Building on research she has conducted over the past few years in the lab of University of Colorado Anschutz Cancer Center leader Eduardo Davila, PhD, Gabriella Albert, a PhD student in the CU Anschutz School of Medicine, has received a Ruth L. Kirschstein National Research Service Award (NRSA) Individual Predoctoral Fellowship from the National Cancer Institute (NCI) to study T cell–based immunotherapy exhaustion.
“Our lab works on the CD8α:MyD88 receptor, which is a combination receptor of intracellular signaling through a molecule called MyD88 appended to an extracellular CD8α, which is found on most antitumor T cells,” Albert says. “We have found that if you can engineer CD8α:MyD88 into T cells, it makes them better tumor killers. But the mechanism of why that works hasn't really been discovered. My overarching thesis project is to figure out the mechanism: How is the expression of this receptor on a cell causing these cells to be such good tumor killers?”
Along the road to her thesis, Albert found another unique property of CD8α:MyD88-engineered T cells: They don’t get exhausted in the same way as other antitumor T cells.
“T cells in cancer patients are constantly fighting this battle of trying to eliminate the cancer, but just as humans can't run on a treadmill for years on end, these cells can't continue to fight for years on end, and they become exhausted,” Albert says. “There are a lot of gene expression mechanisms that regulate that. When I realized that our CD8α:MyD88 T cells don't seem to be getting exhausted, I worked my way backward from that mechanism to start looking at the unique molecular profile that allows those cells to resist that path to exhaustion.”
Albert already has conducted research to find which molecules are being expressed differently in the T cells that have the CD8α:MyD88 modification versus unmodified T cells. With the NCI F31 grant — a grant specifically for doctoral candidates performing dissertation research and training for a PhD degree — she will utilize internal molecular assays to characterize the full epigenetic landscape of the cell to better understand how the modified T cells are able to persist and resist terminal exhaustion.
“The goal is to see if we can start further downstream, maybe at a transcription factor or an epigenetic regulator, and take that molecule and overexpress it or force the expression into a regular T cell,” she says. “Do we get the same effect? Can that itself be its own therapeutic? I’m looking to understand not only the full mechanism of how this co-receptor works, but also to see if we can pull out a new molecular regulator that could potentially cause a similar effect.”
The results of the research, Albert says, could have an impact on the treatment of solid tumors, in which immunotherapy innovations like CAR T-cell therapy have so far proven to be not as effective as they are in blood cancers.
“Studying the CD8α:MyD88 receptor and understanding how it's able to manipulate these cells to oppose terminal exhaustion and stay in the body a lot longer as effective tumor killers is exactly what we need for solid tumors, where the T cells have to infiltrate and stay there and work their butts off to eliminate that mass of tumor,” she says. “If we're able to pull something else out of this project that on its own could be a novel therapeutic, that would be amazing for targeting solid tumors for immunotherapy, which is a big unmet need.”
Albert says she is grateful to the NCI for the grant and the recognition that comes with it. The NCI F31 Predoctoral Fellowship is a highly competitive and prestigious national award, with only approximately 15% of applications funded. Her fellowship received a perfect overall impact score of 1 (10th percentile), representing the highest possible peer-review rating and recognition of the exceptional scientific merit and potential impact of the proposed research.
“I feel so honored to have received it,” she says. “In terms of grant funding for a PhD student, it's one of the highest statuses you can get. I feel really rewarded and thankful that my research was recognized and that I was recognized as somebody who could be successful in the future.”
Albert is also grateful for the mentorship of Davila, who she says encouraged her to apply for the NCI grant.
“I knew from the first time he interviewed me that I was really interested in his lab and also his mentoring style,” she says. “He's always so supportive and gave me the intellectual space to really expand this project. He pushes us to apply for grants and awards, understanding that the sacrifice up front is so rewarding for the student in the end. I wasn't even planning to apply, but he said, ‘You should. Your research is great. You're great.’ He's been a really supportive mentor for me.”
For his part, Davila is glad that Albert applied for — and received — the grant, which he says reflects her skill as a researcher.
“Gabi’s F31 fellowship, which received a perfect score, recognizes both the scientific merit of the proposed research and Gabi’s exceptional potential as an independent physician-scientist,” says Davila, associate director of the CU Anschutz Cancer Center’s Office of Cancer Research Training and Education Coordination (CRTEC). “This prestigious grant reflects Gabi’s intellectual curiosity, scientific rigor, creativity, and commitment to translational research and highlights a very promising trajectory toward becoming a future leader in cancer immunotherapy. I am so incredibly proud of her.”