On November 28, local time, the U.S. Food and Drug Administration (FDA) announced an investigation into the serious risk of causing T-cell malignant tumors by autologous CAR-T products targeting BCMA or CD19.
The FDA stated that it has determined that all BCMA-directed and CD19-directed transgenic autologous CAR-T cell immunotherapies currently approved have a risk of T cell malignancies. Products include Bristol-Myers Squibb's (BMS) Abecma and Breyanzi, Legend Biotech's Carvykti, Novartis' Kymriah, and Gilead's Tecartus and Yescarta.
As soon as the FDA announcement came out, it immediately caused fluctuations in the capital market. On the 28th, U.S. stocks BMS, Gilead, Novartis, and Legend Biotech all fell to varying degrees. On the 29th, pharmaceutical companies related to CAR-T products in the Hong Kong stock market also experienced stock price fluctuations. Keji Pharmaceutical closed down 23.29%, and Legend Biotechnology’s parent company GenScript Biologics closed down 6.02%.
However, on November 30, many pharmaceutical companies and relevant experts related to CAR-T responded to questions from reporters from the "Daily Economic News" and stated that the above-mentioned phenomenon of causing T cell malignant tumors has not yet been found in clinical trials. .
FDA report casts CAR-T into suspicion of carcinogenesis
FDA stated in the announcement that this investigation stems from its receipt of reports of T cell malignancies (including chimeric antigen receptors) in patients receiving autologous CAR-T therapy targeting BCMA or CD19. In vivo CAR-positive lymphoma) reports, the data source of reported adverse events comes from investigational clinical (and/or) post-marketing follow-up.
At the same time, the announcement shows that although the overall benefits of these products for their approved uses still outweigh the potential risks, the FDA is investigating a confirmed risk of T-cell malignancies resulting in serious outcomes, including hospitalization and death and is evaluating whether regulatory action is warranted. In addition, CAR-T therapy, like all gene therapy products containing integrating vectors (lentiviral or retroviral vectors), has been flagged for potential risks of developing secondary malignancies.
It is understood that CAR-T cell therapy is a personalized treatment method that uses the body's own immune system. This therapy helps T cells restore their specific killing activity by introducing a receptor gene (CAR) that can recognize tumor-specific antigens. These modified T cells are cultured and expanded in vitro and then infused back into the patient. It is equivalent to a group of upgraded "special forces" equipped with "special weapons" that can track targets. Once they encounter tumor cells expressing corresponding antigens, they will be activated and expanded again to eliminate tumor cells more accurately.
Despite its amazing efficacy, the safety of CAR-T has always attracted attention from all parties. Xu Pengpeng, deputy chief physician of the Hematology Department of Ruijin Hospital, once said in an interview with a reporter from the "Daily Economic News" that after receiving CAR-T cell therapy, patients may have some complications, such as delayed tumor lysis or B Regeneration disorders of cells and immune cells, these problems need to be screened during regular follow-up. In the next 5 years or even longer, patients will undergo long-term follow-up observation.
In addition, the toxic and side effects after CAR-T cell infusion also require clinical tracking. Xu Pengpeng emphasized that after CAR-T cell infusion, patients need to pay close attention to related toxic and side effects, such as cytokine release syndrome (CRS) and neurotoxicity syndrome (ICANS). Among the toxic and side effects, CRS is relatively common, manifesting as inflammatory reactions such as high fever, nausea, and muscle pain. Sometimes there are also problems such as decreased oxygen saturation or blood pressure, and difficulty breathing. Some patients may also experience problems with the central nervous system, manifested by hand tremors and impairments in consciousness, expression, or orientation.
In addition to the above-mentioned toxic and side effects, as pointed out in the FDA announcement, the potential risk of secondary tumors caused by CAR-T has also attracted continued attention from all parties.
Li Cong, the attending physician of the Lymphoma Department of Zhejiang Cancer Hospital, expressed review opinions in a recent article published by Dingxiangyuan, saying that there is currently insufficient evidence to show that approved gamma retrovirus or lentiviral CAR delivery systems will increase secondary Risk of malignancy.
Regarding the CAR-T products under investigation by the FDA, "We will continue to pay attention to the results of the investigation, closely follow up the patient's status, and maintain a cautious attitude." Xu Pengpeng also responded to reporters via WeChat on November 30: "We have never encountered this kind of situation (causing T cell malignant tumors).”
Many pharmaceutical companies have stated that they have not yet discovered that CAR-T causes T cell tumors
In China, the NMPA (National Food and Drug Administration) has approved a total of 4 CAR-T products, including Fosun Kite’s Yikai. Benoda (Akilenza), which was approved in June 2021, is the first CAR-T cell therapy product approved for marketing in China; WuXi Junuo-B (02126.HK)’s Benoda (Rui) Keolunsai); Reindeer Biotechnology's Fucosu (Ichiolaonsai) was approved for marketing in June 2023, becoming the first BCMA target CAR-T product launched in China; Heyuan Biotechnology's Yuanruida ( Nachiolense) was just approved in November this year. It is the first CAR-T product approved for the treatment of leukemia in China.
Regarding the FDA’s announcement, Keji Pharmaceutical posted on its WeChat public account According to a statement issued on the website, the company has recently paid attention to the FDA's announcement on November 28, 2023, regarding reports of T cell tumors in patients treated with autologous CAR-T cell immunotherapy targeting BCMA or CD19.
Based on the current Publicly published information shows that the incidence of T-cell malignancies in patients receiving CAR-T therapy is very low. Professor Frederick Locke of the Moffitt Cancer Center also mentioned in an interview with MedPage Today, “Among patients receiving CAR-T therapy, , the incidence of T-cell lymphoma is about 1 or 2 per 10,000. FDA Adverse Event Reporting System (FAERS) data shows that there are 936 adverse events among multiple myeloma patients currently treated with BCMA CAR-T therapy. According to the report, there is only one report of T-cell lymphoma. For patients with multiple myeloma, even if they have not received CAR-T treatment, they are prone to develop the disease due to factors such as immunosuppression caused by multiple myeloma disease, chemotherapy and stem cell transplantation. Second tumors. According to different research reports, the incidence of second tumors in multiple myeloma patients is between 0.98% and 1.26%.
As of now, Keji Pharmaceutical is developing CAR-T products and treating patients in clinical trials. The total number of cases exceeds 500, including more than 250 cases of BCMA-targeted CAR-T products, and no cases of T-cell tumors have been observed. "We believe that this incident has no substantial impact on the development and commercialization process of the company's products."
Legend Bio According to reports, multiple myeloma patients may develop T-cell malignancies even without CAR-T cell therapy. In addition, other myeloma-related treatments, such as alkylating agents, immunomodulatory drugs, and autologous stem cell transplantation, are Associated with an increased risk of secondary cancers. Johnson & Johnson said it has shared post-treatment surveillance data with the FDA on Carvykti, which has been used in 2,000 patients to date and has a favorable benefit-risk ratio.
WuXi Junuo Reply The reporter said that overall, Benoda has treated hundreds of patients and no similar risks have been found yet. The company has strict production processes and quality control procedures to ensure product quality. At the same time, it also conducts long-term follow-up work on patients. The company believes that the current FDA safety investigation will not have an impact on the company's R&D and commercialization activities.
Reindeer Bio insiders also said that no similar situation has been found clinically.
Daily Economic News
Keywords:EDITOR_DEFINED-Tumor,STOCK-Legend Bio,STOCK-Bristol-Myers Squibb,STOCK-Johnson & Johnson,EDITOR_DEFINED-Gene Therapy
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