Patients with advanced lung or skin cancer who received a COVID-19 mRNA vaccine within 100 days of starting immunotherapy drugs lived significantly longer than those who did not get the vaccine, researchers have found.

The observation by researchers at the University of Florida and the University of Texas MD Anderson Cancer Center is a defining moment in a decade-plus of research testing mRNA-based therapeutics designed to “wake up” the immune system against cancer. Building on a previous UF study, the observation also marks a significant step toward a long-awaited universal cancer vaccine to boost the tumor-fighting effects of immunotherapy.

The findings from an analysis of more than 1,000 patients’ records at MD Anderson are preliminary, but if validated in a randomized clinical trial now in design, the study could have a widespread clinical impact.

“The implications are extraordinary — this could revolutionize the entire field of oncologic care,” said senior researcher Elias Sayour, M.D., Ph.D., a UF Health pediatric oncologist and the Stop Children’s Cancer/Bonnie R. Freeman Professor for Pediatric Oncology Research. “We could design an even better nonspecific vaccine to mobilize and reset the immune response, in a way that could essentially be a universal, off-the-shelf cancer vaccine for all cancer patients.”

Jeff Coller, Ph.D., a leading mRNA scientist and professor at Johns Hopkins University, said the findings point to yet another way Operation Warp Speed — part of the federal government’s early response to COVID-19 — continues to save Americans’ lives in “unique and unexpected ways.”

“The results from this study demonstrate how powerful mRNA medicines truly are and that they are revolutionizing our treatment of cancer,” Coller said.

Presented today at the 2025 European Society for Medical Oncology Congress in Berlin, the findings build upon Sayour’s eight years of work combining lipid nanoparticles and mRNA. Short for messenger RNA, mRNA molecules are found in every cell and carry the genetic information needed to make proteins.

Notably, Sayour’s lab reported a surprising finding in July: to prompt a strong antitumor reaction, they needn’t go after a specific target protein in a tumor; instead, they could simply rev up the immune system — as if fighting a virus.

Like a one-two punch, pairing Sayour’s patented experimental “nonspecific” mRNA vaccine with common anticancer drugs called immune checkpoint inhibitors triggered a strong antitumor response in lab mice. The experimental vaccine was nonspecific to COVID spike protein or any other virus or cancer but rooted in similar technology to the COVID vaccines.

That discovery, years in the making, sparked a question from former lab member and lead researcher Adam Grippin, M.D., Ph.D., who trained at UF’s Preston A. Wells Center for Brain Tumor Therapy and now works at MD Anderson.

Would the COVID-19 mRNA vaccine work like the nonspecific vaccine?

To find out, the research team analyzed existing data from patients with Stage 3 and 4 non-small cell lung cancer and metastatic melanoma treated at MD Anderson from 2019 to 2023.

What they found was that receiving a COVID mRNA vaccine within 100 days of starting immunotherapy drugs was associated with living longer by a significant amount.

The most dramatic difference, Sayour said, was in patients not expected to have a strong immune response, based on their tumors’ molecular makeup and other factors.

As with any observational study, the findings require confirmation from a prospective and randomized clinical trial.

Nonetheless, the discovery is pivotal.

“Although not yet proven to be causal, this is the type of treatment benefit that we strive for and hope to see with therapeutic interventions — but rarely do,” said Duane Mitchell, M.D., Ph.D., Grippin’s doctoral mentor and director of the UF Clinical and Translational Science Institute. “I think the urgency and importance of doing the confirmatory work can’t be overstated.”

In lung and skin cancers, doctors commonly engage the immune system with drugs designed to “release the brakes” and recognize and attack cancer cells more effectively. In advanced disease stages, however, most patients don’t respond well and often have exhausted other treatment options like radiation, surgery and chemotherapy.

The new study involved records of 180 advanced lung cancer patients who received a COVID vaccine within a 100-day period before or after starting immunotherapy drugs and 704 treated with the same drugs who did not receive the vaccine. Getting the vaccine was associated with a near doubling of median survival, from 20.6 months to 37.3 months.

