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An experimental mRNA vaccine boosted the tumor-fighting effects of immunotherapy in a mouse-model study, bringing researchers one step closer to their goal of developing a universal vaccine to “wake up” the immune system against cancer.

Published today in Nature Biomedical Engineering, the University of Florida study showed that like a one-two punch, pairing the test vaccine with common anticancer drugs called immune checkpoint inhibitors triggered a strong antitumor response.

A surprising element, researchers said, was that they achieved the promising results not by attacking a specific target protein expressed in the tumor, but by simply revving up the immune system – spurring it to respond as if fighting a virus. They did this by stimulating the expression of a protein called PD-L1 inside of tumors, making them more receptive to treatment. The research was supported by multiple federal agencies and foundations, including the National Institutes of Health.

Senior author Elias Sayour, M.D., Ph.D., a UF Health pediatric oncologist, said the results reveal a potential new treatment path – an alternative to surgery, radiation and chemotherapy – with broad implications for battling many types of treatment-resistant tumors.

“This paper describes a very unexpected and exciting observation: that even a vaccine not specific to any particular tumor or virus – so long as it is an mRNA vaccine – could lead to tumor-specific effects,” said Sayour, principal investigator at the RNA Engineering Laboratory within UF’s Preston A. Wells Jr. Center for Brain Tumor Therapy.

“This finding is a proof of concept that these vaccines potentially could be commercialized as universal cancer vaccines to sensitize the immune system against a patient’s individual tumor,” said Sayour, a McKnight Brain Institute investigator and co-leader of a program in immuno-oncology and microbiome research.

Until now, there have been two main ideas in cancer-vaccine development: To find a specific target expressed in many people with cancer, or to tailor a vaccine that is specific to targets expressed within a patient’s own cancer.

This study suggests a third emerging paradigm. What we found is by using a vaccine designed not to target cancer specifically but rather to stimulate a strong immunologic response, we could elicit a very strong anticancer reaction. And so this has significant potential to be broadly used across cancer patients – even possibly leading us to an off-the-shelf cancer vaccine.”

Duane Mitchell, M.D., Ph.D., co-author of the paper

For more than eight years, Sayour has pioneered high-tech anticancer vaccines by combining lipid nanoparticles and mRNA. Short for messenger RNA, mRNA is found inside every cell – including tumor cells – and serves as a blueprint for protein production.

This new study builds upon a breakthrough last year by Sayour’s lab: In a first-ever human clinical trial, an mRNA vaccine quickly reprogrammed the immune system to attack glioblastoma, an aggressive brain tumor with a dismal prognosis. Among the most impressive findings in the four-patient trial was how quickly the new method – which used a “specific” or personalized vaccine made using a patient’s own tumor cells – spurred a vigorous immune-system response to reject the tumor.

In the latest study, Sayour’s research team adapted their technology to test a “generalized” mRNA vaccine – meaning it was not aimed at a specific virus or mutated cells of cancer but engineered simply to prompt a strong immune system response. The mRNA formulation was made similarly to the COVID-19 vaccines, rooted in similar technology, but wasn’t aimed directly at the well-known spike protein of COVID.

In mouse models of melanoma, the team saw promising results in normally treatment-resistant tumors when combining the mRNA formulation with a common immunotherapy drug called a PD-1 inhibitor, a type of monoclonal antibody that attempts to “educate” the immune system that a tumor is foreign, said Sayour, a professor in UF’s Lillian S. Wells Department of Neurosurgery and the Department of Pediatrics in the UF College of Medicine.

Taking the research a step further, in mouse models of skin, bone and brain cancers, the investigators found beneficial effects when testing a different mRNA formulation as a solo treatment. In some models, the tumors were eliminated entirely.

Sayour and colleagues observed that using an mRNA vaccine to activate immune responses seemingly unrelated to cancer could prompt T cells that weren’t working before to actually multiply and kill the cancer if the response spurred by the vaccine is strong enough.

Taken together, the study’s implications are striking, said Mitchell, who directs the UF Clinical and Translational Science Institute and co-directs UF’s Preston A. Wells Jr. Center for Brain Tumor Therapy.

“It could potentially be a universal way of waking up a patient’s own immune response to cancer,” Mitchell said. “And that would be profound if generalizable to human studies.”

The results, he said, show potential for a universal cancer vaccine that could activate the immune system and prime it to work in tandem with checkpoint inhibitor drugs to seize upon cancer – or in some cases, even work on its own to kill cancer.

Now, the research team is working to improve current formulations and move to human clinical trials as rapidly as possible.

As millions of people know firsthand, the most common side effect of mRNA vaccines like the COVID-19 shot is inflammation: soreness, redness and a day or two of malaise. But what if mRNA vaccines could be redesigned to sidestep that response altogether?

