Zhejiang University's new cell therapy technology appears on the clinical results of the "Nature" magazine.

Zhejiang News Customer Council Correspondent Tu Jiayu Correspondent Wu Yalan Kenneng

After 14 different scheme chemotherapy, 20 radiotherapy, whole gastric resection surgery ... After more than 4 years ago, Mr. Sun (pseudonym) from Guangdong was diagnosed with "filled large B -cell lymphoma", and a long and painful treatment began After trying almost all the schemes, the effect was unsatisfactory. In despair, he felt that his fate seemed to have sentenced himself to "death".

In May 2020, Mr. Sun came to the First Affiliated Hospital of Zhejiang University Medical College. After an early evaluation, he received a new PD1-19BBZ CAR-T cell treatment. Today, he has survived for more than 2 years.

"Thanks for the new Car-T therapy and gave me the second life!" Mr. Sun said excitedly.

This is the best clinical result of the global CAR-T cell treatment that is difficult to cure recosting lymphoma in the treatment of recurrent lymphoma. status.

On August 31st, Beijing time, the top international magazine "Nature" published the results of this research. The chief physician of Hu Yongxian, the First Hospital of Zhejiang University, was the first author of the paper. Communication author, his team member Zhang Yanqin is the first author.

For the first time in the world, the development of new CAR-T cell products

In the past, CAR-T cell preparation used the patient's own lymphocytes to transform the virus in vitro to integrate CAR molecules for tumor targets into T lymphocytes to form CAR-T cells.

At present, North America and China have listed a number of CAR-T products, bringing hope for patients with recurrence of recurrence of recurrence of recurrence of malignant lymphoma, and have become the most breakthrough technology in the field of malignant tumors.

However, there are some problems that need to be made in traditional CAR-T products. First of all, CAR-T cells are prepared with virus transfection methods, and there is a situation where targets are randomly inserted and the quality of CAR-T cells is uneven. Random insertion gene fragments also have the risk of changes in tumor genes. In addition, the current completion of the product's complete relief of recurrence of recurrence of lymphoma is only about 50%, and the curative effect needs to be improved. In addition, the rapid killing of tumor cells and cytokine release may also cause severe toxic and side -by -side reactions.

To this end, global scientific researchers are working hard to develop non-virus-targeted genetic transformation technology, eliminate the current lack of CAR-T pre-preparation methods, further transform key genes in immune cells, achieve better efficacy and lower capacity Poisonous reaction.

Professor Yellow River in Zhejiang University and Professor Liu Mingyao of Bang Yao Biology, the team of Professor Liu Mingyao, overcome difficulties in this field. They used the CRISPR/CAS9 gene editing technology to win the Nobel Prize in 2020 to accurately knock on PD1 sites in T lymphocytes, and insert a targeted CD19 CAR molecule for tumor cells at a fixed point to build a new non-virus fixed-point integrated CAR-T Cell (PD1-19BBZ).

The results of laboratory research show that using a linear dual-chain DNA with the length of the homologous arm as 800bp as a template, the number of CAR integrated cells can be obtained through the same-source intermediary repair (HDR) mechanism; PD1-19BBZ is expressed in PD-L1 high expression at high expression in PD-L1 high expressions in high-expression in PD-L1 high. It is still low -expression tumor cells, which shows more powerful and lasting killing effects, and the survival rate of mice has been significantly improved.

The first case in the world, non-traditional CAR-T cells treating lymphoma clinical research

In 2020, when Mr. Sun came to the First Courtyard of Zhejiang University, he had multiple lymphoma lesions in the abdominal cavity, and the lymphoma invaded the intestinal wall. The study of the Yellow River team believes that lymphoma invading intestinal walls is a relatively contraindication of CAR-T therapy, and intestinal perforation is prone to occur when receiving CAR-T cell treatment. Therefore, Mr. Sun is no longer suitable for receiving traditional CAR-T cell therapy.

And the new PD1-19BBZ CAR-T cells, cytokine storms and other complications are low. "Maybe it can give patients a chance to survive."

After completing the approval of various clinical studies, on May 26, 2020, Zhejiang University team infused PD1-19BBZ CAR-T cells for Mr. Sun. On June 9, Mr. Sun's CAR-T cells were lost for 14 days after losing back and were discharged after being evaluated. The PET-CT evaluation of 1 month after the return shows that the large block tumor in the original abdominal cavity invading the intestinal mucosa in the body of Mr. Sun has completely disappeared. Today, Mr. Sun has survived for more than 2 years.

The team conducts further clinical research. The results showed that no neurotoxicity and cytokine release syndrome that was not observed in the treatment of patients was not observed in the treatment patients, which proved that PD1-19BBZ CAR-T cells have excellent clinical safety. In addition, PD1-19BBZ CAR-T cells can obtain rapid amplification and long-term maintenance in the patient's body. Among the patients with recurrence lymphoma, the objective relief rate was as high as 100%, and the complete relief rate reached 87.5%. Using single-cell sequencing technology, the team also comprehensively clarifies the mechanism behind the superior clinical effects of non-virus PD1 fixed-point integration of CAR-T cells.

In the recent follow -up, all the inspection items of Mr. Sun have reached the standard, and the weight has also increased a lot compared to the illness."Now I will play badminton in my spare time, which completely restores my life state before the illness." Mr. Sun said, "Thank you for the new CAR-T cell therapy so that I can see my son go to college. Thank you for the Yellow River of Zhejiang University.The careful treatment of the dean team helped me defeat the disease and get rebirth. "After two years, this summer, Mr. Sun shared good news with medical staff in Hangzhou: The son was determined to be admitted to the Fine Arts of the top domestic university!

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