Of the metastatic melanoma patients, 43 received a vaccine within 100 days of initiating immunotherapy, while 167 patients did not receive a vaccine. With the vaccine, median survival increased from 26.7 months to a range of 30 to 40 months; at the time the data were collected, some patients were still alive, meaning the vaccine effect could be even stronger.

Receiving non-mRNA pneumonia or flu vaccines resulted in no changes in longevity.

To back their findings, UF researchers then used mouse models to pair immunotherapy drugs with an mRNA vaccine targeted specifically at COVID spike protein. Those experiments showed they could turn unresponsive cancers into responsive ones, thwarting tumor growth.

“One of the mechanisms for how this works is when you give an mRNA vaccine, that acts as a flare that starts moving all of these immune cells from bad areas like the tumor to good areas like the lymph nodes,” Sayour said.

The next step is to launch a large clinical trial through the UF-led OneFlorida+ Clinical Research Network, a consortium of hospitals, health centers and clinics in Florida, Alabama, Georgia, Arkansas, California and Minnesota.

“One of our key motivations at OneFlorida is to move discoveries from academic settings out into the real world and the places where patients get care,” said Betsy Shenkman, Ph.D., who leads the consortium.

If confirmed, the new findings unlock numerous possibilities, and the researchers said an even better nonspecific universal vaccine could be designed. For patients with advanced cancers, the increased survival from such a universal vaccine could provide a priceless benefit: more time.

“If this can double what we’re achieving currently, or even incrementally — 5%, 10% — that means a lot to those patients, especially if this can be leveraged across different cancers for different patients,” said Sayour, an investigator with UF’s McKnight Brain Institute.

The study was funded by the National Cancer Institute and multiple foundations. 

Sayour, Grippin and Mitchell hold patents related to UF-developed mRNA vaccines that are licensed by iOncologi Inc., a biotech company born as a “spinout” from UF in which Mitchell holds interest.

Meeting

ESMO Congress 2025

The study, detailed in the forthcoming issue of the Journal of Sport and Health Sciences, represents the first randomized controlled trial in humans to investigate the effects of prehabilitation—exercise performed during chemotherapy—on the tumor immune microenvironment specifically in oesophageal adenocarcinoma. This form of cancer, originating in the glandular cells of the oesophagus, remains a formidable clinical challenge, often presenting poor prognoses due to its aggressive nature and late diagnosis. The trial enrolled 22 patients from the Royal Surrey NHS Foundation Trust, a renowned cancer center, with eleven participants engaging in a 16-week structured exercise regimen, while eleven acted as controls without intervention.

The exercise protocol implemented consisted of two supervised sessions weekly during the chemotherapy phase, approximately spanning eight weeks, followed by a progressive exercise phase leading up to surgical resection. This regimen was meticulously designed to improve patients’ aerobic capacity and overall fitness, parameters believed to influence immune competence. Post-surgery, researchers harvested tumor specimens for in-depth immunological and genomic analyses. Utilizing multispectral immunohistochemistry, they quantified tumor-infiltrating immune cells, while gene expression profiling was conducted with NanoString technology, a high-throughput, precise method for measuring mRNA levels within tumor tissues.

Dr. Nicola Annels, co-senior author and cancer immunologist, highlighted the novelty of the findings, noting that this is the first trial to demonstrate a tangible modulation of the tumor microenvironment through exercise during chemotherapy. Specifically, tumors from patients undergoing the prehabilitation program exhibited a notable increase in cytotoxic immune populations, including CD8+ T cells and natural killer (NK) cells, which are critical effectors in antitumor immunity. These immune cells facilitate targeted destruction of cancer cells and have been correlated with improved responses to oncological treatments, implying that exercise may prime the tumor milieu for enhanced immunological assault.

