Science Translational Medicine: Knock out this epigenetic gene to make CAR-T more effective

CAR-T, namely chimeric antigen receptor T cell immunotherapy
.

To put it simply, CAR-T is to transform the patient's immune T cells in vitro through biotechnology to make them recognize the antigen on the surface of tumor cells, and then inject these cells back into the patient to achieve the therapeutic effect of identifying and killing cancer cells

In 2017, the FDA approved CAR-T therapy for the first time for the treatment of blood cancers such as leukemia and lymphoma.
The successful application of CAR-T therapy has rekindled hope for many desperate people who are waiting for bone marrow matching.
It 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 depletion
.

However, those CAR-T cells that lack the DNA methyltransferase 3α (DNMT3A) gene generally have the ability to continuously attack cancer cells

Recently, researchers from St.
Jude Children’s Research Hospital in the United States published a research paper titled: Deleting DNMT3A in CAR T cells prevents exhaustion and enhances antitumor activity in the journal Science Translational Medicine, a subsidiary of Science
.

The study showed that knocking out the DNA methyltransferase 3α (DNMT3A) gene of CAR-T cells can prevent T cell exhaustion and enhance anti-tumor activity
.

These results indicate that DNMT3A can be used as a general target to improve the effect of CAR-T therapy, providing a new roadmap for the development of more effective CAR-T cell therapy

CAR-T cell therapy is completely changing the treatment of human cancer.
In addition to achieving remarkable results in some blood cancers, more and more studies have begun to use CAR-T cell therapy to pierce solid tumors and chronic viruses.
Infection
.

Although clinical trials have proven the therapeutic potential of CAR-T cell therapy, CAR-T cell therapy is facing an important problem-CAR-T cell exhaustion, CAR-T cells in the tumor microenvironment will be affected by continuous antigen stimulation.
Becomes unresponsive, inhibits more and more receptors, and loses effector functions
.

However, the specific mechanism behind this is still unclear

Previously, the research team has been working on bone marrow transplantation and cell therapy.
They confirmed that epigenetic regulation is directly involved in T cell failure, and T cell failure has a great impact on the clinical response of cell therapy
.

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

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

After knocking out the DNA methyltransferase 3α (DNMT3A) gene in CAR-T cells, these CAR-T cells can generally retain their proliferation and anti-tumor response capabilities during prolonged exposure to tumors

The research team further revealed that the enhancement of CAR-T cell function by knocking out the DNMT3A gene is combined with the up-regulation of interleukin 10 (IL-10), and the gene map for epigenetic silencing was defined through genome-wide methylation analysis.

.

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

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

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

Regarding these findings, Giedre Krenciute, the co-corresponding author of the paper, said that CAR-T therapy is tumor-specific and may be more effective and safer than conventional therapies such as chemotherapy or radiotherapy
.
This study shows that no matter which tumor type or antigen is targeted, knocking out the DNMT3A gene of CAR-T cells will indeed be more effective
.
This highlights the core role of DNMT3A in controlling the function of human CAR-T cells, and it is hoped that this research will enter clinical transformation as soon as possible
.

Professor Stephen Gottschalk, the co-corresponding author of the study and the head of the Department of Bone Marrow Transplantation and Cell Therapy at St.
Jude Children’s Research Hospital, said that this study demonstrates the tremendous advantages of bringing together researchers with complementary expertise.
This study combines With the advantages of synthetic biology and gene editing, it is expected to develop more effective immunotherapy for cancer patients
.

Original source:

Original source:

BROOKE PRINZING, et al.
Deleting DNMT3A in CAR T cells prevents exhaustion and enhances antitumor activity .
SCIENCE TRANSLATIONAL MEDICINE, 17 Nov 2021, Vol 13, Issue 620.

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