In a new paper in Nature Biomedical Engineering, researchers at the University of Pennsylvania show that tweaking the structure of the ionizable lipid, a key component of the lipid nanoparticles (LNPs) that deliver mRNA, not only reduces inflammation but also boosts vaccine effectiveness for preventing or treating a range of diseases, from COVID-19 to cancer.

The key change? Adding phenol groups, chemical compounds with anti-inflammatory properties famously found in foods like olive oil.

By essentially changing the recipe for these lipids, we were able to make them work better with fewer side effects. It’s a win-win.”

Michael J. Mitchell, Associate Professor in Bioengineering (BE) and the paper’s senior author

Revising the recipe 

Until now, the ionizable lipids in LNPs – one of four types of lipids in LNPs, and arguably the most important – have largely been synthesized using chemical reactions that combine two components into a new molecule, much like two halves of a sandwich coming together. 

“Because these processes have been so successful, there hasn’t been much effort to look for alternatives,” says Ninqiang Gong, a former postdoctoral fellow in the Mitchell Lab and co-first author of the paper. 

Looking back at the history of chemistry, the team found an alternative approach: the Mannich reaction, named after the German chemist who discovered it more than a century ago. 

Rather than two components, the Mannich reaction combines three precursors, allowing for a greater variety of molecular outcomes. “We were able to create hundreds of new lipids,” says Gong. 

Exploring that “library” of lipids led the team to discover that adding a phenol group – a combination of hydrogen and oxygen connected to a ring of carbon molecules – substantially reduced inflammation. 

“It’s kind of like the secret sauce,” says Gong. “The phenol group not only reduces the side effects associated with LNPs, but improves their efficacy.” 

The power of phenols 

Previous studies have found that phenol-containing compounds reduce inflammation by negating the harmful effects of free radicals, molecules with unpaired electrons that can disrupt the body’s chemistry. 

Too many free radicals and too few antioxidants result in “oxidative stress,” which degrades proteins, damages genetic material and can even kill cells. 

By checking various markers associated with oxidative stress, the researchers compared the inflammatory effects of LNPs formulated using different lipids.

“The best-performing LNP, which we built using a phenol-containing ionizable lipid produced by the Mannich reaction, actually caused less inflammation,” says Emily Han, a doctoral student in BE and co-author of the paper.

Less inflammation, higher performance 

With these encouraging signs of reduced inflammation, the researchers next tested whether the new lipids also improved vaccine performance. 

Across multiple experiments, C-a16 LNPs, which incorporated the most anti-inflammatory lipid, outperformed LNPs used in on-the-market mRNA technologies. 

“Lowering oxidative stress makes it easier for LNPs to do their job,” says Dongyoon Kim, a postdoctoral fellow in the Mitchell Lab and co-first author of the paper. 

C-a16 LNPs not only produced longer-lasting effects, but also improved the efficacy of gene-editing tools like CRISPR and the potency of vaccines for treating cancer.

Fighting genetic disease, cancer and COVID-19

To test how well the new C-a16 lipids worked in an animal model, the researchers first used them to deliver into cells the gene that makes fireflies glow – a classic experiment for checking the strength of genetic instructions. 

The glow in mice was about 15 times brighter compared to the LNPs used in Onpattro, an FDA-approved treatment for hereditary transthyretin amyloidosis (hATTR), a rare genetic liver disease.

The C-a16 lipids also helped gene-editing tools like CRISPR do a better job fixing the faulty gene that causes hATTR. In fact, they more than doubled the treatment’s effectiveness in a mouse model compared to current delivery methods.

In cancer treatments, the results were just as striking. In an animal model of melanoma, an mRNA cancer treatment delivered with C-a16 lipids shrank tumors three times more effectively than the same treatment delivered with the LNPs used in the COVID-19 vaccines. The new lipids also gave cancer-fighting T cells a boost, helping them recognize and destroy tumor cells more efficiently – and with less oxidative stress.

Finally, when the team used the C-a16 lipids for preparing COVID-19 mRNA vaccines, the immune response in animal models was five times stronger than with standard formulations.

“By causing less disruption to cellular machinery, the new, phenol-containing lipids can enhance a wide range of LNP applications,” says Kim. 

Old chemistry, new frontiers

Besides investigating the immediate potential of the new lipids to reduce side effects in mRNA vaccines, the researchers look forward to exploring how overlooked chemical processes like the Mannich reaction can unlock new LNP-enhancing recipes. 

“We tried applying one reaction discovered a century ago, and found it could drastically improve cutting-edge medical treatments,” says Mitchell. “It’s exciting to imagine what else remains to be rediscovered.” 

