The Race for Personalized mRNA Cancer Vaccines: Phase 3 Trials Aim to Transform Melanoma and Lung Cancer Treatment

Key Facts

• Pivotal Phase 3 trials underway: Two personalized mRNA cancer vaccines have reached Phase 3 testing – one for high-risk melanoma and another for resected non-small cell lung cancer (NSCLC) – marking the first mRNA cancer vaccines to advance to late-stage trials jhoonline.biomedcentral.com, trial.medpath.com. These global studies are enrolling hundreds of patients across dozens of sites in the U.S., Europe, and beyond.
• Big pharma and biotech collaborations: Moderna and Merck (MSD) jointly sponsor multiple Phase 3 trials of Moderna’s individualized neoantigen vaccine (mRNA-4157, also called V940) in combination with Merck’s immunotherapy pembrolizumab (Keytruda) merck.com. BioNTech, in partnership with Genentech/Roche and the UK’s NHS, is advancing a rival personalized mRNA vaccine program, while startups like Gritstone Bio and Nouscom are testing their own neoantigen vaccines in earlier-phase trials labiotech.eu, onclive.com. Academic cancer centers (e.g. Memorial Sloan Kettering, MD Anderson, and NYU Langone) are key trial sites and collaborators, providing scientific leadership and patient enrollment merck.com, mskcc.org.
• Promising early results: A Phase 2 trial in melanoma showed that adding a personalized mRNA vaccine to pembrolizumab reduced the risk of cancer recurrence or death by 44% compared to immunotherapy alone merck.com, jhoonline.biomedcentral.com. In that study, one-year recurrence rates dropped from ~40% with pembrolizumab to ~22% with the vaccine combo targetedonc.com, jhoonline.biomedcentral.com. These unprecedented results – the first randomized evidence that an mRNA neoantigen vaccine can improve outcomes in melanoma – catalyzed the move to Phase 3 merck.com. Early-phase data in other cancers (pancreatic, colorectal) have also hinted at robust immune responses and longer progression-free survival with personalized vaccines, even in “cold” tumors traditionally unresponsive to immunotherapy onclive.com, pmc.ncbi.nlm.nih.gov.
• Innovative trial designs: Ongoing Phase 3 trials are typically randomized, placebo-controlled, double-blind studies where all patients receive standard checkpoint inhibitor therapy, and half also receive the custom mRNA vaccine mskcc.org, merck.com. For example, the global melanoma Phase 3 (INTerpath-001) is enrolling ~1,089 patients with high-risk Stage IIB-IV melanoma after surgery merck.com; all receive pembrolizumab, with half getting the personalized vaccine and half a placebo injection, to rigorously test if the vaccine improves recurrence-free survival (primary endpoint) targetedonc.com. A similar Phase 3 in NSCLC (INTerpath-002) is recruiting ~868 patients with Stage II–IIIB NSCLC after surgical resection and chemotherapy merck.com, randomizing to vaccine + pembrolizumab vs. pembrolizumab alone. Endpoints include disease-free survival (in adjuvant settings) and overall survival, with interim analyses planned as events accrue merck.com.
• Mechanism: truly personalized immunotherapy: Each mRNA vaccine is individually manufactured to encode a set of neoantigens – abnormal protein fragments arising from a patient’s unique tumor mutations merck.com, mskcc.org. Injecting this mRNA (often packaged in lipid nanoparticles) turns the patient’s own cells into vaccine factories, producing the tumor-specific neoantigen peptides inside the body. These peptides are naturally processed and presented on cell surfaces, training T cells to recognize and attack cancer cells harboring those mutations merck.com. This approach “gets [the patient’s] own immune system to really target what is going on with that particular patient’s tumor,” explained Dr. Jeff Yorio, an oncologist involved in the melanoma trial targetedonc.com. Unlike off-the-shelf cancer vaccines, which target common tumor antigens, these mRNA vaccines are fully bespoke – each patient’s dose is a unique formulation designed via AI-driven algorithms analyzing that individual’s tumor DNA/RNA sequence trial.medpath.com.
• Comparing to other immunotherapies: Personalized mRNA vaccines aim to complement therapies like checkpoint inhibitors rather than replace them. Checkpoint blockers (e.g. anti-PD-1 antibodies such as pembrolizumab) release the brakes on existing T cells, but they do not generate new immune specificities. A neoantigen vaccine supplies a fresh arsenal of T cells primed against the patient’s tumor mutations merck.com, potentially turning “cold” tumors hot. “By combining Keytruda with V940, a promising new modality, we are researching innovative approaches for earlier-stage lung cancer,” said Dr. Marjorie Green of Merck merck.com. Other immunotherapy modalities like CAR-T cells or TCR-engineered cells target single antigens and require cell harvesting and genetic modification, whereas an mRNA vaccine can encode dozens of neoantigens (up to 34 in Moderna’s design) and is delivered by simple injection merck.com. Traditional cancer vaccines (peptide-, DNA-, or virus-based) have shown limited success, partly because they were not personalized and the antigens could be escaped by tumors. mRNA vaccines potentially avoid that by targeting a private neoantigen set for each patient, making immune escape more difficult – however, they still rely on a functioning immune system and often work best in tandem with checkpoint blockade or other immunostimulatory agents.
• Key challenges: Manufacturing a custom vaccine for every patient is logistically complex and expensive – currently over $100,000 per patient by some estimates pmc.ncbi.nlm.nih.gov. Traditionally it has taken 2–4 months to identify a patient’s neoantigens, synthesize the mRNA, and release a personalized batch jhoonline.biomedcentral.com, which is impractical for aggressive cancers. Fortunately, advances in automation and AI are speeding this up: Merck and Moderna report using high-throughput sequencing and machine learning to design each vaccine in weeks trial.medpath.com, and recent manufacturing innovations have cut production time from ~9 weeks to under 4 weeks for personalized mRNA vaccines pmc.ncbi.nlm.nih.gov. Another hurdle is regulatory – since each vaccine is unique, regulators are developing new frameworks to evaluate safety/quality for these “N-of-1” products. Clinically, not all tumors have lots of mutations; low-mutational-burden cancers or highly immunosuppressive tumor microenvironments may respond less vigorously. “Pioneering new spaces carries inherent risks,” notes Dr. Andrew Allen, CEO of Gritstone Bio, which is testing a personalized vaccine for colorectal cancer. Even so, early data showing molecular and survival benefits in otherwise therapy-resistant metastatic colorectal tumors suggest that “a personalized neoantigen-directed vaccine can potentially drive efficacy in a metastatic ‘cold’ tumor,’’ Dr. Allen saysonclive.com.
• Outlook and potential: If Phase 3 trials confirm the efficacy seen so far, personalized mRNA vaccines could become a new pillar of cancer therapy – especially in the post-surgery (adjuvant) setting to prevent relapse. “This combination therapy shows great promise and has become the first mRNA vaccine to progress into Phase 3 trials,” noted a recent review in J. Hematology & Oncologyjhoonline.biomedcentral.com. Experts envision approvals within a few years: regulatory submissions for the melanoma vaccine are anticipated as early as 2026 if Phase 3 is successful pmc.ncbi.nlm.nih.gov. The UK has invested heavily in this field – the NHS is creating a “Cancer Vaccine Launch Pad” to fast-track trials, aiming to treat “up to 10,000 patients with personalized cancer immunotherapies by 2030,” according to a 2023 UK government agreement with BioNTech gov.ukgov.uk. In the U.S., Merck’s oncology head Dr. Dean Li heralded the Moderna collaboration’s progress as “an important milestone… combining our expertise in mRNA and immuno-oncology” and is rapidly expanding trials to additional tumor types merck.com (including ongoing Phase 2 studies in renal cell carcinoma, colon cancer, and squamous skin cancer merck.com). Scientists caution that more research is needed to determine which patients benefit most and how to integrate vaccines with other treatments. Still, optimism abounds. “Personalised cancer vaccines have the potential to completely revolutionise the way we treat this cruel disease,” said UK Prime Minister Rishi Sunak gov.uk. By training each patient’s immune system to hunt down their cancer’s unique mutations, these mRNA vaccines exemplify the promise of precision oncology – turning the tide in cancers like melanoma and NSCLC, and potentially many more in the future.

