Science: Knockout of this epigenetic gene gives CAR-T cells the ability to continuously attack cance

Simply put, CAR-T is to transform the patient's immune T cells in vitro by biotechnology, so that they recognize antigens on the surface of tumor cells, and then inject these cells back into the patient to achieve the therapeutic effect of recognizing and killing cancer cells.

In 2017, CAR-T therapy was first approved by the FDA for the treatment of blood cancers such as leukemia and lymphoma.

The successful application of CAR-T therapy has renewed hope for many desperate people, who are waiting for bone marrow matching. This also marks the arrival of the era of cell therapy.

Today, CAR-T has become one of the most important new developments in cancer immunotherapy, and many breakthroughs have been made in hematological tumors, but CAR-T therapy is usually limited by T cell failure.

However, those CAR-T cells lacking the DNA methyltransferase 3α (DNMT3A) gene usually have the ability to continuously attack cancer cells.

Recently, St. Researchers at Jude Children's Research Hospital published a research paper entitled "The Deleting DNMT3A in CAR-T cells Enhancement Antitumor Activity Prevention" in the Science Translational Medicine.

Studies have shown that knockdown of DNA methyltransferase 3α (DNMT3A) gene in CAR-T cells can prevent T cell failure and enhance anti-tumor activity. These results suggest that DNMT3A can be used as a universal target to improve the therapeutic effect of CAR-T, providing a new roadmap for the development of more effective CAR-T cell therapy.

CAR-T cell therapy is revolutionizing the treatment of human cancers. In addition to significant results in some blood cancers, an increasing number of studies are beginning to use CAR-T cell therapy to penetrate solid tumors and chronic viruses.

Although clinical trials have demonstrated the therapeutic potential of CAR-T cell therapy, CAR-T cell therapy faces an important problem—CAR-T cell failure, which is affected by continuous antigenic stimulation in the tumor microenvironment. It becomes unresponsive, inhibits more and more receptors, and loses its effector function. However, the specific mechanism behind this is unknown.

Previously, the research team had been working on bone marrow transplantation and cell therapy.

They confirmed that epigenetic regulation is directly involved in T cell failure, which has a great impact on the clinical response to cell therapy.

The team also studied DNA methyltransferase 3α (DNMT3A) in a mouse model and in the setting of chronic viral infection.

These studies suggest that epigenetic modulation modulates long-term T cell memory.

In this study, the team found that CAR-T cell depletion was caused by epigenetic suppression of the pluripotent developmental potential of T cells.

After knockdown of DNA methyltransferase 3α (DNMT3A) gene in CAR-T cells, these CAR-T cells can usually maintain their proliferation and anti-tumor response ability after prolonged exposure to tumors.

The team further found that knockdown of DNMT3A resulted in enhanced CAR-T cell function combined with up-regulation of interleukin 10 (IL-10), and determined the genetic map of epigenetic silencing by genome-wide methylation analysis.

This figure analyzes the depletion of CAR-T cells at the molecular level, including many transcriptional regulators that limit the "stemness" of immune cells, including CD28, CCR7, TCF7, and LEF1.

Finally, the team also demonstrated that this epigenetic regulation is closely related to the clinical results of previous CAR-T cell therapy.

These data document the key role of epigenetic mechanisms in limiting the fate potential of human T cells and provide a roadmap for the use of this information to improve the efficacy of CAR-T cell therapy.

Regarding these findings, Giedre Krenciute, co-corresponding author of the paper, said that CAR-T treatment is tumor-specific and may be more effective and safe than conventional treatments such as chemotherapy or radiotherapy.

This study shows that knocking out the DNMT3A gene of CAR-T cells will indeed be more effective regardless of the tumor type or antigen targeted.

This highlights the central role of DNMT3A in controlling human CAR-T cell function, with the hope that this study will enter clinical translation as soon as possible.