Chimeric antigen receptor (CAR) T cell therapy is an immunotherapy that makes a clinical difference for patients with certain blood cancers, solid tumors, and chronic viral infections. Scientists at St. Jude Children’s Research Hospital have now identified how an epigenetic program causes T cell depletion. Their work shows how deleting the DNMT3A gene invigorates CAR T cell responses, which has implications for the next generation of clinical trials currently testing this treatment. The results were published today in Science Translational Medicine.
While clinical trials have shown that CAR T cell therapy has the potential to provide a lasting response for certain diseases, this therapy can be significantly limited by depletion of T cells. However, deletion of the T cell gene. DNA methyltransferase 3 alpha (DNMT3A) in CAR T cells universally preserved the cell’s ability to attack cancer cells.
“When you design CAR T cells to be tumor specific, they have the potential to be more effective and safer than conventional therapies such as chemotherapy or radiation therapy,” the author said co- correspondent Giedre Krenciute, Ph.D., St. Jude Department of Bone Marrow Transplant and Cell Therapy. “By evaluating human CAR T cells that target a panel of tumor antigens in different solid tumor models, we have shown that, indeed, the elimination of DNMT3A works, regardless of the type of tumor or the antigen we are using. let’s target. This highlights the central role of DNMT3A in controlling human CAR T cell function, and we are excited to translate our approach into early phase clinical trials in the future. “
Epigenetics reveal a universal regulator
The results of this article build on previous work by co-corresponding author Benjamin Youngblood, Ph.D., St. Jude Department of Immunology, and co-lead author Caitlin Zebley, MD, Ph.D., St Jude Department of Bone Marrow Transplant and Cell Therapy. They showed that epigenetic regulation is directly involved in T cell depletion, and that depletion (not just the presence of CAR T cells) makes a difference in clinical response. Youngblood’s lab has also studied DNMT3A in mouse models as well as in the context of chronic viral infection. The work has shown that an epigenetic regulator modulates the memory of T lymphocytes in the long term.
“This article is the latest in a body of work that explores the basic mechanisms regulating T cell differentiation, the upstream signaling events involved in these processes, and the impact of these mechanisms on the efficacy of immunotherapies based. of T cells, âYoungblood said. “We have shown that these epigenetic programs are, in fact, coupled with a decline in clinical response, offering a potential way to extend the utility of CAR T cell therapy.”
Researchers have shown that removing DNMT3A invigorates CAR T cells in a variety of mouse models. These models presented CAR T cells with different specificities, signaling domains and tumor types. The variety of models and conditions the researchers tested show the importance of DNMT3A as a universal target.
Using clinical trial data, the researchers also showed how this epigenetic program is firmly linked to outcomes. The results provide a roadmap for leveraging this information to improve the efficiency of CAR T cells. CAR T cells are tested in numerous clinical trials. These therapies are being developed on the basis of findings such as these to optimize treatment in near real time.
âThis work represents a huge team effort and has brought together researchers with complementary expertise,â said co-correspondent author Stephen Gottschalk, MD, chair of St. Jude’s department of bone marrow transplantation and cell therapy. “This highlights the virtue of team science and the promise of synthetic T-cell biology, in particular gene editing, to develop effective immunotherapies for cancer patients, for whom conventional therapies fail. are not effective. “
The co-first authors of the study are Zebley, Brooke Prinzing and Christopher Petersen of St. Jude. Additional authors are Yiping Fan, Alejandro Allo Anido, Zhongzhen Yi, Phuong Nguyen, Haley Houke, Matthew Bell, Dalia Haydar, Charmaine Brown, Shannon Boi, Shanta Alli, Jeremy Chase Crawford, Janice Riberdy, Jeoung-Eun Park, Sheng Zhou, Mireya Paulina Velasquez, Chris DeRenzo, Cicera Lazzarotto, Shengdar Tsai, Peter Vogel, Shondra Pruett-Miller and Deanna Langfitt of St. Jude.
Brooke Prinzing et al, Suppression of DNMT3A in CAR T Cells Prevents Depletion and Enhances Antitumor Activity, Science Translational Medicine (2021). DOI: 10.1126 / scitranslmed.abh0272
St. Jude Children’s Research Hospital
Elimination of a specific gene prevents T cell depletion and stimulates CAR T cell responses (2021, November 17)
retrieved November 17, 2021
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