Global Phase 3 Trials: Melanoma Leads the Way

The first personalized mRNA cancer vaccine to reach Phase 3 is Moderna’s mRNA-4157 (V940) in melanoma – a groundbreaking collaboration with Merck that has quickly become a bellwether for the field. Melanoma was a logical first target: it’s a notoriously aggressive skin cancer but also highly immunogenic (due to a high mutational load from UV damage), meaning it often responds to immune therapies. In a Phase 2b trial (KEYNOTE-942) reported in late 2022, 157 patients with high-risk stage III/IV melanoma received either mRNA-4157 plus the anti–PD-1 checkpoint inhibitor pembrolizumab (Keytruda) or pembrolizumab alone after surgery merck.com. The personalized vaccine, encoding up to 34 neoantigens tailored to each patient’s tumor, was given in nine doses over a year alongside standard pembrolizumab therapy merck.com. The result was the first positive randomized trial for an mRNA cancer vaccine: recurrence-free survival (RFS) improved significantly, with the combination reducing the risk of recurrence or death by 44% versus immunotherapy alone merck.com, pmc.ncbi.nlm.nih.gov. At 18-month follow-up, only 22% of vaccine-treated patients had relapsed, compared to 40% with pembrolizumab alone jhoonline.biomedcentral.com. “For the first time ever, we have demonstrated the potential for mRNA to impact outcomes in melanoma,” said Moderna CEO Stéphane Bancel, calling the results “highly encouraging for the field of cancer treatment” merck.com. Dr. Jeffrey Weber of NYU (the trial’s principal investigator) likewise stated “these data provide the first evidence that a personalized neoantigen approach may be beneficial in melanoma,” improving on what PD-1 blockade alone can achieve merck.com.

