mRNA Vaccines Brings Renewed Innovation and Hope for Cancer Treatment

In early October, Katalin Karikó and Drew Weissman were awarded the Nobel Prize in Physiology or Medicine for discoveries that contributed to the development of effective messenger RNA (mRNA) vaccines against COVID-19. Over the last few years, many of the bottlenecks that once plagued the therapeutic uses of mRNA, especially when it comes to infectious diseases, were resolved. The first mRNA vaccine was approved by the U.S. Food and Drug Administration (FDA) in 2020. A frenzied undertaking soon followed to design similar vaccines for many other viruses with the potential to cause widespread outbreaks.

Already, there are several approved iterations of SARS-CoV-2 vaccines against continually evolving variants. Companies have various strains of influenza vaccines in development, including a universal formulation at the National Institute of Allergy and Infectious Disease. Other mRNA vaccines at various stages of development include those against monkeypox, Zika, Nipah viruses, respiratory syncytial virus (RSV; under FDA review), and the more slippery Cytomegalovirus and HIV, among others.

Beyond microbes, researchers are directing rekindled attention toward cancer vaccines capable of training the immune system to seek out and destroy rogue cells. Here we will examine the obstacles overcome, those that persist, and review some of the ongoing early clinical trials of vaccines against deadly tumors.

The pandemic accelerated mRNA research

The silver lining of the pandemic is the mRNA vaccine.

Making mRNA against antigens from microbes is relatively simple in the lab. The hard part, which took nearly 30 years to decipher, is how to deliver that mRNA to a person’s cells in vivo.¹ Naked mRNA is almost immediately destroyed once it enters the body. Scientists figured out how to modify mRNA to make it more stealthy, while also determining how to use microscopic lipid nanoparticles (LNPs) to parcel and dispense the message into target cells. Cellular machinery produces proteins, which are then displayed in an attempt to train the immune system to mount an attack against the invader.² When COVID-19 came, scientists from China rapidly identified the structure of all the genes of the responsible coronavirus (including for the critical spike protein) and openly published their findings within a few weeks. Companies already had platforms that could potentially develop mRNA vaccines given the right code for a particular infectious disease. With the sequence decrypted, researchers got to work designing vaccines that would be approved for widespread use all in under a year (prior to that no vaccine had been produced in under four).³

Paving the way to mRNA cancer vaccines, but not without new obstacles

The idea for anticancer vaccines dates back to the first unsuccessful attempts in 1910. With only one cancer vaccine emerging after decades of research—Sipuleucel-T, a cellular immunotherapy with minimal survival benefits for prostate cancer—vaccines have a poor track record.⁴ T-VEC, an oncolytic viral therapy for metastatic melanoma, is the only other FDA-approved therapeutic cancer vaccine.⁵ (Although there are a few preventive ones that target viruses, such as HPV, which can lead to cancer.) Scientists have long sought a vaccine-based approach that could be used to train the immune system to attack tumors, but time and time again promising candidates would fail in clinical trials. A 2004 study showed that only 2.6% of patients experienced a reduction in tumor size after administration of a cancer vaccine.⁶

Despite advances in diagnostics and traditional therapeutic practices, reliable cures and prevention of cancer continues to be elusive. There are over 5,000 new cases, and over 1,000 cancer-related deaths each day in the United States.⁷ However, we may finally be at a turning point. The success of other mRNA vaccines has reignited the quest for cancer vaccines, notoriously difficult to an extent.  because of the rapid mutations of malignant cells. In this respect, mRNA stands out because dozens of antigens on tumor cells can be targeted at once, making it tougher for the cancer to evolve ways of dodging the immune response prompted by the vaccine.

But there are still significant challenges, like finding the right antigens to target. Unlike viruses, cancer cells arise from our normal cells making distinguishing self from non-self more complicated (advances in sequencing have made this aspect easier). Nanoparticle packaging of the mRNA, too, must be considered as it can influence where in the body the message travels. There’s also administration of the vaccine and how to get it in the vicinity of the tumor while avoiding the deactivation factors present in the microenvironment of the cancer cells. Further, some patient populations, such as the elderly and those with cancer, have weakened immune systems—even if the vaccine signal gets to immune cells, they may not be able to mount enough of a fight.²

And yet, despite these issues, there are now multiple therapeutic mRNA cancer vaccines being evaluated in preclinical and clinical trials, with encouraging early-phase results.

Success in early clinical trials for some cancers

As of September of this year, there are more than 40 clinical trials of mRNA cancer vaccines underway.² Several of these involve the use of personalized mRNA—vaccines tailored to antigens specific to individual patient tumors, or neoantigens. Customized treatment is becoming a reality, in no small part, because mRNA vaccines are generated much more quickly than recombinant-based protein versions. This is especially exciting for cancers that currently have poor prognoses with limited options.

