Steve Jobs, who suffered from pancreatic cancer, once said that he was probably the last person to die of cancer. At the beginning of this year, scientists at the University of London also said at the Royal Society Cancer Symposium that by the middle of the 21st century, human beings are expected to achieve "no one under 80 years of age dying of cancer." Of course, the rhetoric of these people is not a slogan.
In recent years, scientists' breakthroughs in the field of tumor immunotherapy are enough to make everyone believe in these words. Speaking of immunotherapy, there are two most exciting new results, one is immune checkpoint blockade, including antibodies against T lymphocyte antigen 4 (CTLA-4) (Ipilimumab) and against CD8-positive T cells. The antibody of PD1/PD-L1 is the antibody of the programmed death factor; the second type is adoptive immunotherapy (passive immunization) based on CAR-T cell technology, including LAK cells, CIK cells, CTL cells, TIL cells, and the like. And CAR-T is the protagonist of our discussion today.
Perhaps during this time, people who are concerned about life sciences and oncology are constantly being bombarded with a concept, that is, CAR-T. Although some people are attracted by the unlimited potential of CAR-T in cancer treatment, some people are admired by the superior financing ability of the CAR-T industry. In any case, CAR-T has successfully gathered the attention of the world.
Just as every foreigner has a Chinese name, CAR-T also has its own Chinese name: chimeric antigen receptor T cell technology. Although CAR-T is not a completely new thing, in recent years, the improved CAR-T technology has been successfully applied to the clinical treatment of cancer as a new type of cell therapy. And the lucky little girl Emily Whitehead, please remember her smile, because she will always be included in the annals of human fighting with malignant diseases. Before the advent of CAR-T technology, the traditional medical treatment goal was mainly to "prolong the life expectancy of patients". The usual indicators were "1 year survival rate" and "5 year survival rate". No one would dare to cure cancer. However, the emergence of CAR-T has enabled humans to see the dawn of a complete cure for cancer. We can finally say "Going out! Tumor Jun".
Lucky Girl Emily Whitehead
The current status of CAR-T therapy: the world and China
The author conducts online search with the keyword “chimeric receptorâ€, which can generally show the overall situation of CAR-T clinical work in the world. At present, we can retrieve 122 clinical cases, including 77 in the United States, 24 clinical trials in China, 16 in the European Union, 2 in the Middle East, and 1 in Japan, Southeast Asia and Australia. China has become the second largest country in the world to carry out CAR-T clinical research. If you see here, are you still a little excited? However, China's rapid development in the CAR-T field is far more than that! The United States was the first country to conduct CAR-T clinical trials. Before 2010, global CAR-T registered clinical trials were concentrated in the United States. In 2011, CAR-T clinical registration was also started in Europe. Since 2013, China 301 Hospital has also joined the army of CAR-T clinical research. So far, the number of registrations for China's CAR-T projects has increased year by year. By November 2015, the number of registered CAR-Ts in China has surpassed that of the United States, reaching 50% of the total number of newly registered CAR-T clinics.
However, regarding China's CAR-T research, we should be alert to the emergence of some problems behind the fiery. It is undeniable that China's scientific research soil is not so "pure". At present, the biggest problem in such a large-scale CAR-T project is how to ensure the quality of research. Relevant departments should do a good job of supervising and eliminate some scientific research institutions and hospitals that do not have the strength of CAR-T research and follow the trend blindly. In addition, China's CAR-T research must do a valuable patent application and actively participate in the development of international CAR-T standards. Otherwise, your CAR-T technology is no better, and you will always be subject to people in the future business application. Such dumb loss is enough for us.
Regional distribution of global CAR-T clinical registration projects as of December 12, 2015
At present, researchers around the world are more inclined to CAR-T treatment research in hematoma (leukemia), of course, the main reason for this situation is due to the obvious weakness of CAR-T in the treatment of solid tumors. In the existing CAR-T clinical trials, the most common target is still CD19. A total of 59 clinical trials worldwide selected CD19 as a target, which is consistent with the CAR-T clinical preference for hematological tumors. The remaining targets were Her2 (7 items), GD2 (7 items), CEA (6 items), and mesothelin (5 items). In addition, the global clinical research is mainly based on the second generation of CAR-T technology, the mainstream co-stimulatory factors are 4-1BB and CD28. Among all projects, projects using three generations/four generations of technology accounted for less than 10% of the total. China and the United States may be the only countries in the world that have conducted four generations of CAR-T clinical trials.
Typical second-generation CAR-T technology targeting CD19
CAR-T combined with CRISPR! ? What are the big names in the industry?
Although CAR-T is still some time away from the final commercial application, Novaris Pharmaceuticals (Novatris), a leading company in the CAR-T research field, has taken precautions. At the beginning of this year, it invested in Intellia Therapeutic, a startup that specializes in CRISPR technology. Co-develop the most promising new drugs. However, just in the past few months of investment in Novartis, CAR-T newcomer Juno Therapeutics has reached a $737 million cooperation agreement with Editas Medicine to jointly develop cancer immunotherapy CAR-T and TCR (high-affinity T cell) in conjunction with CRISPR technology. Receptor). Last year, Juno and Novartis had settled some of the CAR-T-related patent disputes, but it seems that the two companies want to open a second battlefield on CRISPR technology.
And the background of the two CRISPR technology companies they invested in is very intriguing. Intellia is behind the Greek goddess Jennifer Doudna, and Editas Medicine is Zhang Feng's back garden. Doudna was a co-founder of Editas and later dismissed the original team because of patent issues and licensed his intellectual property to Intellia Therapeutics. In the end, the game of the Central Plains became "Novo + Jnnifer Doudna" PK "JUNO + Zhang Feng".
Jnnifer Doudna and Zhang Feng
CAR-T's tomorrow
Although CAR-T treatment has not yet fully entered the commercialization stage, Professor Carl, the inventor of CAR-T technology, said that CAR-T technology began its first clinical trial in 2010, and it is estimated that it will be approved by the US FDA in 2017. In seven years, this is already very fast.
The current serious immune response is the biggest side effect of CAR-T therapy, because many factors that activate immune cells are released, and the most serious reaction of patients during treatment is fever. But if there is no fever reaction, it means there is no therapeutic effect, so side effects are part of the treatment process. What we need to solve is how to control this side effect. In response to this problem, a research published in the journal Science in September this year, researchers at the University of California, San Francisco, designed a "molecular switch" that can strictly control the behavior of T cells. This breakthrough is expected to solve T cell therapy. A major obstacle to serious side effects. This research has subverted the development of the "silent" CAR-T system, which can accurately make CAR-T cells self-apoptotic after exercising their mission, greatly alleviating serious side effects, and indeed making CAR-T immunotherapy effective. Sex and reliability are elevated to a new level.
At this stage, CAR-T therapy also faces many technical challenges. It is imperative to automate and streamline the CAR-T treatment process, unify the standards, thereby reducing costs, and laying a solid foundation for the final CAR-T to “close contact†with the general patients. basis. Finally, we believe that the arrival of this day will not let the world wait too long.
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