Buoyed by these findings, Moderna/Merck launched a Phase 3 melanoma trial (protocol INTerpath-001, NCT05933577) in mid-2023 merck.com. This global trial aims to enroll ~1,089 patients with resected stage IIB to IV melanoma at high risk of recurrence. Patients are randomized to receive adjuvant pembrolizumab plus personalized mRNA-4157 vaccine versus pembrolizumab plus a placebo vaccine merck.com, mskcc.org. The study is double-blinded and placebo-controlled – an impressive feat, since each patient’s vaccine is unique. (In practice, the control arm gets saline injections on the same schedule, to maintain blinding, alongside active pembrolizumab in both arms merck.com.) The primary endpoint is recurrence-free survival, and key secondaries include distant metastasis-free survival, overall survival, and safety targetedonc.com. With such endpoints, these trials will likely run for 2–3 years to accumulate enough relapse events, but an interim analysis could indicate efficacy sooner if differences are large. The Phase 3 is truly international: as of late 2023 it was open in 14 countries across North America, Europe, Israel, and Australia merck.com, expanding to ~165 sites in over 25 countries by 2024 targetedonc.com. This reflects the broad interest in this approach – major cancer centers like MD Anderson, Memorial Sloan Kettering, and the Mayo Clinic are participating, as are community networks such as Texas Oncology in the U.S. targetedonc.com. “We can always try to improve upon [current] results – that’s the goal of a trial like this, to lower the risk of recurrence and hopefully save more lives,” explained Dr. Jeff Yorio of Texas Oncology targetedonc.com, who is helping run the trial.

Notably, the melanoma vaccine is being tested in the adjuvant setting – given after complete surgical removal of the tumor, to eliminate micrometastatic disease and prevent the cancer from coming back. This setting leverages the strengths of a vaccine (stimulating long-term immune surveillance) at a time when patients have minimal residual cancer. Pembrolizumab is already an approved adjuvant therapy for resected melanoma; the hope is that adding the personalized mRNA will further cut recurrence rates and improve cure rates. If successful, this could herald the first regulatory approval of an mRNA cancer vaccine. Observers speculate this could come as early as 2026–2027, assuming Phase 3 data are positive pmc.ncbi.nlm.nih.gov. “We look forward to advancing this program into the next phase of development,” Merck R&D president Dr. Dean Li said after the Phase 2 results, underscoring that Merck exercised its option to co-develop and co-commercialize the vaccine with Moderna worldwide merck.com.

While Moderna/Merck currently lead the melanoma vaccine race, they are not alone. BioNTech – Moderna’s German mRNA vaccine counterpart – has an oncology pipeline including both “off-the-shelf” antigen vaccines and fully personalized neoantigen vaccines. BioNTech’s fixed-target BNT111 (encoding 4 non-mutated melanoma antigens) recently showed positive Phase 2 results in advanced melanoma when combined with a PD-1 inhibitor (cemiplimab), improving response rates in PD-1–refractory disease labiotech.eu. Meanwhile, BioNTech’s individualized neoantigen vaccine autogene cevumeran (also known as BNT122 or RO7198457, developed with Genentech) has been tested in Phase 1/2 trials across melanoma and other tumors. In fact, a small trial at Memorial Sloan Kettering in New York recently combined an mRNA neoantigen vaccine with atezolizumab (another checkpoint inhibitor) in pancreatic cancer patients after surgery – notoriously a very tough cancer – and reported that half the patients mounted T cell responses, correlating with delayed cancer recurrence pmc.ncbi.nlm.nih.gov. Those promising signals in pancreatic cancer (published in Nature in 2022) have encouraged BioNTech to initiate a Phase 2 in pancreatic ductal carcinoma pmc.ncbi.nlm.nih.gov. BioNTech’s co-founder/CEO Uğur Şahin has been openly optimistic about personalized mRNA vaccines, and the company forged a strategic partnership with the UK government to run trials in early-stage cancers. The UK’s NHS will help recruit patients through a national “vaccine launch pad”, with the aim of “providing personalized cancer treatments for up to 10,000 patients by 2030” gov.uk. This bold initiative will include trials in melanoma and other tumor types (for example, BioNTech and the NHS plan a trial in personalized lymphoma vaccines in the near future). It’s a sign that internationally, personalized cancer vaccines are viewed as a burgeoning frontier worth heavy investment.

