Clinical vaccine research efforts target long-term goal of cancer prevention
Douglas R. Lowy, MD, FAACR, acting director of the National Cancer Institute, chaired an Annual Meeting symposium on Tuesday, April 12, that provided an update on clinical vaccine research efforts designed to prevent human papillomavirus (HPV), pancreatic cancer, and Lynch syndrome. The session, Immunoprevention and Clinical Trials, can be viewed on the virtual platform by registered meeting participants through July 13, 2022.
Lowy opened the session with an update on HPV vaccines. In the U.S., about 60 percent of HPV-associated cancers occur in women. Globally, however, about 90 percent of HPV-associated cancers are cervical cancer, with about 95 percent occurring in women, he said.
There are currently three HPV vaccines approved by the U.S. Food and Drug Administration: Cervarix (HPV16/18), Gardasil (HPV 16/18; HPV6/11), and Gardasil-9 (HPV6/11; HPV 16/18; HPV31/33/45/52/58). The vaccines have very high efficacy and confer sterilizing immunity, meaning they prevent infection not just disease, Lowy said.
Data from Denmark, which has had a very high uptake of HPV vaccines, shows about a 90 percent decrease in the incidence of cervical cancer among women who received the HPV vaccine at age 16 or younger. Studies have reported similar decreases in Sweden and the United Kingdom.
“If you vaccinate women when aged 20 or older, you don’t get the same degree of protection because a higher percentage of cancer-causing infections occur relatively soon after sexual debut,” Lowy said.
Despite the efficacy of these agents, only about 10 percent of eligible young women in low- and middle-income countries receive an HPV vaccination each year, Lowy said.
Recent studies have shown that there seems to be no difference in protection between one, two, or three doses of an HPV vaccine. Recommendations are changing as a result.
In February, the United Kingdom’s Joint Committee on Vaccination and Immunisation issued interim advice to reduce the number of doses of HPV vaccine from two to one for girls younger than 15. More recently, the World Health Organization’s Strategic Advisory Group of Experts on Immunization announced that one or two doses of the HPV vaccine for women aged 9 to 20 years offers “solid protection” against HPV.
Based on these recommendations, Lowy said that “control of HPV-associated cancers as a worldwide public health problem may soon be feasible.”
Elizabeth M. Jaffee, MD, from Johns Hopkins University, discussed efforts to intercept pancreatic cancer development with oncogene-targeted immunotherapy.
There are several reasons why the time for interception vaccines is now, she said. Decades of research on cancer genetics has identified driver genes that initiate and/or potentiate the progression from normal cells to cancer cells, and cohorts have been identified who are at high risk for developing cancer.
“In some cancers, like pancreatic cancers, those driver genes are pretty homogeneous, giving us a good opportunity to have an off-the-shelf vaccine to target that oncogene,” Jaffee explained.
Immunology studies have shown that the immune system actively prevents cancer development early on, but eventually loses control through immune editing, she explained. Pancreatic cancer could be a good model for developing immune protection strategies because KRAS mutations occur early in the process, Jaffee said, and it appears that there is an opportunity to take advantage of the immune system’s early alert.
“We have a window of opportunity because it is estimated that it takes 10 years from the first gene alteration to pancreatic ductal adenocarcinoma,” Jaffee said.
Jaffee and her research colleagues have been working to develop a vaccine to take advantage of that opportunity, with proof-of-concept established in a mouse experiment published in 2015. Since then, experiments have combined the vaccine with immunotherapy agents such as an anti-CTLA-4 to reduce the rate of progression of pancreatic intraepithelial neoplasia.
A study of immunogenicity of mutant KRAS peptide vaccine in patients with resected pancreatic adenocarcinoma provided more insights. Jaffee and colleagues have found that vaccination with pooled mutant KRAS-targeted long peptide vaccine induces activated T cells against most KRAS epitopes included in the vaccine in peripheral blood post-vaccine. The vaccine induced robust T-cell response against G12V and G12R KRAS mutants. Additionally, they observed activated and poly-functional mutant KRAS-specific CD4+ and CD8+ T-cell responses and increased mutant KRAS-specific CD4+ to CD8+ T-cell ratio after vaccination.
Jaffee and colleagues recently enrolled the first patient into a study of an off-the-shelf mutant KRAS peptide vaccine for patients at high risk of developing pancreatic cancer.
Eduardo Vilar-Sanchez, MD, PhD, of the University of Texas MD Anderson Cancer Center, discussed an experimental Lynch syndrome vaccine designed to target a range of cancer mutations. Lynch syndrome has a prevalence of about one in 279 people, with about 1 million carriers in the U.S. The tumors are caused by mutations in the mismatch repair (MMR) genes and display a high degree of genomic instability.
“Lynch syndrome is a multicancer genetic condition, which means we are not only going to be developing a vaccine that potentially can prevent one cancer, but multiple cancers,” Vilar-Sanchez said.
The researchers have been working to characterize the neoantigen landscape in premalignant lesions in patients with Lynch syndrome to identify shared mutated neoantigens that could be leveraged to develop vaccines. This work led to the development of Nous-209, a vaccine made with manmade copies of some of the neoantigens produced in Lynch syndrome. The viruses in the vaccine are modified to encode for 209 frameshift-neoantigens found in tumors associated with Lynch syndrome.
Vilar-Sanchez is leading a soon-to-open phase Ib/II trial of Nous-209 for patients with Lynch syndrome. The trial will evaluate the safety and tolerability of a primer and boost vaccination, and the neoantigen-specific immunogenicity of each.
“We have a very aggressive but hopeful goal of having Lynch syndrome be the first genetic disease prevented with a vaccine,” Vilar-Sanchez said.
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