New study using gene "magic scissors" to combat malignant tumors has initially proved feasible
A few days ago, "Nature·Medical" published the world's first human phase I clinical trial of CRISPR for tumor treatment. The test target is patients with advanced non-small cell lung cancer, which uses "magic scissors" technology to edit non-small cells The PD-1 gene of T cells in patients with lung cancer is then reinfused into patients for treatment.
In the third generation of gene editing, the CRISPR/Cas9 gene editing technology nicknamed "Magic Shear" has been widely used in various clinical studies. The research paper published this time further confirmed the feasibility of CRISPR gene editing in the field of cancer treatment.
CRISPR/Cas9 is a special DNA cutting system for searching, cutting, and replacing specific sequences of DNA. Compared with traditional restriction enzymes, it can recognize multiple different DNA sites, which is equivalent to an "adjustable molecular scissors." In this phase I clinical trial, in addition to verifying the safety of gene editing cells in humans, we must further explore the feasibility of this program in personalized and precise treatment, and on the premise of safety and feasibility. The editing effect of the target gene was observed.
What is the background of this clinical experiment? How is it implemented? How's the effect? When will it enter clinical application? Recently, a reporter from Science and Technology Daily interviewed relevant experts in the industry.
Screening patients inspired by PD-1 monoclonal antibody was a big problem
Conventional cancer treatments such as chemotherapy and radiotherapy often "kill the enemy by one thousand and damage themselves by eight hundred", causing great damage to the human immune system.
With the launch of PD-1 monoclonal antibody drugs in late 2014, cancer patients seem to see a glimmer of light—blocking a signaling pathway by binding to PD-1 protein can prevent tumor cell-induced immune cell death and completely destroy the tumor Cell-induced immune tolerance "conspiracy". However, this PD-1 monoclonal antibody also has disadvantages: for example, in order to prevent the cancer cells from continuously proliferating, patients need to be continuously injected, and the overall cost is relatively high. "According to the price at the time, each person spent as much as 900,000 to 1.2 million yuan per year." The above-mentioned paper is tied to the first author and Deng Tao, chief scientist of Chengdu Meijiesell Company. There are no generic drugs in China and they cannot be legally imported.
With the opening of the era of tumor immunotherapy and cell therapy, the development of innovative cell biotherapy technologies and products as soon as possible has become the common expectation of cancer patients and clinical experts. So, can we use the most advanced gene editing technology to directly delete the PD-1 gene on T cells? Deng Tao said that the team's research believes that this idea may have the same effect as PD-1 monoclonal antibody drug treatment. If immune memory cells can be partially formed, the treatment may be more thorough. With the future large-scale production, the cost will also be relatively Controllable.
The world's first human phase I clinical trial of CRISPR for tumor therapy was completed by the cooperation of the research team of Professor Lu Yu of the West China Hospital of Sichuan University and the team of product developers Deng Tao. Deng Tao told reporters that at the beginning of the phase I clinical trial, there were no precedents to follow. Among them, only the goal of completing the minimum 11 patients required by the international new drug standard, the research team groped for 2 years. "One of the biggest problems is to screen patients." Dr. Yu Kun, a team member and the technical director of Mejcel, said that patients must meet at least two conditions: first, it must be ineffective through standard first-line, second-line, and third-line treatment Advanced patients; second, the tumor cells have PD-1 target gene expression.
"Some patients haven't waited until the edited cells are cultured in sufficient quantities, and people will go." Deng Tao said that from mid-2016 to the end of 2018, the team processed data according to the requirements of standard phase I clinical trials. , And finally showed the complete phase I clinical trial results.
Six major links to complete the test T cells are separated and then "armed"
If the patient's immune function is good, the tumor is not terrible. Cancer cells can be recognized, suppressed, and eliminated by the immune surveillance function. Even if a small number of cancer cells exist in the body, patients can coexist with them in harmony. However, once "cunning" cancer cells break through the body's immune cell line of defense and metastasize and proliferate, it is difficult to be "destroyed". From a certain point of view, gene editing T cell therapy is to "arm" the body guardian-immune cells, play an immune killing role, control tumor growth, and remove cancer cells.
So, in this clinical trial, how is the gene editing technology implemented? The implementation process of this research experiment mainly includes six major steps: screening patients, drawing blood, separating components (T cell extraction), performing gene editing, engineering amplification and third-party detection, and retransmitting to the human body.
For example, Deng Tao said that, like the blood drawing process, 50-100 ml of peripheral blood is generally drawn and then distributed to the relevant GMP (to meet the requirements of good manufacturing practices) clean cell laboratory; in the gene editing process, researchers use "magic scissors" The technology cuts and reconnects the PD-1 gene to eliminate the protein expression of the PD-1 gene; in the engineering amplification process, the edited T cells need to be expanded in the GMP laboratory for large-scale expansion, related gene editing and cells Quality control testing. In addition, the edited T cells have to be sent to a third-party platform for testing to ensure that they are safe and free of any pollution; while in the process of retransfusion to the human body, qualified cell products must be distributed to GLP (short for Good Laboratory Practice) ) The ward is returned to the patient under strict monitoring.
"During the operation of clinical trials, different patients have different treatment options. In the monitoring and treatment of critically ill patients, a more complex comprehensive plan is often required." Yu Kun said that this is because advanced critically ill patients are immune Cells are relatively fragile, and it is more difficult to edit the survival rate and expansion of T cells, so it requires more effort and more optimized processes.
Deng Tao also said that unlike stem cells and embryonic cells that are "eternally immortalized", propagated, and passaged in the human body, this edited immune cell is a terminally differentiated cell, which will be normally metabolized within a few months until it is eliminated from the human body, almost There is no genetic risk.
Although the safety feasibility target has been achieved, the sample needs to be expanded
"As the treatment progresses, the immune diversity of TIL (Tumor Infiltrating Lymphocytes) and peripheral blood PBMC (Peripheral Blood Mononuclear Cells) in the tumor tissue gradually increases... This shows that the treatment is extremely effective in rebuilding the patient's immune ecology The big effect..."This is the analysis and description of the effect of this experiment.
Yu Kun said that 11 patients who had been enrolled in the late stage of conventional treatment did not have side effects above grade 3 after receiving gene-edited T cell reinfusion therapy, and 3 patients achieved a stable effect for 8 weeks. In addition, the median mutation frequency of off-target events was only 0.05%.
When can this highly anticipated new technology be put into first-line treatment? "We are starting to declare new drug clinical trials (IND) to the State Drug Administration." Deng Tao said. At the same time, many people are also worried, what if the price is too expensive? Yu Kun said that with the further optimization of the process flow, the cost will further decrease significantly.
At present, CRISPR gene editing technology is mainly used for the treatment of genetic diseases, AIDS, tumors, etc. Among them, in terms of genetic diseases, the team of Zhang Feng used CRISPR technology to treat the single-gene genetic disease-Leber's congenital Hemeng 10 (LCA10), and clinical trials are currently underway; Removed from the patient's hematopoietic stem cells and transplanted back into the patient's body, in order to achieve a better long-term low-toxic survival state; and in the treatment of tumors, the team of Deng Tao and the team of Carl Juno in the United States have obtained relevant treatments for lung cancer and osteosarcoma respectively Clinical results.
"The biggest risk of these gene editing clinical trials is how to ensure accuracy. If the wrong gene is cut, it is prone to off-target risk. This type of risk is mainly focused on the field of germ cell and embryonic stem cell editing. The editing of adult cells such as T cells has a much smaller risk." Deng Tao said, "The main purpose of this phase I clinical trial is to verify safety and feasibility, and the goal has now been reached."