Several biotech startups and academic groups are also in the melanoma vaccine arena. For instance, Evaxion (Denmark) has an AI-guided peptide-based neoantigen vaccine (EVX-01) that showed a 67% response rate in a Phase 1/2 melanoma study with pembrolizumab labiotech.eu; a Phase 2 trial of EVX-01 began in 2023. Another startup, Nouscom (Switzerland/Italy), is using viral vectors: their vaccine NOUS-209 (encoding 209 shared neoantigens found in microsatellite-unstable tumors) is in Phase 1b for gastrointestinal cancers and has shown “potent and broad immune responses” in combination with pembrolizumab labiotech.eu. Nouscom’s NOUS-PEV is a fully personalized viral-vector vaccine now in early trials, which induced durable neoantigen-specific T cells in a pilot study labiotech.eu. These efforts, while using different platforms, underscore the excitement around melanoma vaccines. Melanoma has historically been at the forefront of immunotherapy (it was the first cancer where checkpoint inhibitors showed dramatic success). Now it’s leading the charge for personalized vaccines; success here could pave the way for similar approaches in other cancers that are immunogenic. As Dr. Yorio noted, “melanoma led the way” in immunotherapy advances over the past decade, and it makes sense that “a vaccine like this could work well in melanoma” – then “hopefully in other cancers that have some immunogenic component as well” targetedonc.com.

Breaking New Ground in Lung Cancer (NSCLC)

Lung cancer is the leading cause of cancer mortality worldwide, so the stakes for improving therapy are enormous merck.com. Merck and Moderna have accordingly expanded their partnership into NSCLC, launching two Phase 3 trials in 2023–2024 that apply the personalized mRNA vaccine concept to lung cancer. NSCLC is a very different tumor from melanoma – often less mutation-rich (especially in non-smokers) and with a more immunosuppressive microenvironment. Yet immunotherapy has become standard in certain lung cancer settings (checkpoint inhibitors are FDA-approved in both metastatic and early-stage NSCLC), and combining a vaccine could further boost the immune attack on lung tumors.

The first NSCLC Phase 3 trial, INTerpath-002 (NCT06077760), began in late 2023 merck.com. This trial enrolls patients with completely resected Stage II, IIIA, or IIIB (N2) NSCLC – i.e. lung cancers that were surgically removed but were locally advanced. All patients must have received standard platinum-based adjuvant chemotherapy after surgery (the current standard of care for resected Stage II–III lung cancers). The trial then randomizes ~868 patients to either V940 (mRNA-4157) + pembrolizumab versus pembrolizumab alone, given as adjuvant therapy for up to ~one year merck.com. (Pembrolizumab has itself become an approved adjunct in resected NSCLC: as of 2021, the FDA authorized one year of pembrolizumab after surgery and chemo for stage IIB–III NSCLC, given its benefit in the PEARLS/KEYNOTE-091 trial. Both INTerpath-002 arms receive pembrolizumab to reflect this standard care, with the experimental arm layering the personalized mRNA vaccine on top.) The primary endpoint is disease-free survival (DFS) – essentially measuring if the vaccine can further reduce the risk of lung cancer recurrence beyond what surgery, chemo, and PD-1 therapy already achieve merck.com. Secondary endpoints include overall survival, distant metastasis-free survival, lung-cancer-specific survival, safety, and quality of life merck.com. Dr. Marjorie Green of Merck noted that lung cancer still kills ~1.8 million people globally each year, and “there is a need for continued scientific advancements to help fight this disease at earlier stages when patients have the best chance for better outcomes” merck.com. By moving the vaccine into the early-stage (curative) setting, the hope is to “have the most impact” on long-term survival merck.com.

INTerpath-002 is truly a global trial: the first patients enrolled were in Australia merck.com, and it is expected to open at sites across North America, Europe, and Asia. At Memorial Sloan Kettering Cancer Center in New York, for example, Dr. Jamie Chaft is the investigator for this study, explaining to patients that “the vaccine is custom-made for each patient using tumor and blood samples… [it] uses the genes in your cancer to teach your immune system to fight your specific cancer” mskcc.org. Like the melanoma trial, it’s double-blind with a placebo injection used in the control arm (so participants get pembrolizumab + placebo versus pembrolizumab + mRNA vaccine) mskcc.org. Notably, patients cannot have had prior immunotherapy for their lung cancer (to ensure a clean comparison), and those with targetable EGFR mutations are excluded (since they would follow a different standard treatment path with targeted EGFR inhibitors) merck.com. The personalized vaccine approach in lung cancer is especially intriguing because lung tumors (particularly in smokers) do carry many mutations; however, past vaccine efforts in lung cancer (using non-mRNA platforms) have largely failed to improve outcomes in Phase 3 trials trial.medpath.com. mRNA technology offers a potent new way to deliver antigens, and by focusing on earlier-stage disease, the INTerpath trials give the vaccine a better chance to work in an minimal residual disease setting.

