In a white lab, a young doctor is carefully adding a specific chimeric antigen receptor (CAR) gene to T cells isolated from white blood cells, modifying them into CAR T cells, and then placing them in the lab to grow and multiply until they are transformed into "super-soldiers" capable of recognizing and destroying cancer cells.
This is CAR-T**, a revolutionary tumor method that uses genetic engineering technology to engineer human autoimmune cells, bringing new hope to countless patients with hematologic cancers. Since 2017, the FDA has approved six CAR-T cell products for patients with **advanced** or refractory blood cancers. Among them, Gilead's product Yescarta sales reached 3$9.1 billion.
However, this emerging ** also faces some challenges and risks, such as security issues. At the end of November 2023, the U.S. Food and Drug Administration (FDA) announced that it had received 19 reports of patients developing a T-cell malignancy after receiving CAR-T**, and that the agency was investigating the associated risks.
However, it is undeniable that CAR-T cells** are still one of the most potential tracks in the biotechnology industry map, and the market is also looking forward to them as a game-changer for cancer**. According to data from Precedence Research, a foreign research company, the global CAR-T cell** market size was $3.8 billion in 2022 and is expected to reach $885 by 2032around $200 million, with a CAGR of 298%。
At present, CAR-T cells** are mainly aimed at hematologic cancers, what are the technical difficulties in this technology?Where is the next frontier?The reporter of "Daily Economic News" interviewed Waseem Qasim, professor of cell and genetics at University College London. In 2022, he led the world's first base-edited cell for T-cell leukemia patients
With scientists gaining a deeper understanding of the pathophysiology and pathogenesis of cancer, cancer has entered a new era – from traditional surgery, radiotherapy and chemotherapy to individualized and precise targeting, and safer and more effective immunity. Chimeric antigen receptor modified T cells (CAR-T cells)** are the most rapidly developing form of adoptive cellular immunity**.
CAR-T** extracts the patient's own T cells and then uses genetic engineering technology to introduce a special receptor, the chimeric antigen receptor (CAR), into the T cells. These engineered T cells are reinfused back into the patient's body and are able to recognize and attack cancer cells that carry specific antigens. T cells can be collected from other healthy donors (allogeneic) in addition to the patient themselves (autologous).
Explaining the technical principles of the ** to reporters, Vasim Qasim said, "T cells are white blood cells and are an important part of our immune system. Normally, they work to fight infection, kill infected cells, and can also attack certain types of cancer. ”
In CAR-T**, we collect these cells and modify them using 'genes**. In this case, CAR-T cells are designed to be active against only one target, able to recognize the markers on the surface of that target cell, and then kill that cell. He further explained.
Vasim Qasim is also currently working on blood and bone marrow stem cell transplantation at Great Ormond Street Hospital for Children in London. He told reporters that there are a lot of T cells in blood and bone marrow stem cells, and in more than 20 years of practice, he and his team have accumulated rich experience in how to collect and modify T cells.
Qasim told reporters, ".Currently, CAR-T cells** are mainly targeted at hematologic cancers, including leukemia and lymphoma in children and**.
Last year, University College London and Great Ormond Street Hospital provided a 13-year-old patient with **sex T-cell leukaemia** with base-edited T cells**. This is the world's first CAR-T cell to use base editing**, and the base editing technology used was designed and developed by a team led by Qasim.
Screenshot of the official website of University College London.
Referring to this case, Qasim told reporters, "Last year, the world's first base-edited CAR-T cells were used to ** drug-resistant leukemia. The patient was in good condition and was cured of leukemia after more than a year. ”
Base editing is a advancement in CRISPR technology, and instead of cutting DNA, we can now chemically alter individual letters of the DNA code. He said. At the same time, he mentioned the potential of CRISPR technology in CAR-T**, "CRISPR refers to a new technology that cuts genes like molecular scissors, which helps to improve the design and function of CAR-T cells. ”
In traditional cancers, such as radiation or chemotherapy, there is no clear distinction between healthy and cancerous cells. This means that while traditional** attacks both types of cells at the same time, resulting in severe***, CAR-T** uses the patient's own immune system to fight cancer and recognizes cells more accurately.
The (engineered) T cells are like living drugs, they not only enter the tissues, but they can also track down cells that escape normal**, such as leukemia. Wasim Qasim told the "Daily Economic News" reporter, "Because of this, we use CAR-T to **difficult** blood cancer." ”
While CAR-T may represent a great step forward in the field of cancer, there is still a long way to go for it to be widely promoted. Every reporter has noticed that one of the obstacles of CAR-T** is T cell dysfunction, including cell failure or senescence, which will make them less efficient after entering the human body.
For example, CAR-T cells may also proliferate uncontrollably when infused into a patient, leading to potentially life-threatening inflammation and toxicity. In addition, allogeneic CAR-T also carries high safety risks, such as immune rejection and graft-versus-host disease (**HD).
It is worth noting that on November 28 this year, the U.S. Food and Drug Administration (hereinafter referred to as the FDA) announced that it had received 19 reports of patients suffering from a T-cell malignancy after receiving CAR-T**. The FDA said that all current CAR-T** targeting BCMA and CD19 carries a risk of causing T-cell lymphoma. The agency is investigating the risks involved and is assessing the need for regulatory action.
According to Maksim Mamonkin, a CAR-T specialist at the Center for Cells and Genetics at Baylor College of Medicine, secondary cancers "are definitely not frequent and are not what we expect" in clinical trials. But when a commercial product is used in thousands of patients, this can become an episodic problem. He explains that T-cell cancers can develop after patients have undergone chemotherapy for other cancers**. If precancerous cells are inadvertently collected and used for CAR-T**, secondary cancers may occur.
