Recently, the top academic journal Nature has published a major study related to CAR-T treatment, a research team led by Professor Car June, the professionals in cancer Immunotherapy and the pioneer of CAR-T therapy unexpectedly discovered a genetic mutation that could overturn traditional CAR-T treatment and is expected to cure patients with leukemia who are hopelessly treated.
CAR-T is a breakthrough anti-cancer therapy that can separate immune T cells from patients, genetically engineer them in vitro, insert receptors that recognize cancer cell antigens, and then return them to patients. In specific, scientists have installed exclusive anti-cancer weapons on T cells to make them effective in eliminating cancer. In 2017, the first and second CAR-T therapies were approved by the FDA, and the history of human cancer has opened a new chapter.
The advent of innovative anti-cancer therapies is naturally inseparable from rigorous clinical trials. In these trials, a patient with chronic lymphocytic leukemia caught the attention of researchers such as Professor Carl June. According to the trial plan, the patient will undergo 3 infusions of CAR-T cells, however, his condition has not been effectively alleviated after receiving two treatments.
"Until the 50th day after treatment, the patient developed a cytokine release syndrome, indicating that CAR-T therapy has finally had an anti-tumor effect," said Professor J. Joseph Melenhorst, another head of this study. ‘Subsequent medical image analysis also proved the results. After the last course of treatment, the patient's condition was thoroughly controlled. Since receiving treatment in 2013, he has been cancer-free for 5 years and has achieved clinical cure.’
Figure 1. Evaluation of clinical responses following adoptive transfer of CAR T cells in a patient with CLL.
Despite the ideal therapeutic effect, the tortuous treatment process of this patient has made the researchers confused. In general, CAR-T therapy either works immediately or is completely ineffective. So what makes it to suddenly take effect after more than 50 days? ‘This treatment is what we expect, but we can learn a lot from every patient,’ Professor Carl June said. ‘We returned to the lab and wanted to know as much as possible what was going on behind the treatment of patients.’
The analysis of this patient reveals a surprising fact - in his body, 94% of CAR-T cells actually come from the same ancestor! ‘This is a surprising discovery,’ said Professor Joseph A. Fraietta, the lead author of the study. ‘telling us that the lowest dose required for CAR-T therapy is just a cell!’
Scientists have discovered through sequencing that the chimeric antigen receptor (CAR) sequence was accidentally inserted into a gene called TET2 during the genetic modification process. In normal conditions, TET2 controls the production of blood cells, avoiding their excessive proliferation. Once the structure of the TET2 gene is destroyed, the CAR-T cell begins to multiply rapidly, thereby, the leukemia of the patient will be eliminated.
Figure 2. Diagram of the vector at the TET2 integration site locus.
In order to confirm that the TET2 gene is key to the onset of CAR-T therapy, the researchers suppressed their expression with shRNA. It is obvious that the significant expansion of CAR-T cells occurred once the expression level of the TET2 gene was down-regulated. Based on data obtained from patients and validation of in vitro experiments, the researchers concluded that the inactivation of TET2 may contribute to the production of potent CAR-T cells which can take effect quickly and survive for a long time. Researchers estimate optimistically that a single CAR-T cell may be sufficient to effectively control the condition of patients with advanced leukemia. If this case can be repeated in more clinical trials, it will undoubtedly greatly shorten the preparation process of CAR-T cells and bring revolution to this therapy.
Scientists consider this discovery as a miracle brought by ‘a series of small probability events’. After clarifying the mechanism, we will look forward to the further development and the future application in leukemia treatment.
Reference
Disruption of TET2 promotes the therapeutic efficacy of CD19-targeted T cells. Nature, 2018.