editing or non-gene editing, and amplifies them in vitro, and then can be injected into multiple patients. Its advantages are low cost and can be used at any time. Currently, this therapy is still in its early stages.

Xu Huji's team is making ward rounds. Image source: Changzheng Hospital

Is cheaper CAR-T therapy not far away?

An IIT study (investigator initiated trial) conducted by Xu Huji's team from the Department of Rheumatology and Immunology of the Second Affiliated Hospital of Naval Medical University (Shanghai Changzheng Hospital) showed that the condition of three patients with severe relapsed and refractory rheumatic immune diseases improved significantly after receiving universal CAR-T cell therapy. On the evening of July 15, 2024, the study was published online in the journal Cell. Professor Xu Huji was the first author of the article, and Professor Du Bing from the School of Life Sciences of East China Normal University, Professor Wu Huaxiang from the Second Affiliated Hospital of Zhejiang University, and Professor Liu Mingyao from the School of Life Sciences of East China Normal University were co-corresponding authors.

On July 16, 2024, Changzheng Hospital held a press conference on research results. The hospital said that according to the search, this research result is the first international report on the successful treatment of autoimmune diseases with universal CAR-T. Xu Huji introduced on the spot that there are about 20 universal CAR-Ts in clinical research in the world, and the results have not yet been officially released.

The condition of 3 patients improved significantly

CAR-T cell therapy is "chimeric antigen receptor T cell immunotherapy". Most of the CAR-T therapies that have been marketed and are under development are autologous CAR-T therapies. Researchers extract immune-functioning T cells from patients and edit them in the laboratory to produce proteins called chimeric antigen receptors (CARs). When CAR-T cells are returned to patients, they will seek out and destroy specific targets. Over the past decade, CAR-T therapy has shined in the field of hematological tumors, and in recent years, it has shown its potential to treat autoimmune diseases in many studies.

Autoimmune diseases refer to a type of disease caused by the body's immune system breaking its tolerance to its own components, thus attacking its own organs, tissues or cells, causing damage. B cells play a key role in the occurrence of autoimmune diseases. Dysfunctional B cells produce antibodies against the body's own tissues, leading to the development of the disease. CAR-T cell therapy works by transforming the patient's T cells to recognize and attack abnormal B cells in the body.

Public information shows that universal CAR-T cell therapy, also known as allogeneic CAR-T cell therapy, is a therapy in which T cells are isolated and extracted from healthy donors, modified through gene editing or non-gene editing, and amplified in vitro, and finally can be injected into multiple patients.

The subjects of the above study were three patients with severe relapsed and refractory rheumatic autoimmune diseases. Xu Huji introduced that the first patient was a patient with immune-mediated necrotizing myositis (IMNM). Before treatment, he needed two nurses to help him weigh himself. After one month of treatment, he could squat and stand up, and his muscle strength was fully restored. MRI and pathology showed that muscle inflammation was significantly relieved, laboratory tests showed that muscle enzymes dropped from abnormally high levels to normal levels, and autoantibodies were completely eliminated.

The other two were patients with systemic sclerosis (SSc, also known as scleroderma). Before treatment, their skin was as hard as leather. After treatment, their skin softened, and doctors could give them injections more easily. The patients felt that their condition had improved, and they could open their mouths easily. Skin biopsies confirmed the improvement of inflammation and the formation of new accessory glands. CT and MRI showed that the fibrosis of important organs such as the heart and lungs had reversed damage, and continued to improve during the 6-month follow-up period.

"This is beyond our expectations. We originally thought that fibrosis was irreversible. Now we can see from ultrasound and pathology that fibrosis can be reversed. This is a new scientific issue," Xu Huji said in an interview with the media after the meeting.

In terms of safety, Xu Huji introduced that both clinical observations and laboratory tests showed that universal CAR-T has good safety, indicating that universal CAR-T can be used to treat rheumatic and immune diseases and has huge therapeutic potential and market value.

Xu Huji said that rheumatic autoimmune diseases affect more than 8% of the population, with high incidence, high disability rate and high treatment costs. According to statistics from the National Health Commission, there are more than 100 million people with rheumatic diseases in China. Data from the China Disabled Population Census show that China's disabled population mainly comes from rheumatic autoimmune diseases. In 2021, the hospitalization costs for several major types of rheumatic autoimmune diseases reached 52.4 billion yuan. There is currently no cure for the disease, and existing treatment options include hormone immune preparations and biological preparations. However, some patients are still difficult to control their condition after using the above-mentioned drugs, often involving important organs and endangering their lives. Therefore, this study provides new treatment options for patients with rheumatic autoimmune diseases who currently lack effective treatments.

Universal CAR-T is low-cost and available at any time

"The advantage of universal CAR-T is that it can be used at any time." Xu Huji told the media that the production and use of autologous CAR-T is very complicated, requiring five links from production to patient use, and the cycle is very long. Autologous CAR-T is an individualized therapy. CAR-T cells are derived from the patient's own T cells, but patients with autoimmune diseases have certain problems with their own immune systems and have been receiving immunosuppressants for a long time, so their T cells may have a certain degree of defects, while universal CAR-T cells come from healthy people and are in a more ideal state of use. On the other hand, universal CAR-T can be mass-produced, and one healthy donor's blood can make 200 CAR-T cells, so the cost can be greatly reduced and it can be used at any time.

Currently, there are five CAR-T cell therapies on the market in China, with the lowest price being 999,000 yuan per vial. "Based on cost estimates, the price of universal CAR-T can be reduced to more than 100,000 yuan," said Xu Huji.

According to Xu Huji, the universal CAR-T used in this study was developed by Shanghai Bangyao Biotechnology Co., Ltd. (hereinafter referred to as "Bangyao Bio"). Liu Mingyao is the founder and chairman of the company, and Du Bing is the co-founder and head of CAR-T research and development. According to an announcement released by Bangyao Bio on July 16, 2024, the universal CAR-T therapy used in the study is called TyU19, a candidate cell therapy product targeting CD19.

The announcement stated that universal CAR-T is available in stock and has perfect commercial properties. It has become an important development direction for the immune cell therapy industry, but the development of universal CAR-T generally faces a number of important technical challenges. Du Bing said that the development of allogeneic universal CAR-T has always been the biggest technical challenge facing the industry. The existing gene editing strategy can effectively prevent patients from developing graft-versus-host disease (GvHD), but the rejection problem faced by allogeneic CAR-T cells in patients has never been effectively solved. Traditional allogeneic universal CAR-T has always been in the clinic. There are huge infection risks for patients due to excessive immunosuppression, short retention time in the body, and poor effectiveness, which greatly limits its clinical accessibility.

It is understood that after 8 years of research, the research team of the project has effectively solved the above-mentioned problems with gene editing technology. The universal CAR-T developed by them has achieved long-term retention and effective killing in the patient's body under the condition of FC pretreatment (standard lymphocyte clearing pretreatment regimen) lower than that of autologous CAR-T. Various indicators such as safety and effectiveness have reached or even exceeded those of traditional autologous CAR-T.

The product is still in its early stages. IIT research refers to activities conducted by medical institutions that use individuals or groups (including medical health information) as research subjects, not for the purpose of drug and medical device registration, to study the diagnosis, treatment, rehabilitation, prognosis, etiology, prevention and health maintenance of diseases. "Currently, this study has only evaluated three patients, and the effectiveness and safety of this therapy will need to be evaluated in a wider patient population in the future." Xu Huji revealed that 12 patients have been treated so far.