Merck/Moderna’s second NSCLC Phase 3 trial, INTerpath-009 (NCT06623422), was announced in late 2024 merck.com. This trial targets an even more specific niche: patients with Stage II–IIIB NSCLC who received neoadjuvant pembrolizumab + chemotherapy before surgery but did not achieve a pathologic complete response (pCR) merck.com. In other words, these patients had some cancer remaining at surgery despite pre-operative immunochemotherapy – indicating a higher risk of relapse. INTerpath-009 will enroll ~680 such patients, and after surgery they are randomized to adjuvant mRNA-4157 + pembrolizumab vs. pembrolizumab alone merck.com. By focusing on the pCR-negative subgroup, the trial enriches for those who need additional therapy to eradicate residual disease. “While [NSCLC] survival rates have improved in recent years, lung cancer continues to be the leading cause of cancer death… We are pleased to expand the INTerpath program with Moderna, evaluating V940 in combination with Keytruda to pursue meaningful advances for lung cancer,” said Dr. Green merck.com. Moderna’s oncology head Dr. Kyle Holen added that with INTerpath-002 and -009, “we believe our mRNA technology has the potential to improve outcomes… in early-stage lung cancer, with and without prior neoadjuvant therapy” merck.com. In essence, Moderna and Merck are blanketing the early-stage NSCLC space: INTerpath-002 covers the scenario of surgery + chemo (no immunotherapy prior), and INTerpath-009 covers patients who got immunotherapy pre-surgery but had an incomplete response. Together, these two trials could position the personalized vaccine as part of the standard multimodal therapy for operable NSCLC, aiming to prevent postoperative recurrences, which are common and deadly in lung cancer.

It’s worth noting that other therapeutic cancer vaccines have also made progress in lung cancer. For example, OSE Immunotherapeutics in France developed a peptide vaccine (Tedopi) targeting 5 shared tumor-associated antigens for HLA-A2+ NSCLC patients. In a Phase 3 trial (ATALANTE-1) for advanced NSCLC patients who had failed immunotherapy, Tedopi showed improved survival versus chemotherapy in a subset, and OSE is now seeking approval in the EU labiotech.eu. While Tedopi is not personalized or mRNA-based, its impending approval would make it one of the first cancer vaccines to reach the market for lung cancer, highlighting that immunotherapy vaccines are at last demonstrating tangible clinical benefit. Another approach, by Scancell in the UK, uses a DNA vaccine (ImmunoBody) targeting melanoma antigens but is also being explored for lung and other tumors in early trials labiotech.eu. And in China, several companies (e.g. Stemirna Therapeutics) are reportedly testing personalized mRNA vaccines for lung cancer, contributing to the fact that China and the U.S. together host the majority of mRNA cancer vaccine trials to date trial.medpath.com.

Still, Moderna’s program is the clear front-runner in NSCLC for personalized vaccines. If their lung trials succeed, it could be a paradigm shift. Potentially, after a lung tumor is removed, doctors would send the tumor for rapid genomic analysis, have an mRNA vaccine made to measure, and administer it within weeks to mop up residual cancer cells. This would be akin to how we use adjuvant chemotherapy or immunotherapy now, but far more specific. Oncologists find this prospect exciting given lung cancer’s historically high relapse rates. As Dr. Holen put it, each patient’s cancer presents “a labyrinth of genetic mutations” and demands “individualized medicines manufactured based on the distinct molecular tumor profile for each patient.” An “individualized neoantigen therapy can be [the] catalyst for innovation and drive us toward the next frontier of cancer care,” Holen said, crediting the patients and trial teams “for helping us in this mission.” merck.com. Translating that vision into an approved therapy will require clear success in these Phase 3 trials, but confidence is growing: the mRNA vaccine already proved it can induce T cells in lung cancer patients (Phase 1 data from BioNTech’s off-the-shelf BNT116 vaccine for advanced NSCLC showed immune responses in all patients, for example pubmed.ncbi.nlm.nih.gov). Now the question is whether those immune responses can prevent recurrences or extend survival. The oncology community is watching closely, as a positive outcome would open the door to testing personalized mRNA vaccines in many other cancers.