The addition of nimotuzumab to chemotherapy led to improvements in progression-free survival (PFS) and overall survival (OS) vs chemotherapy alone for the first-line treatment of patients with recurrent or persistent cervical cancer, according to data from a phase 3 study (NCT06781073) presented during the 2025 ASCO Annual Meeting.¹

Patients who received the combination (n = 55) achieved a median OS of 15.7 months (95% CI, 11.8-26.9) compared with 12.4 months (95% CI, 7.9-21) among patients who received placebo plus chemotherapy (n = 63; HR, 0.72; 95% CI, 0.46-1.11). The median PFS was 7.4 months (95% CI, 4.9-8.9) vs 5.6 months (95% CI, 4.1-6.1), respectively (HR, 0.66; 95% CI, 0.42-1.05).

“[Findings from] our study showed that the incorporation of nimotuzumab into chemotherapy [for] the first-line treatment of [patients with] recurrent or persistent could [lead to] an improvement of PFS and OS,” Zexuan Liu, MD, of the Department of Gynecologic Oncology, National Cancer Center /National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, said during the presentation.

Phase 3 Study Design and Baseline Characteristics

The multicenter, double-blind trial enrolled patients 18 to 75 years old with histologically confirmed cervical cancer. Patients needed to have stage IVB or first recurrent or persistent cervical cancer per FIGO 2018 criteria, measurable primary tumors per RECIST 1.1 criteria, an ECOG performance status of 0 or 1, a life expectancy of at least 3 months, and adequate organ function.

Eligible patients were randomly assigned 1:1 to receive nimotuzumab at 400 mg per week for 18 weeks followed by maintenance nimotuzumab at 400 mg every 2 weeks for 60 weeks or matching placebo. Patients in both arms also received paclitaxel and cisplatin every 3 weeks for up to 6 cycles. Treatment in both arms continued until disease progression or intolerable toxicity.

The primary end point was OS. Secondary end points included PFS, overall response rate, and quality of life measure.

At baseline, the median age in the overall population (n = 118) was 51.2 years (SD, 9.66). Most patients underwent maintenance therapy for less than 24 weeks (90.68%), had FIGO stage disease other than IV (85.59%), and received concurrent chemoradiotherapy (52.54%). Patients had poorly- (31.36%), moderately- (27.97%), and well-differentiated (4.24%) disease; 36.44% of patients had unknown disease differentiation.

Additional Efficacy Findings and Safety Data

Additional findings from the phase 3 study revealed that patients with recurrent disease in the investigational (n = 51) and placebo (n = 58) arms achieved a median OS of 21.7 months (95% CI, 21.1-32.9) and 12.4 months (95% Ci, 8-21.4), respectively (HR, 0.62; 95% CI, 0.39-0.98; P = .04). An OS benefit was observed in most of the prespecified subgroups; the most significant benefits in favor of the nimotuzumab arm were reported among patients of the age of 60 years (HR, 0.48; 95% CI, 0.13-1.83; P = .28), those with poorly differentiated disease (HR, 0.55; 95% CI, 0.24-1.27; P = .16), and those with more than 1 organ lesion (HR, 0.65; 95% CI, 0.36-1.20; P = .17).

In terms of safety, grade 3 or higher adverse effects (AEs) occurred at rates of 78.2% and 71.4% in the investigational and control arms, respectively. Serious AEs (14.5% vs 20.6%) were reported in both arms. Notably, no AEs leading to death occurred in either arm. The most common AEs in the nimotuzumab arm included anemia (41.8%), leukopenia (36.4%), nausea (29.1%), and alopecia (20.0%). These AEs were reported at rates of 0%, 26.9%, 30.0%, and 31.7%, respectively, in the control arm.

The most common grade 3 or higher treatment-related AEs (TRAEs) in the nimotuzumab arm included neutropenia (69%), leukopenia (47%), decreased hemoglobin levels (5%), and decreased platelet counts (5%). The most common grade 3 or higher TRAEs in the control arm included neutropenia (49%), leukopenia (32%), and hypertension (6%).

“The combination therapy demonstrated well-tolerated toxicity,” Liu said. “We believe that nimotuzumab combined with chemotherapy can be considered as a potential first-line therapy option [for patients with] recurrent or persistent cervical cancer.”

Disclosures: Liu listed no disclosures.

Reference

An J, Wang J, Wang C, et al. Nimotuzumab combined with chemotherapy in the first-line treatment for patients with stage IVB, recurrent or persistent cervical squamous cell carcinoma: a multi-center, randomized, double-blind, and controlled study. J Clin Oncol. 2025;43(suppl 16):5510. doi:10.1200/JCO.2025.43.16_suppl.5510