Despite the promising results, Dr. Annels emphasized the exploratory nature of the study and the necessity for further research to consolidate these observations. Previous investigations, predominantly conducted in animal models, have suggested exercise-mediated enhancement of immune surveillance and suppression of tumor growth. However, analogous human studies, largely focused on prostate and colorectal cancers, failed to observe an increase in tumor-infiltrating immune cells, underscoring the complexity of translating preclinical findings into clinical practice.

The involvement of Dr. David Bartlett, co-first author and exercise physiologist, further elucidates the relationship between aerobic fitness and immune response. His team discovered a positive correlation between improvements in patients’ cardiorespiratory fitness and the density of immune cells within their tumors. Notably, they identified mature tertiary lymphoid structures—organized immune cell aggregates that function as local immune hubs—within tumor tissues from fitter individuals. The presence of these structures associates with heightened antitumor responses and better clinical outcomes, suggesting that exercise may facilitate the formation or maturation of these critical immune architectures.

The OPTIMUS trial, currently expanding with a target enrollment of 50 subjects, aims to robustly assess the impact of prehabilitation on clinical endpoints. Participants are randomized to either the previously tested moderate intensity exercise group or a novel higher intensity protocol hypothesized to elicit superior immunomodulatory effects. Preliminary data from seven patients already enrolled in OPTIMUS have revealed cases of complete tumor regression where no residual tumor was detected during operative examination—a rare phenomenon occurring in only about 6% of such patients under standard care. This early indication, while anecdotal, alludes to the transformative potential of exercise interventions in neoadjuvant cancer therapy.

Clinically, patients involved in the trial have exhibited improved physical resilience, translating into better perioperative outcomes and enhanced recovery trajectories. Mr. Charles Rayner, co-first author and specialist surgeon, remarked on the increased fitness levels allowing patients to withstand surgical stress and recuperation more effectively. This functional improvement is pivotal given that surgical morbidity and mortality remain significant concerns in oesophageal cancer management.

Senior author Mr. Nima Abbassi-Ghadi underscored the real-world impact of these findings, affirming that patient feedback overwhelmingly reflects augmented well-being and capability through preoperative exercise engagement. Remarkably, some participants who might otherwise have been ineligible for curative surgery due to frailty have attained sufficient fitness levels to undergo successful resections, highlighting the pragmatic implications of integrating structured exercise into therapeutic pathways.

Patient testimonies provide a poignant narrative complementing the scientific data. One participant described the OPTIMUS program as a vital source of agency and support amid the turmoil of cancer treatment. The emotional intelligence and personalized care offered by the research team were as critical as the physical conditioning itself, illustrating the holistic benefits—both psychological and physiological—that exercise prehabilitation confers during oncological care.

Researchers encourage eligible patients receiving treatment at Royal Surrey Cancer Centre to inquire about participation in the ongoing trial. Direct contact can be made via Dr. Bartlett and Dr. Annels, endorsing a collaborative and accessible research environment focused on transforming cancer treatment paradigms.

This study was generously funded by the World Cancer Research Fund as part of their International grant program, reflecting a global commitment to innovative cancer research that bridges basic science and clinical application. The emerging evidence from this research promises to redefine the role of exercise as a potent adjunct in cancer therapy, fostering a multidisciplinary approach to improving patient survival and quality of life.

Subject of Research: Effects of structured exercise prehabilitation during neoadjuvant chemotherapy on tumor-infiltrating immune cells in oesophageal adenocarcinoma

Article Title: Prehabilitation during neoadjuvant chemotherapy results in an enhanced immune response in oesophageal adenocarcinoma tumours: a randomised controlled trial

News Publication Date: 9-Jun-2025

Web References:
DOI link

References:
Available upon embargo lift through mediarelations@surrey.ac.uk

Image Credits:
An image of Dr. Nicola Annels and Dr. David Bartlett available via contact with mediarelations@surrey.ac.uk

Keywords: Cancer immunology, Esophageal cancer, Cancer cells, Cancer research, Oncology, Physical exercise