In addition to the above risk factors, Qasim told the reporter of "Daily Economic News", ".Cost, time, and the need for special laboratories are the main hurdles at the moment. However, it is expected that new technologies will emerge in the future should help address some of these issues. ”
It has been reported that it takes a considerable amount of time to extract, engineer, expand, and infuse T cells for each patient, which means that patients have to wait a long time for them to undergo it**. In addition to this, this process places stringent demands on specialized facilities, scientific and logistical support.
These limitations also mean that the economic cost of this is extremely high. Taking Novartis' CAR-T cell technology as an example, the cost of one time is 4750,000 US dollars (about 3.3 million yuan).
According to data from Kalorama Information, a medical market research publisher, in the first three quarters of 2023, a total of $27 billion was raised in the global cell and gene field, mainly in the direction of T cells** (CAR-T, TCR-T, TIL), and NK cells**. At present, more than 1,500 companies have participated in this field, and the most active companies include Oxford Biomedical, Astellas Pharmaceuticals, Takeda Pharmaceuticals, Eli Lilly, Bristol-Myers Squibb, Novartis, etc.
Among them, CAR-T cells** have shown great market potential. Since 2017, the U.S. Food and Drug Administration (FDA) has approved six CAR-T cell products for patients with **advanced** or refractory blood cancers: Bristol-Myers Squirrel's Breyanzi and its collaborators**ABECMA, Johnson & Johnson's Janssen and Legend Biotech's Carvykti, Novartis' Kymriah, and Gilead Sciences' Tecartus and Yescarta.
Edited by Lan Su British Cartography.
According to Gilead Sciences' recently released financial results for the third quarter of 2023, yescarta's sales increased 23% year-over-year to 3$9.1 billion. Tecartus sales increased 18% year-over-year to $96 million. Legend Biotech's Carvykti achieved sales of $1 in its first year on the market in the United States$3.4 billion.
In the domestic market, in early November this year, Heyuan Biotech's CD19 CAR-T naki-cel injection was approved for marketing for first-class or refractory B-lymphoblastic leukemia. This is the first CAR-T product for leukemia approved for marketing in China, and the fourth CAR-T to be marketed. The three CAR-T** models that have been previously launched in China are Fosun Kite Yikaida, WuXi Junuo Beinuoda and Reindeer Bio Fukesu.
According to data from Precedence Research, a foreign research company, the global CAR-T cell** market size was $3.8 billion in 2022 and is expected to reach $885 by 2032around $200 million, with a CAGR of 298%。
Edited by Lan Su British Cartography.
As far as the domestic market is concerned, the potential should not be underestimated. According to Xinhua News Agency, the data released by "The Lancet Haematology" shows that from 2018 to 2021, the financing amount of domestic CAR-T cell ** companies will be as high as 23$700 million. According to research firm Frost & Sullivan**, China's CAR-T market is expected to reach 28.9 billion yuan (about 4 billion U.S. dollars) by 2030.
For the next frontier of this technology, experts at Memorial Sloan Kettering Cancer Center believe that it lies in the field of solid tumors, such as lung cancer, kidney cancer, bone cancer, and more.
An article published in the international medical journal Molecular ** Oncology wrote that CAR-T*** solid malignancies are an exciting frontier area, but have not yet been realized, andSeveral hurdles must be overcome, including solid tumor antigens for CAR-T cell targeting, transport (of T cells) to the tumor, successful infiltration and binding of tumor antigens, overcoming intrinsic factors of CAR-T cells, and extrinsic factors that may affect the potency and persistence of this cell.
Among these obstacles, the question of solid tumor antigen is the most noteworthy. The ** mentioned that this antigen is lacking in most solid tumors, and although neoantigens (a class of HLA binding peptides produced by tumor-specific mutations are highly immunogenic and thus bypass thymic tolerance because they are not present in normal tissues) can avoid the common problem of antigen target selection for CAR-T cells, they are not suitable for a large number of patients.
In addition, even after the optimal antigenic target has been selected, the function of CAR-T depends on factors such as the ability to prevent tumors from escaping immunogenic epitopes, that is, there is still the possibility of tumor evasion. All of these factors contribute to the poor performance of this product in solid tumors.
However, researchers are exploring ways to improve the safety and efficacy of this **, for example by improving the design or developing new targets.
For example, John Heymach, chief of the Department of Thoracic Head and Neck Medical Oncology at the University of Texas MD MD Anderson Cancer Center, and his team saw the potential for small cell lung cancer. Their results, recently published in the journal Cancer Cell, suggest that when combined with targeted drugs, CAR-T cells can more effectively delay the onset of complete drug resistance by targeting cell surface proteins expressed by drug-resistant long-lasting cells.
We believe these findings may be broadly applicable to other tumor types that develop different types** of resistance mechanisms. Heymach said.
Although there is still a lot of work to be done, researchers are optimistic about the future of CAR-T cells** in solid tumors. "We have seen some very encouraging results, such as successful transport and penetration into the (solid) tumor, as well as significant objective responses noted in selected patients. Samer Srour, professor of stem cell transplantation at the University of Texas MD MD Anderson Cancer Center, said. "This reaffirms the use of CAR-T cells in solid tumors and provides a proof of concept. ”
According to Qasim, "it may take longer for the same approach to work for more complex cancers, and some of them may be combined with drugs or chemotherapy." ”
However, as a representative of cells, the glorious future of CAR-T may not be far away.
National Business Daily.