According to report of Cellectis Company, a 78-year-old man with blastic plasmacytoid dendritic cell neoplasm (BPDCN) had fatal reactions and died 8 days after receiving the treatment of the company’s CAR-T therapy, which is reminiscent of Juno Therapeutics’ treatment of cancer patients with CAR-T therapy last year where 7 patients also died, however, CAR-T was not marketed at that time, with relatively small attention.

Due to such event, FDA immediately put subsequent CAR-T clinical trials on hold, which is a blow to and puts a brake on the just approved CAR-T therapy.

Market prospects

Cellectis showed a highlight in other strict safety data: no GvHD complication, an acute or chronic complication after bone marrow transplantation.

Note: Cellectis used the T cell of a donor instead of the patient himself in the treatment, meaning that it could possibly have caused the complication of patient’s host rejection. This good news may help Cellectis achieve drug mass production and industrialization in the future without separately collecting T cells of patients themselves.

This good news will improve the ambitions of Novartis that has relevant therapy approved and Kite Pharma that is to become a part of Gilead in future expansion on CAR-T market. And Roche’s tocilizumab has been basically recognized as the best adjuvant drug for treating adverse reactions.

Shares in Cellectis were down about 30% in Paris after FDA released the news.

Tumor immunotherapies

Tumor immunotherapies are currently the hottest R&D direction of oncology drugs, especially, CAR-T and PD-1 receive much attention. The attention on such therapies reached a new peak after Novartis’ first CAR-T therapy received FDA’s approval last month, and such therapies have been called the "most effective bane of tumors", however, we don’t know whether that is true, whether there are loopholes in mechanism, and whether we are too optimistic and say that prematurely.

PD-1, also an immunotherapy, also had a new situation in the research. PD-1 can be called one of the most successfully developed tumor immune drugs, and has currently been approved for lung cancer, renal cancer, Hodgkin's lymphoma, bladder cancer, and colorectal cancer, etc., however, the biggest downside of PD-1 is that the patient response rate is only 15-25%, so low that the drug combination becomes the most promising way out for PD-1. But unfortunately, many recent studies show that the PD-1 antibody combined therapies do not have good effect, and may even be "detrimental"!

For example, researchers have recently pointed out on the international authoritative journal Clinical Cancer Research that mice were given OX40 antibody and PD-1 antibody at the same time, and it turned out that instead of enhancing the efficacy, PD-1 reduced the therapeutic effect of OX40 antibody and resulted in severe side effects like spleen enlargement of the mice. Likewise, another article published on Cancer Immunology Research mentioned that the strategy of PD-1 in combination with CTLA-4 antibody achieved certain effects in melanoma treatment, but did not have satisfactory effects for lung cancer and renal cancer, etc.

The above events and research results all demonstrate that CAR-T and PD-1 still have many problems to solve, as emerging immunotherapy. The biggest problem of CAR-T that must be solved at present is: how to avoid "sudden death" of patients receiving treatment. Perhaps not many patients would dare to use a therapy if it caused "sudden death", no matter how good the efficacy is, namely, it is difficult for such therapy to have big market. And the biggest problem of PD-1 is how to improve patient response rate. Its drug combinations have been blocked repeatedly, however, there are still great development hopes, such as solution by selecting the administration order and dosage of the combined drugs, but this is an arduous and complex task, as Professor Samir N. Khleif put it: …treating a patient with one immunotherapy could change the tumor microenvironment…when you give another immunotherapy it might work very differently than what is expected and could exhibit the exact opposite outcome than it was supposed to.

Undeniably, from the aspect of mechanism, PD-1 combined therapy and CAR-T therapy are both potential blockbuster therapy for tumor treatment, however they are new therapy in their beginning, not mature enough, and have many problems to be solved. To put it simply, we have not understood them sufficiently, and failed to consider or have not yet met many problems, which brings enormous challenges to the future R&D and utilization of PD-1 combined therapy and CAR-T therapy.

Global progress

It is reported that there have been over 2,400 gene therapies entering the clinical trial phase, but only a few are approved. CAR T-cell therapy, namely, Chimeric Antigen Receptor T-Cell Immunotherapy, is regarded as the "ultimate cancer therapy", and has showed significant efficacy in clinical trials of hematologic neoplasms. In fact, CAR-T is a highly personalized method, with different cells and treatments for everyone, for example, if many patients have received various therapies, like bone marrow transplant, chemotherapy and targeted therapy, before receiving CAR-T therapy, the preparation and programming of the T cells received will also be varied. In the previous approval announcement of Kymriah, FDA expressed: each dose of Kymriah is a customized treatment created using an individual patient’s own T-cells. "The patient’s T-cells are collected and sent to a manufacturing center where they are genetically modified to include a new gene that contains a specific protein (a chimeric antigen receptor or CAR) that directs the T-cells to target and kill leukemia cells that have a specific antigen (CD19) on the surface. Once the cells are modified, they are infused back into the patient to kill the cancer cells." In addition, FDA reminded: treatment with Kymriah has the potential to cause severe side effects, and many cytokines that kill tumor cells will be released in the CAR-T treatment, with general side effects of fever, hypotension and brain swelling, etc.

Refer to:

http://www.cphi.cn/news/show-143990.html

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