Following the success of CAR T-cell therapy for blood cancers, Alliance for Cancer Gene Therapy Research Fellows and other leading scientists are working to replicate the results for other cancers, notably hard-to-treat solid tumors. One of the challenges for utilizing this emerging cell and gene therapy for solid tumors is T-cell exhaustion.
Stephen Gottschalk, MD, of St. Jude Children’s Hospital, and an Alliance for Cancer Gene Therapy Research Fellow, is dedicated to finding solution to this obstacle.
Dr. Gottschalk and his research team have found a genetic mechanism linked to T-cell suppression – and are testing ways to bypass this suppression to strengthen CAR T cells. By editing one gene, DNMT3A, the St. Jude Children’s Hospital researcher may have discovered a way to make CAR T cells more effective against resistant tumors.
Alliance for Cancer Gene Therapy grant for sarcoma cancer study
Dr. Gottschalk is chair of St. Jude’s Department of Bone Marrow Transplantation and Cellular Therapy. He received a grant from Alliance for Cancer Gene Therapy in 2019 to investigate how to make an effective CAR T-cell therapy for pediatric sarcoma cancers.
His laboratory is focused on pediatric sarcoma cancer, but the scientific findings may be applicable to other types of cancer, including pancreatic cancer or the brain cancer glioblastoma, two areas of focus at Alliance for Cancer Gene Therapy.
The Alliance is committed to the advancement of new cancer therapies focusing on enhancing the natural immune system rather than relying on external toxins like chemotherapy and radiation. CAR T-cell therapy – already approved for blood cancers – is the cell and gene therapy showing the most potential to usher in this new era of cancer treatment.
Shutting down gene improves CAR T cell activity
One of the issues with T-cell exhaustion is understanding why these therapeutic T-cells lose their power the longer they are exposed to cancer cells. Alliance for Cancer Gene Therapy has reported in the past how this biological phenomenon affects CAR T-cell therapy – and ways Alliance partners are trying to bypass the issue.
Dr. Gottschalk and his team’s new findings, published in the journal “Science Translational Medicine”, point to the DNMT3A gene as a culprit, at least in pediatric sarcoma cancer. The gene’s full name is “DNA methyltransferase 3 alpha.” Knocking out this gene to improve response was the cancer gene therapy Dr. Gottschalk put to the test – with encouraging results.
The St. Jude Children’s Hospital research team noticed upticks in tumor response, CAR T-cell activity, and additional promising results after shutting down the gene in mouse models. This discovery may lead to other doctors to target the gene, hopefully enabling CAR T cells to attack cancer cells with more power and endurance.
“This work brought together investigators with complementary expertise and presents a huge team effort. It highlights the virtue of team science, and the promise of synthetic T-cell biology, in particular gene editing, to develop effective immunotherapeutics for cancer patients, for whom conventional therapies are not effective.” — Stephen Gottschalk, MD
How to support similar cancer research initiatives
The Alliance is proud to partner with Dr. Gottschalk and excited about his continued advancement of trailblazing cell and gene therapy research. The discovery of DNMT3A’s role in this cancer – and its potential importance in using CAR T-cell therapy for other cancers – will only strengthen his ACGT-funded research as well as other scientists working to arm the immune system with stronger T cells.
A contribution from you can help expedite the funding of critical research making the most of Dr. Gottschalk’s discovery. There are many important initiatives and programs at top cancer centers currently seeking funding. Backed by the expertise of our Scientific Advisory Council, our goal at ACGT is to select those with the greatest potential to advance cures.
Private contributions help Alliance for Cancer Gene Therapy support Dr. Gottschalk’s work, and your donation can allow us to continue funding the most brilliant researchers and their groundbreaking science. If you’d like more information before donating to the Alliance, please read about some of the most recent Fellows receiving grant funding thanks to donors.
Page sources
- Deleting DNMT3A in CAR T cells prevents exhaustion and enhances antitumor activity. Science Translational Medicine. Retrieved from: https://www.science.org/doi/10.1126/scitranslmed.abh0272. Accessed: 01/24/2022.
- Knocking out specific gene prevents T-cell exhaustion, boosts CAR T-cell responses. MedicalXpress. Retrieved from: https://medicalxpress.com/news/2021-11-specific-gene-t-cell-exhaustion-boosts.html. Accessed: 01/24/2022.
