An Oregon Health & Science University-developed platform for cytomegalovirus-based vaccines shows promise as a "shield" against cancer. The findings were recently published in the journal Science Advances.
Cytomegalovirus, or CMV, is a common virus that infects most people in their lifetimes and typically produces mild or no symptoms.
Cancer cells, like many viruses, often evade the immune system by escaping T cell control; T cells help protect the body from infection. OHSU researchers used CMV to transport cancer-related antigens that would cause an immune response. This triggered the production of T cells that specifically target cancer cells and established a long-lasting defense by the immune system.
"We show that cytomegalovirus can induce unconventional T cells to cancer antigens and that these unconventional T cells can recognize cancer cells," said Klaus Früh, Ph.D., professor in OHSU's Vaccine & Gene Therapy Institute, or VGTI. "The idea is that by throwing a type of T cell against the cancer that the cancer hasn't seen before, it will have a harder time evading immunity."
Früh and his colleagues Louis Picker, M.D., professor in VGTI, and Scott Hansen, Ph.D., associate professor in VGTI, have been working on developing this vaccine platform since the early 2000s. In 2016, their OHSU startup company TomegaVax was acquired by San Francisco-based Vir Biotechnology. The company is currently testing the platform in a human clinical trial for HIV.
Their initial research focused on using the platform as an HIV T cell vaccine. While the first human clinical trials for the HIV vaccine established safety of the platform, the researchers have since modified the vaccine to elicit the desired immune responses. They expect the first batch of immune response data from the clinical trial later this year.
Expanding the platform
The new study expands their preclinical research, showing the promise of the CMV vaccine platform against cancer.
Researchers used genetically modified rhesus CMV to induce cancer-specific T cells in rhesus macaques at OHSU's Oregon National Primate Research Center. In their earlier preclinical research, they showed that the rhesus CMV can be genetically programmed to stimulate T cells differently from typical vaccines. These T cells recognize infected cells in a unique manner.
They aimed to answer two questions: Can the vaccine made from rhesus CMV prompt an unusual immune response against common cancer antigens? And if so, can these unique immune cells identify and attack cancer cells?
The answer to both questions is yes. The way T cells reacted to cancer-related antigens was similar to how they reacted to viral antigens, both in terms of strength and precision. Working with Mt. Sinai Hospital in New York, they also found that when the animal model was exposed to a prostate cancer antigen, T cells became activated by prostate cancer cells. This suggests that the cancer cells could be targeted by this unique immune response.
"Eliciting T-cells to cancer antigens is not easy, because you are trying to elicit an immune response to a self-antigen, which the immune system has been trained not to do," Früh said. "Overcoming this immunological tolerance is a challenge for all cancer vaccines."
The hope: Cancer vaccine
The potential for the vaccine platform to help the fight against cancer is exciting, Früh said. Since the T cells elicited by CMV vaccines are maintained for life, it might be particularly useful as a way to keep cancers such as prostate or breast cancer from reoccurring. The hope is that, if someone has had prostate cancer once, the vaccine would prevent that cancer from coming back.
"If you've had cancer, you are worried the rest of your life that it may come back," he said. "So having a vaccine that can elicit cancer-specific T cells that act as an immune shield continuously patrolling your body and that would protect you for the rest of your life, it's just really exciting."
The researchers first need to find out if the results they found in an animal model can be replicated in humans. CMVs are species-specific, so the rhesus CMV may not yield the same immune response in humans. The ongoing clinical trials for HIV will give early evidence to help decide if further testing and development would yield results. Human clinical trials for other pathogens and cancers are next on the horizon.
REFERENCE: Ravi F. Iyer, Marieke C. Verweij, Sujit S. Nair, David Morrow, Mandana Mansouri, Dimple Chakravarty, Teresa Beechwood, Christine Meyer, Luke Uebelhoer, Elvin J. Lauron, Andrea Selseth, Nessy John, Tin Htwe Thin, Siarhei Dzedzik, Colin Havenar-Daughton, Michael K. Axthelm, Janet Douglas, Alan Korman, Nina Bhardwaj, Ashutosh K. Tewari, Scott Hansen, Daniel Malouli, Louis J. Picker, and Klaus Früh. CD8+ T cell targeting of tumor antigens presented by HLA-E, Science Advances, May 10, 2024, DOI: DOI: 10.1126/sciadv.adm7515. https://www.science.org/doi/10.1126/sciadv.adm7515
This work was funded by U.S. Army Medical Research and Development Command grant W81XWH1910358 to K.F., sponsored research agreement 84517 by Vir Biotechnology, the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (R01 AI095113, P01 AI094417, and R37 AI054292; R01 AI059457), and the National Institutes of Health Office of the Director (P51OD011092). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute Of Allergy And Infectious Diseases or the National Institutes of Health.
All research involving animal subjects at OHSU must be reviewed and approved by the university's Institutional Animal Care and Use Committee (IACUC). The IACUC's priority is to ensure the health and safety of animal research subjects. The IACUC also reviews procedures to ensure the health and safety of the people who work with the animals. The IACUC conducts a rigorous review of all animal research proposals to ensure they demonstrate scientific value and justify the use of live animals.
In our interest of ensuring the integrity of our research and as part of our commitment to public transparency, OHSU actively regulates, tracks and manages relationships that our researchers may hold with entities outside of OHSU. With regard to this research, OHSU's Picker, Hansen and Frueh have a significant financial interest in Vir Biotechnology Inc., a company that may have a commercial interest in the results of this research and technology.
The HIV T cell vaccine trial is supported by the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, and the Bill & Melinda Gates Foundation, and is being conducted by the HIV Vaccine Trials Network.
