"I just became a father at that time. I read in the email about the loss of nerve and digestive symptoms and weight gain of this child under one year old. It is undoubtedly the most joyful moment since I started scientific research." From the United States Dr. Jing Ran from Harvard Medical School and Boston Children's Hospital said.
Previously, a hospital in Wisconsin, USA admitted a young child with the rare disease . The doctor asked the patient to take the compound screened in the study (a non-prescription nutrition) based on the results of a study by Jing Ran. supplements, so no clinical trial approval is required). Glad that the doctor then observed signs of improvement in various symptoms.
Figure | Jingran (Source: Jingran)
Recently, Dr. Jingran and his team developed a new type of stem cell based on stem cell CAR-T cell platform and related papers have been published.
It is reported that the core of this field is whether T cells derived from stem cells have similar functions and characteristics compared with human peripheral T cells.
This work has conducted a multi-faceted "head-to-head" comparison of T cells "made" in the laboratory and T cells extracted from human blood for the first time. stem cells are derived from in vitro experiments or animal models. T cells all show the characteristics of mature T cells and their strong anti-tumor ability.
Therefore, Jing Ran hopes that this new technical route can allow CAR-T therapy to get rid of its dependence on autologous cells, thereby greatly improving its accessibility.
Apply "fire eyes" to T cells
According to reports, this study aims to explore Recruiting new immune cell therapy methods, especially novel chimeric antigen receptor T cells (CAR-T, Chimeric Antigen receptor T-Cell Immunotherapy )therapy.
At present, cell therapy and gene therapy are hot topics in the medical and health field, and CAR-T therapy may be one of the most successful examples of this.
From the earliest clinical trial to the present, CAR-T cell therapy has been developing for more than ten years. From an exploratory therapy at the beginning, it has become a very mature and widely used treatment method today. It is effective Sex has also been fully verified.
Some of the first patients with lymphocytic leukemia who received CAR-T cells had no tumor cells detected in their bodies for more than ten years after one treatment. Therefore, even the always cautious clinicians and researchers are now beginning to use a word like “cure” that is rarely used in the field of tumor therapy to describe CAR-T cell therapy.
So, what is the special treatment? The scientific principles are not complicated. In our immune cell , T cells are like patrol soldiers, responsible for responding to various health threats, including pathogens from outside the body and tumor cells that mutate themselves.
Therefore, almost all cancers are accompanied by the "debt of duty" of these soldiers - T cells sometimes cannot effectively identify tumor cells, or their functions are inhibited.
And CAR-T cell treatment is to extract and collect T cells in the patient's body, and then equip them with chimeric antigen receptors (CAR) through the method of gene editing . Give it peace to identify tumor cells in a specific way.
Then, these modified T cells are re-introduced back to the patient's body, and CAR-T cells can efficiently identify and attack tumor cells.
As a "living drug", CAR-T cells can survive, proliferate, and even have "memory" for a long time, just like the T cells in our body. Researchers have shown that after a decade of treatment, these modified CAR-T cells still exist in patients and are always "monitored" to prevent tumor cells from reappearing.
Although CAR-T cell therapy has the above advantages, it also has its limitations. For example, CAR-T cells are far less effective than blood tumors.
In addition, the current clinical sources of CAR-T cells are all the patients' autologous T cells. Although this can avoid rejection, especially the occurrence of graft-versus-host disease, it also greatly limits the application of CAR-T cells .
First of all, it can be very difficult for some patients, such as young children, or some patients who have undergone multiple rounds of chemotherapy in the early stage, to collect sufficient number of healthy T cells from their bodies.
Secondly, autologous CAR-T cell therapy is essentially an individualized treatment. There is heterogeneity between T cells in different patients. Moreover, every time CAR-T cell production is produced, it requires T cell extraction, purification, gene editing, A series of processes such as in vitro amplification have greatly increased the complexity and production cycle of the production process.
A recent survey showed that patients in the United States currently need to wait for CAR-T treatment to be placed on CAR-T treatment, and in the end only one-quarter of patients can receive CAR-T treatment. The high threshold for production and quality control directly leads to high prices for treatment.
2021, as soon as CAR-T treatment entered the Chinese market, its high fees of up to one million yuan caused controversy among all parties. This study by Jingran hopes to solve these problems by exploring new sources of CAR-T cells.
The strategy it adopts does not rely on collecting peripheral blood cells, but artificially "made" T cells in the laboratory. That is, with the help of inducible pluripotent stem cells, this cell is similar to embryonic stem cell , and can proliferate infinitely and have the potential to differentiate into different cell types. By gene editing and specific and efficient differentiation of stem cells in vitro, a kind of cell can be obtained. Novel stem cell-derived CAR-T cells.
This new cell is named EZ-T cell. has similar functions and characteristics to T cells in the human body, and can effectively and continuously kill tumor cells.
Recently, the relevant paper used "EZH1 inhibits the production of mature iPSC-derived CAR T cells, with enhanced anti-tumor activity" (EZH1 repression generates mature iPSC-derived CAR T cells with enhanced antitumor activity) published on Cell Stem Cell (IF 25.2), and became the cover article of the current issue. Professor George Daley, Dean of Harvard Medical School, Fellow of the National School of Medicine, and Fellow of the American Academy of Arts and Sciences, is the corresponding author [1].
