Project Funded by the National Cancer Institute
T-cell based immunotherapies have emerged as some of the most effective treatments which promote long-term survival of cancer patients. Yet, the significant potential of this treatment has been hindered by safety concerns. Through the power of cancer-fighting T-cells, healthy cells can also be targeted and attacked.
In an innovative initiative to make immunotherapy safer and more personalized, a University of Houston research team was awarded an R21 grant to further refine two immunotherapy tools, CrossDome and HLA-Arena 2.0.
UH researchers, Dinler Amaral Antunes, assistant professor of computational biology in the Department of Biology and Biochemistry and postdoctoral researcher Martiela Vaz De Freitas lead the R21 initiative which was funded $414,649 by the National Cancer Institute. Both Antunes and Vaz De Freitas are members of UH’s Center for Nuclear Receptors and Cell Signaling.
“We want to improve the capacity of researchers to identify the best targets for patients--to help develop their own personalized therapies,” Antunes said. “There’s always a risk. Once you treat the immune system, you can also attack some healthy cells. We are developing a new database, in which we are predicting potential off-targets for a large dataset of known cancer targets.”
The overarching focus of the project is to help researchers predict the risks associated with specific immunotherapies that could potentially attack healthy cells.
Citing one specific case, Antunes shared how researchers designed T-cells which were intended to target a protein found in a type of skin cancer, melanoma. Yet, the T-cells also attacked a protein in the heart cells of patients. This led to damage to the heart.
“It is difficult to predict the risk. It’s not usually done as a screening protocol,” Antunes said. “The researchers’ focus is to find the best targets for a specific cancer. Then, they can test potential to see if there is some toxicity locally. They cannot know for example--if this thing will attack or if there are toxicity rates for other tissues. Some of the patients’ T-cells were also killing the cardiac cells, so patients were dying for toxicity to the heart. The idea is how can we predict this risk in the context of clinical trials.”
The UH research team has developed two essential computational tools, HLA-Arena 2.0 and CrossDome, which use bioinformatic methods to make peptide-centered predictions, assessing if the T-cells are mistakenly attacking healthy cells. In 2023, Antunes published his findings in the Frontiers of Immunology.
“With CrossDome, it will try to see the biochemical properties of the peptides,” Antunes said. “Based upon that biochemical signature, we try to see what else we have in the healthy cells that might be similar. Depending upon how similar they are, you have a risk associated with that. We have already been developing and making predictions with CrossDome—and now we want to make a large database and share these predictions. This could potentially reduce the cost of the treatment as well.”
Vaz De Freitas underscored the importance of a workflow for new structural modeling and analysis of cellular immunity receptors.
“What we have right now is a workflow,” Vaz De Frietas said. “We will try to find the best cancer targets, then we go to CrossDome to find the potential off-targets. The idea is to have the most efficient and safe protocol as possible.”
From Antunes’ perspective, the R21 award was a significant step forward in integrating new tools in cancer research.
“It’s a big milestone for me, as a researcher,” Antunes said. “This is awesome. This my first external funding. This is something that I needed as an independent researcher. Since I joined UH, I wanted to design a proposal that could be funded by NCI/ITCR. It took me a while to get things right--and then we finally submitted the grant. I was super excited that I got this funding. We hope to integrate our tools with other available methods, so that everyone in the cancer research community can benefit from this.”
This year, Antunes was previously awarded a Pilot Program Grant to launch another immunotherapy study entitled, Improving the Design of Immunotherapies for Underrepresented Minorities. The initiative is a joint collaboration with UH doctoral candidate, Jaila Lewis, and was funded $50,000 by NIMHD and HEALTH-RCMI.
The in-depth study of the immune system has always ignited Antunes’ curiosity and inspired his passion for research.
“I lost both grandparents on my father’s side, because of cancer,” Antunes said. “Yet, my research trajectory was not focused on cancer directly. It was focused on the immune system. I was more focused on how the immune response was specific or could be less specific. I became interested in using what I had learned from viral immunology—and I wanted to apply this to cancer research. This would make a more direct impact in that context. Immunotherapy is becoming such an important mode of treatment. There are so many challenges because the immune system is so complex, and there are different genetic backgrounds.”
For Vaz De Freitas, collaborating with Antunes on this project has been an intrinsically rewarding step in her research path.
“Everything I have done before has brought me here to this lab,” Vaz De Freitas said. “When I was doing my Ph.D., we worked in gene therapy. I saw how therapy can have a different impact on different populations. What I want to give people is a safe standard that they can rely upon, in terms of immunotherapy—something that will be good for them.”
The research paths of both Antunes and Vaz De Frietas intersected first in Brazil, where Antunes had completed his Ph.D.
“I find it interesting how my research path and Martiela’s path crossed,” Antunes said. “She was in my lab when I was doing Ph.D. in Brazil. When I went to the U.S., she reached out to me about a postdoctoral opportunity. All the pieces came together. Now we have the funding to do the research we have in mind. Everything is now in place. We are excited about the next two years of collaboration.”
Designing therapies which are efficient and safer is the ultimate goal of this project, Antunes emphasized.
“We wanted to provide the tools for the design of new therapies,” Antunes said. “As soon as the patient starts seeking treatment, you can look at what is the genetic background for that patient and find the best target for the tumor of that patient. Then, we can develop a vaccine or therapy for that patient. It will also impact the cost of the treatment. The goal is to make this faster, safer, and at a lower cost. We also want to make sure that the methods are equally reliable for patients from different ethnic groups."
- Alison Medley, UH Health Research Institute