How Personalized mRNA Vaccines Work (and How They Differ)

Personalized mRNA cancer vaccines represent a confluence of genomics, immunology, and RNA technology. The process starts with sequencing a patient’s tumor to identify DNA mutations (and often RNA expression data as well) jhoonline.biomedcentral.com. Specialized bioinformatics algorithms then predict which mutations create neoantigens – peptide fragments likely to be displayed on the patient’s HLA molecules and recognizable as “non-self” by T cells jhoonline.biomedcentral.com. Each patient’s tumor might harbor dozens or even hundreds of mutations, but only a subset will produce strong neoantigens. Companies like Moderna and BioNTech have developed AI-guided pipelines to filter and prioritize candidates by factors like how abundantly the mutant protein is expressed, how different it is from normal self-proteins, and how well the peptide is predicted to bind the patient’s HLA alleles jhoonline.biomedcentral.com. For example, Moderna’s approach selects up to 34 neoantigen sequences for mRNA-4157 merck.com, whereas BioNTech’s autogene cevumeran codes for up to 20 neoantigens in one vaccine molecule jhoonline.biomedcentral.com. These neoantigen sequences are then synthesized as one long messenger RNA construct (essentially like encoding multiple small protein fragments in a single transcript, separated by linker sequences). When this mRNA vaccine is injected (typically intramuscularly), it is taken up by cells (e.g. muscle cells and local antigen-presenting immune cells). The cells’ ribosomes translate the mRNA into the encoded peptide sequences, which are then chopped up and loaded onto MHC molecules to be presented to T cells – mimicking the way an infected cell would present viral antigens, for instance merck.commskcc.org. Additionally, the RNA and its delivery vehicle (often lipid nanoparticles, LNPs) have an adjuvant effect, activating innate immune sensors (like endosomal Toll-like receptors) to stimulate the immune system. The end result is to generate a new T-cell response specifically against the patient’s tumor mutations.

In essence, the vaccine turns the patient’s body into the bioreactor for producing custom tumor antigens in situ. This is more efficient and flexible than older approaches like peptide vaccines (where you had to manufacture and purify each peptide externally and mix them with adjuvant). mRNA can also encode multiple neoantigens at once, potentially hitting several tumor targets simultaneously merck.com. This is important because cancer cells are notorious for heterogeneity – different clones in one tumor might have distinct mutations. A multi-epitope vaccine casts a wider net for the immune system to find and kill cancer cells. It also reduces the chance that the tumor can “escape” by dropping one antigen (since other antigens would still be targeted).

Checkpoint inhibitors vs. vaccines: Checkpoint inhibitor drugs (like pembrolizumab) work by blocking inhibitory pathways (e.g. PD-1/PD-L1) that tumors use to mute T-cells. They release the brakes on existing anti-tumor T cells, allowing those T cells to attack the cancer. However, if a patient never had T-cells that recognized the tumor in the first place, a checkpoint inhibitor alone may do little. That’s where vaccines come in: they teach new T-cells to recognize the cancer (pressing the “gas pedal” of the immune response, in a sense). In melanoma, for example, many patients already have some T cells that see tumor antigens (hence anti-PD-1 drugs can work by reinvigorating them). But adding a vaccine can recruit additional T cells targeting mutations that the immune system hadn’t naturally picked up on merck.com. This could be why the mRNA-4157 plus pembrolizumab combo outperformed pembrolizumab alone jhoonline.biomedcentral.com – the vaccine brings new soldiers to the fight, while PD-1 blockade emboldens all soldiers. In more immunologically “cold” tumors (like MSS colorectal cancer), checkpoint drugs alone do very little because the baseline anti-tumor T cells aren’t there; a personalized vaccine could initiate an immune response from scratch, and then a checkpoint inhibitor could help amplify it. We’re already seeing hints of this synergy: in Gritstone’s study, some colorectal patients’ tumors shrank or their disease stabilized on the vaccine + dual checkpoint combination, whereas historically checkpoint therapy alone almost never helps in that disease onclive.comonclive.com.

Vs. cell therapies: Another personalized immunotherapy route is to extract a patient’s T cells and genetically engineer them to target tumor antigens (CAR-T or TCR-T cell therapy). Those have had success in certain blood cancers and melanomas, but they are extremely expensive, labor-intensive, and for solid tumors they face challenges like T cell trafficking and immunosuppressive tumor environments. A vaccine is a much simpler outpatient intervention – no need to handle cells in a lab, and it can induce both CD8+ “killer” T cells and CD4+ “helper” T cells in vivo jhoonline.biomedcentral.com. However, vaccines may take longer to generate a full immune response (weeks to months), whereas cell therapies infuse ready-made tumor-killers. This is one reason cancer vaccines are often deployed in settings where immediate tumor reduction isn’t needed (e.g. after surgical resection, or in slow-growing disease, or as maintenance therapy). In fast-growing metastatic disease, a vaccine alone might be too slow-acting, but combined with other therapies it could still contribute to longer-term control.