Pancreatic ductal adenocarcinoma (PDAC) has a survival of only 12% and incidence is on the rise. It is also very resistant to treatments, with surgery being the only potential cure (despite surgery, recurrence rates are nearly 90%).⁸ About eight years ago, scientists realized that the slim percentage of patients who escaped recurrence had an especially large T-cell population in their tumors. This T-cell response was caused by neoantigens, proteins that tumors express following accumulated genetic mutations. In most people, these neoantigens go undetected by the immune system. However, in this rare subset of individuals, the neoantigens did not go unnoticed, effectively unmasking the tumor to T cells. In fact, the group published a paper on how to select neoantigens with the best chance of generating immunogenicity—these neoantigen qualities may serve as a biomarker for responsive tumors and guide immunotherapeutic approaches.⁹

These findings led to BioNTech and Genentech collaborating on a new personalized mRNA vaccine treatment for PDAC. In Phase I clinical trials, nearly 50% of patients who responded positively to the treatment—mRNA targeting neoantigens specific to each patient’s tumor plus a checkpoint inhibitor following surgical resection—had almost no recurrences at 18 months. Researchers found that in some patients the vaccine caused dendritic cells to manufacture the neoantigen proteins, which trained the rest of the immune system to find and destroy cells with the same markers. T cells remain on high alert against cells with these proteins, which may lower the risk of recurrence.⁸

Phase II is now enrolling patients and will study approximately 260 patients from around the world to determine if the vaccine performs superior to standard treatments.

Another personalized vaccine developed by Moderna in partnership with Merck demonstrated a 44% decrease in the recurrences of melanoma and a 65% decrease in distant metastases when given alongside the anti-PD-1 checkpoint inhibitor Keytruda in high-risk (stage III/IV) patients. Between 9 and 34 patient-specific neoantigens were used, with the process from sample collection to delivery of the LNP-coated mRNA taking about 6 weeks.¹⁰ In July, the biotech companies announced the beginning of Phase III clinical trials, with plans to expand the regimen to other cancers such as non-small cell lung cancer. Of note, the most common side effects were fatigue, chills, and pain at the injection site.¹¹

Looking toward the future

Future work will likely continue to hone sequencing methods and neoantigen selection, as well as mRNA modifications and delivery platforms in order to optimize treatment. Tweaking mRNA by incorporating pseudouridine, a modified nucleoside with normal functional activity that acts as a cloaking mechanism, protects the message from getting destroyed (it was also used in the COVID-19 vaccine). Other adjustments, such as using circular mRNA constructs (instead of the normal linear form), prevent enzymes from disposing of the message too quickly and enhance protein production.¹² On the packaging front, current research on mRNA parceling materials strives to understand how components protect mRNA and impact delivery. For example, CARTs, or charge-altering releasable transporters, are synthetic polymers that can deliver mRNA to different organs, like lungs or spleen, depending on the building blocks used.¹³

There is still a lot of work to be done, but time will soon tell if the pandemic gave cancer therapeutics its greatest gift yet.

References

1. National Institutes of Health, Decades in the Making: mRNA COVID-19 Vaccines, January 10, 2023

2. Wang B, Pei J, Xu S, Liu J, Yu J. Recent advances in mRNA cancer vaccines: meeting challenges and embracing opportunities. Front Immunol. 2023 Sep 6;14:1246682

3. Anthony L. Komaroff, Harvard Health Publishing, Why are mRNA vaccines so exciting? Nov 1, 2021

4. Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, Redfern CH, Ferrari AC, Dreicer R, Sims RB, Xu Y, Frohlich MW, Schellhammer PF; IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010 Jul 29;363(5):411-22

5. NIH National Cancer Institute, FDA Approves Talimogene Laherparepvec to Treat Metastatic Melanoma, Nov 25, 2015

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7. Siegel, RL, Miller, KD, Fuchs, HE, Jemal, A. Cancer statistics, 2022. CA Cancer J Clin. 2022

8. Rojas, L.A., Sethna, Z., Soares, K.C. et al. Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer. Nature 618, 144–150 (2023)

9. Balachandran, V., Łuksza, M., Zhao, J. et al. Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer. Nature 551, 512–516 (2017)

10. Merck news release, June 5, 2023

11. Merck and Moderna Initiate Phase 3 Study Evaluating V940 (mRNA-4157) in Combination with KEYTRUDA® (pembrolizumab) for Adjuvant Treatment of Patients with Resected High-Risk (Stage IIB-IV) Melanoma, July 26, 2023

12. Chen, R., Wang, S.K., Belk, J.A. et al. Engineering circular RNA for enhanced protein production. Nat Biotechnol 41, 262–272 (2023)

13. Zhong Y, Du S, Dong Y. mRNA delivery in cancer immunotherapy. Acta Pharm Sin B. 2023 Apr;13(4):1348-1357