A cancer vaccine that had little success in clinical trials for patients with advanced tumors could potentially have efficacy if administered earlier in the treatment cycle, according to a study from Vanderbilt researchers.
The investigators demonstrated in a mouse model that the cancer vaccine can block tumor progression if administered when the lesions are at an early stage.
Results of the study, which were published in the Journal for ImmunoTherapy of Cancer, revealed that tumor-specific T cell populations are present in mice with early-stage lesions and can be therapeutically exploited by vaccination, but mice with advanced tumors do not retain these cells. The inquiry by the Vanderbilt researchers differed from most cancer vaccine studies, which have focused on patients with advanced tumors.
The findings support further vaccine investigation to make long-term, progression-free survival a reality for more cancer patients, said the study’s senior author Mary Philip, MD, PhD, associate director of the Vanderbilt Institute for Infection, Immunology and Inflammation.
With the development and widespread use of mRNA vaccines for COVID-19, there is growing excitement about using personalized vaccines to treat and prevent cancer.
“Our study suggests that the timing of vaccination is important,” said Philip, assistant professor of Medicine in the Division of Hematology and Oncology, and assistant professor of Pathology, Microbiology and Immunology. “A unique feature of our study is that these mice are at high, essentially 100% risk of developing cancers, so the fact that a single immunization at the right time can give lifelong protection is pretty striking. There are not many cancer studies where mice have been followed so long after vaccination and remain tumor free for two years.”
The study also showed that early treatment with a cancer vaccine blocked tumor progression when immune checkpoint blockade (ICB) therapies were ineffective. ICB therapies are approved for treating advanced cancers, but only a subset of patients with certain types of cancer achieve durable remission with them.
“ICB works by taking the brakes off T cells, but if the T cells have never been properly activated, they are like cars without gas, and ICB doesn’t work,” Philip said. “The vaccination boosts the T cells into a functional state so that they can eliminate early cancer cells.”
The researchers developed a clinically relevant genetic cancer mouse model in which hepatocytes (liver cells) sporadically undergo oncogenic transformation. They found that mice with early lesions retained a progenitor TCF1+tumor-specific CD8 T cell population, but not mice with advanced tumors.
Philip and colleagues investigated a vaccine previously tested in human clinical trials for advanced cancers. This vaccine uses a gram-positive intracellular bacterium that induces strong CD4 and CD8 T cell responses, and it is engineered to express the tumor epitope, which boosts tumor-reactive T cells. All mice that received vaccination at an early stage remained tumor free, but the vaccine failed to slow liver tumor progression when administered at a later point (age 100 days).
The researchers concluded that the presence of a progenitor TCF1+tumor-specific CD8 T cell population is necessary for cancer vaccines to be effective.
The study’s first author is Carlos Detrés Román, a Vanderbilt University graduate student working in Philip’s lab. Other authors are Megan Erwin, Michael Rudloff, MD, PhD, Frank Revetta, Kristen Murray, Natalie Favret, Jessica Roetman, Joseph Roland, PhD, and Kay Washington, MD, PhD. The digital object identifier for the study is 10.1136/jitc-2024-009129.
The National Institutes of Health supported the research with grants R37CA263614, T32CA009592, T32GM008554, T32AR059039, T32GM007347 and P30DK058404.