Vs. traditional vaccines: It’s important to clarify that therapeutic cancer vaccines (like these neoantigen mRNA vaccines) are different from preventive cancer vaccines (such as the HPV vaccine or hepatitis B vaccine, which prevent virus-caused cancers). Here we are treating existing cancer, not preventing it from occurring. The “vaccine” terminology refers to the mechanism of action (training the immune system), but patients already have cancer when they get these shots. Therapeutic cancer vaccines have a long history of attempts – from whole-cell vaccines to peptide cocktails – but with limited success (Provenge, a dendritic cell vaccine for prostate cancer, is one of the few that made it to market, with modest benefit). mRNA vaccines are basically the latest, highly customizable iteration of this concept, turbo-charged by the mRNA delivery advances from the COVID-19 vaccine experience. They also benefit from our modern ability to sequence tumors and use computational immunology to predict neoantigens, which simply wasn’t feasible decades ago.

Challenges on the Road Ahead

While the recent progress is thrilling, experts caution that significant challenges remain before personalized mRNA cancer vaccines realize their full potential in melanoma, NSCLC, and beyond. Manufacturing and scalability are top concerns. Each patient’s vaccine must be made individually under tight time constraints. This involves obtaining a high-quality tumor biopsy or resected tumor sample, performing whole-exome sequencing (and often RNA sequencing) of tumor and normal tissue, running bioinformatics pipelines to select neoantigen targets, then actually manufacturing the mRNA-LNP product under GMP conditions. In early trials, this process could take 3–4 months per patient – workable in an adjuvant setting (where patients are recovering from surgery) but still far from ideal. The Merck/Moderna team has streamlined their pipeline significantly: patients in the Phase 2 melanoma trial had to start pembrolizumab within 13 weeks of surgery, during which time the custom vaccine was designed and produced merck.com. According to a 2025 review, industry innovations (automation, parallelization, and possibly even on-demand local mRNA manufacturing units) have now shortened production to under one month for personalized vaccines pmc.ncbi.nlm.nih.gov. Moderna’s CEO noted that AI and improved algorithms have reduced the in silico design step from weeks to mere hours in some cases trial.medpath.com. Still, if someday thousands of patients require their own mRNA vaccines, manufacturing capacity and supply chains (for reagents, lipids, etc.) will need to scale dramatically. It’s a very different model from traditional one-size-for-all drug production; some have likened it to a “micro-brewery” model in pharma, where each batch is unique.

Cost is the other elephant in the room. Present estimates suggest a personalized cancer vaccine therapy course will cost on the order of low-to-mid six figures (USD). One recent analysis pegged it at over $100,000 per patient in current trials pmc.ncbi.nlm.nih.gov This partly reflects the bespoke manufacturing and laborious QC for each batch. As technology improves, costs could come down (just as genome sequencing costs have plummeted), but it remains to be seen how payers will handle an ultra-tailored therapy. There is precedent with CAR-T cell therapies, which cost $350-500k but have been reimbursed due to their curative potential in leukemia/lymphoma. If mRNA vaccines can demonstrably cure a significant fraction of high-risk melanoma or NSCLC patients (who would otherwise relapse and need expensive metastatic treatments), a one-time $100k expense might be justifiable. Nonetheless, widespread adoption will likely require cost reductions through process improvements or automation. It’s encouraging that BioNTech and others are exploring shared neoantigen vaccines (for example, vaccines targeting common KRAS or TP53 mutations that many patients’ tumors share) jhoonline.biomedcentral.com. These would not be fully personalized – more like “off-the-shelf” products for subsets of patients – but could be manufactured in bulk, lowering cost. However, the truly individualized vaccines might remain premium therapeutics unless cost efficiencies are found.

Another challenge is regulatory and logistical. Regulators like the FDA are familiar with approving drugs with fixed compositions, but here every lot is unique. Ensuring potency and consistency for each personalized vaccine is non-trivial. Companies have to validate that their antigen selection and mRNA synthesis processes reliably produce an immunogenic product even though the sequence varies each time. So far regulators have been accommodating, treating the whole process as the “product” (with defined quality checks like verifying each neoantigen mRNA is correctly made and the LNP formulation meets specs). The FDA has even issued guidance on cancer vaccine development, hinting at flexibility in trial design given the personalized nature pmc.ncbi.nlm.nih.gov. Distribution is another aspect – the final mRNA-LNP product has to be shipped frozen to the clinical site and administered to the patient possibly within a certain time window. This demands coordination, especially if a patient is one of only a few at a site getting the vaccine (not a typical mass-produced vial).

