Messenger RNA (mRNA) vaccines were created with the goal of fighting cancer. As they approach this goal, a group of researchers has noticed that a beneficial side effect of immunization in cancer patients is the improvement in the effectiveness of the treatments they receive.
While expanding the understanding of why this phenomenon occurs and if it is applicable to more types of cancer, the study focuses on a specific group of people diagnosed with melanoma or lung cancer. Those who received an mRNA injection against Covid in the 100 days following the start of immunotherapy had twice the chances of surviving three years after starting treatment, according to a new study led by researchers at the MD Anderson Cancer Center at the University of Texas.
This discovery, which includes more than 1,000 patients treated between August 2019 and August 2023, was presented at the European Oncology meeting taking place these days in Berlin. In the ESMO session titled "From the laboratory to the patient's bedside: emerging discoveries shaping oncology practice," Adam Grippin, senior resident in Radiation Oncology and second author of the study, presented these findings yesterday.
The full trial, with its details, will be published this Wednesday in the journal Nature. In the article, they will reveal "whether better results are obtained with one dose or two," added the researcher, who anticipated that "we have not seen a difference between the first shot and the boosters." Grippin pointed out that "the reason lies in the alpha interferon response to RNA, which drives this effect."
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"Through this work, we have demonstrated that mRNA vaccines against Covid available [marketed by Pfizer and Moderna] can train patients' immune systems to eliminate cancer," said Grippin. When combined with immune checkpoint inhibitors, "these vaccines generate potent anti-tumor immune responses that are associated with significant improvements in the survival of cancer patients."
Benjamin P. Fairfax, Professor of Immunogenetics in the Department of Oncology at the University of Oxford (United Kingdom), was responsible for assessing this achievement in the same session. "The immune system has evolved to protect against viruses and other pathogens, and cancer drugs exploit these conserved antiviral responses," he commented on the proposed mechanism.
How did they discover this positive effect?
The benefits of mRNA injections as potent immune activators emerged from research conducted by Grippin during his postgraduate work at the University of Florida, in Elias Sayour's laboratory. While developing personalized mRNA-based cancer vaccines for brain tumors, Grippin and Sayour discovered that mRNA vaccines trained the immune system to eliminate cancer cells, even when the mRNA did not aim to directly attack the tumors.
This finding led to the hypothesis that other types of mRNA vaccines could have the same effect. Thus, the approval and use of SARS-CoV-2 mRNA-based vaccines offered them the opportunity to test this hypothesis. Lin and Grippin embarked on a significant project to retrospectively study whether MD Anderson patients who received mRNA vaccines against Covid lived longer than those who did not.
How do Covid mRNA vaccines influence immunotherapy responses in cancer?
To better understand the mechanisms that may help explain the clinical data, Lin and Sayour's laboratories at both institutions studied preclinical models. They found that mRNA vaccines act as an alarm, putting the immune system on high alert to recognize and attack cancer cells.
Cancer cells begin to produce the immune checkpoint protein PD-L1, which acts as a defense mechanism against the body's immune system. Currently, in the oncology toolkit, there are drugs designed to neutralize these checkpoints (checkpoints). These are inhibitors that block PD-L1 function (anti-PDL1), unleashing the body's armies against cancer.
These preclinical observations also were supported throughclinical studies. Researchers found similar mechanisms, including immune activation in healthy volunteers and increased PD-L1 expression in tumors in patients who received mRNA vaccines against Covid-19.
While the mechanisms "are not yet fully understood, and we will continue working to unveil them," -Grippin pointed out- "this study suggests that mRNA vaccines against Covid-19 are powerful tools to reprogram the immune response against cancer."
What are the key findings of the study?
This study included multiple cohorts of various cancer types, evaluating patients who received an mRNA vaccine within 100 days of starting immunotherapy treatment. Regarding the window of opportunity, Grippin explained that his research team demonstrated that, to optimize results, vaccination should be done within 30 days. "However, undoubtedly, [the vaccine] should be administered before starting treatment. The data we analyzed are within a timeframe to start reviewing," said the U.S. researcher.
A first vaccinated group, of 180 advanced non-small cell lung cancer patients, had a median survival of 37.33 months, compared to 20.6 months for the 704 patients who did not receive the vaccine. In a second cohort of patients with metastatic melanoma, the median survival was 26.67 months in 167 patients who were not immunized, but it had not yet been reached in 43 patients who did receive it, suggesting a significant improvement.
Grippin highlights that these survival improvements were more pronounced in patients with "cold" immunologically tumors, that is, "those associated with a lower response to immunotherapy." These patients, with very low PD-L1 expression in their tumors, experienced an almost fivefold improvement in overall three-year survival with the Covid-19 vaccine.
What are the main implications of this discovery?
"The truly exciting aspect of our work is that it points to the possibility that widely available and low-cost vaccines have the potential to dramatically improve the effectiveness of certain immune therapies," said Grippin. "We hope that mRNA vaccines not only improve the outcomes of patients treated with immunotherapies but also allow the benefits of these therapies to reach patients with treatment-resistant diseases."
Currently, a randomized multicenter phase III trial is being designed to validate these findings and investigate whether mRNA vaccines against Covid-19 should be part of the standard treatment for patients receiving immune checkpoint inhibition. Under the acronym UNIFIER (Universal Immunization to Fortify Immunotherapy Efficacy and Response), Grippin concluded the presentation with this project, with which they seek to learn more details to develop UNIFYER vaccines (Universal Immune Fortifying RNAs).