Figure | Related papers (Source: Cell Stem Cell)
Reviewers highly recognize the originality and application value of this study. The experimental data obtained by the research team is also the key to the support of paper publication by reviewers and journal editors.
Transforms T cells from laboratory "manufactured" into CAR-T cells
This project was first launched at In 2018, data collection and analysis, as well as paper writing were completed in early 2022. Although it has been affected by some reasons due to the epidemic, it is generally smooth, especially considering the long research cycle of stem cells, for example, it takes nearly two months for each differentiation from stem cells to T cells.
This study is mainly divided into three stages: the first stage is to explore the technical route and optimal conditions for stem cell differentiation. This is also a problem that has plagued the field for many years.Before
, most of the differentiation of stem cells into T cells required the help of a mouse-derived stromal support cell. Moreover, the maturity and functionality of the obtained T cells are significantly different from those of peripheral T cells.
From the very beginning, the team has clearly defined the research goal: to develop a cell culture and differentiation system suitable for clinical transformation. Therefore, they abandoned the use of mouse-derived stromal support cells.
Based on this, it further regulates specific epigenetic factors through gene editing during cell differentiation, thereby maximizing the differentiation efficiency and specificity, while promoting the maturation of T cells in vitro. After
overcomes the technical bottleneck of cell differentiation, the research team mainly used a variety of molecular biology methods to analyze the characteristics of EZ-T cells. The focus of this stage of research is to answer a question of whether it is similar or not, that is, to what extent, the T cells obtained from stem cells are similar to T cells in the human blood.
When the experimental data show extremely high similarity, the research enters the third stage and begins to solve the problem of "can it be used". At this stage, the team transformed the T cells "made" in the laboratory into CAR-T cells, and then tested their ability to kill and suppress tumors in vitro and in animals.
The results found that EZ-T cells not only show anti-tumor ability similar to donor-derived T cells, but also can produce a subpopulation similar to memory T cells, which has a duration of CAR-T cells. Plays a key role. Through the above three steps, the research team completed a complete closed loop from establishing an experimental system, analyzing cell characterization, and detecting cell functions.
Test personal experience of the "Boston Mode"
Jing Ran said: "Every progress in the research is the It is delighted that if the research results can help patients, it is particularly memorable. "
During his PhD study in South Carolina Professor Stephen Duncan, a professor of regenerative medicine and cell biology at Na Medical University, uses stem cells to differentiate liver cells to study a rare genetic disease. The disease is symptomatic and fatal in young children and childhood, and has no treatment.
After drug screening, Jing Ran and his colleagues discovered some compounds with potential therapeutic value, and also published an earlier paper.
Later, after he graduated from his Ph.D. and moved to Boston to start a new job, he received an email from Professor Duncan, telling the good news at the beginning of the article - the child's illness began to get better.
and Jingran's love for scientific research may start with going to college. He studied , , Central South University, and when he was doing his graduation thesis at the National Key Laboratory of Medical Genetics at Xiangya Medical College, he personally felt the charm of life medicine research for the first time. After
, he entered the Department of Biochemistry, School of Medicine, Peking University, and studied under Teacher Ni Juhua. He said: "Teacher Ni helped me further establish my interest in scientific research. With the encouragement and support of my teacher, I went to the United States after completing my master's degree and went to study for my doctorate degree at Wisconsin Medical School." Stephen, a doctoral supervisor at
jing Ran Professor Duncan is one of the first scholars to use stem cells to study liver development and disease. During his PhD in the lab, he decided to use stem cells in regenerative medicine as his long-term research direction. After graduating from his PhD, he joined the team of Professor George Daley at Harvard Medical School and Boston Children's Hospital to continue his work in stem cells.
"Professor George Daley is a pioneer in the field of stem cells and an expert in blood development and related diseases. Here I can work with outstanding scientific researchers from all over the world to conduct cutting-edge research on immune cell therapy. In addition to the small environment of the laboratory, Boston The region's large ecology is also unique. From the development of basic research, patent application and authorization, cooperative transformation of technology platforms, to the incubation and incubation of new companies, I have the honor to personally experience the "Boston model" of the innovation of the life pharmaceutical industry, which provides me with There is a very valuable learning opportunity," he said.
The next step of work focus is the transformation and application of research results. During this study, he and his colleagues applied for patents on this new technology in many countries. In the summer of 2021, the team completed the patent licensing of a Boston-based biotech company, Elevate Bio, and the conversion of the technology platform has begun since then.
On August 4, 2022, on the same day the paper was published, led by Academician George Daley, Dean of , Harvard Medical School, Boston Children's Hospital and Elevate Bio reached a cooperation agreement and announced the establishment of a new company. Let's focus on this clinical application of technology.
"In this cooperation framework, the teams in the academic and industry are further optimizing and developing the technology platform. We hope that the promotion of these work can accelerate the transformation of research results into clinical applications." Jing Ran finally said.
Reference:
1.Jing, R., Scarfo, I., Najia, M. A., da Rocha, E. L., Han , A., Sanborn, M., ... & Daley, G. Q. (2022). EZH1 repression generates mature iPSC-derived CAR T cells with enhanced antitumor activity. Cell Stem Cell, 29(8), 1181-1196.