From a clinical perspective, researchers will be closely watching for safety and immune-related side effects. So far, mRNA neoantigen vaccines have shown a favorable safety profile. In the Moderna Phase 2, for instance, the combination of vaccine + pembrolizumab didn’t significantly add to toxicity beyond what pembrolizumab alone causes merck.com. The most common vaccine-related effects were injection-site reactions and transient flu-like symptoms (fever, fatigue) – expected immune activation signs. Serious treatment-related adverse events were reported in 14.4% of patients on the combo vs 10% on pembrolizumab alone merck.com, which is not a huge difference. However, when combining with checkpoints, there is always a risk of autoimmune side effects being amplified. Thus far no red flags have emerged, but larger Phase 3 populations will be needed to fully assess safety. There’s also the theoretical concern of immune escape: if a patient’s cancer has thousands of mutations but the vaccine targets 20–30, could the tumor simply outgrow the immune pressure by relying on untargeted mutations? Possibly, but the hope is that the chosen neoantigens are clonal (present on all tumor cells) or essential enough that the cancer can’t easily ditch those targets. Monitoring of tumor clones and resistance patterns will be an ongoing aspect of these trials (some include analysis of circulating tumor DNA to see if particular mutations persist or get eliminated under vaccine pressure).

One pragmatic challenge is patient selection and timing. Not every cancer patient has a tumor sample and time to wait for a personalized vaccine. In rapidly progressing disease, a patient might not be stable long enough to manufacture a vaccine – this was seen in some trials where a portion of patients couldn’t get the vaccine because their cancer worsened too fast. For adjuvant settings, this is less of an issue since patients are NED (no evidence of disease) after surgery, but in metastatic settings it remains a consideration. Clinicians will need to identify who are the best candidates: e.g. patients with intermediate tumor burden, or those who achieved a partial remission with chemo/IO and can use a vaccine as consolidation. In the future, earlier use might be possible: one could imagine vaccinating before surgery (neoadjuvant vaccine) to try to shrink tumors and prime immunity early. Some Phase 1 trials are exploring neoadjuvant personalized vaccines, but none are phase 3 yet.

Despite these challenges, the potential rewards are enormous. For melanoma, if the Phase 3 proves positive, it would add a powerful tool to keep patients cancer-free after surgery. For lung cancer – which sees only about 25% of stage III patients cured by current therapy – an effective vaccine could push that cure rate higher, translating to thousands of lives saved annually. Beyond melanoma and NSCLC, the pipeline is rapidly expanding. In 2024, over 60 mRNA cancer vaccines were in clinical trials across various cancers, and more than 120 trials of RNA-based cancer vaccines (including mRNA, self-amplifying RNA, etc.) were ongoing if you include all phases and indications trial.medpath.com. Companies are trialing personalized mRNA vaccines in colorectal cancer, renal cell carcinoma, head & neck cancer, and even difficult entities like glioblastoma pmc.ncbi.nlm.nih.gov. As Dr. J. Randolph Hecht of UCLA commented regarding the colorectal vaccine data, “unlike patients with melanoma and lung cancer, [MSS colorectal patients] have not benefited from checkpoint inhibitors. These preliminary results indicate [the vaccine] is inducing a significant immune response in a disease that has been felt to be immunologically cold.” onclive.com Such findings broaden the horizon for vaccines into cancers previously thought unresponsive to immunotherapy.

Conclusion

The coming 2–3 years will be pivotal in determining whether personalized mRNA vaccines fulfill their promise as “game changers” in oncology or remain a niche experimental approach. The Phase 3 trials in melanoma and NSCLC are not just trials of two products – they are a proof of concept for an entire paradigm of truly individualized cancer treatment. Success in these trials would likely lead to regulatory approval of the first personalized mRNA vaccine (perhaps in melanoma by the mid-late 2020s), ushering in a new era where “tailor-made” cancer vaccines join surgery, chemotherapy, radiation, and targeted drugs as part of standard care. It would also validate mRNA technology’s versatility beyond infectious disease, cementing the mRNA platform (born from COVID-19 vaccine triumphs) as a mainstay in cancer immunotherapy development.

On the other hand, if the trials disappoint (for example, if the vaccine combo ultimately doesn’t significantly outshine Keytruda alone in melanoma), that would prompt a reevaluation – perhaps the need for better neoantigen selection, higher vaccine potency, or different combinations. Cancer is a formidable foe, and as decades of past vaccine attempts have shown, generating immunity is one thing, but translating that into clinical benefit is another. Personalization seems to be the key that was missing before, and now that we can truly customize vaccines to each patient’s cancer, the field has leapt forward. As the CEO of Gritstone put it, “today’s preliminary results are highly encouraging… The overall trend of PFS improvement [with our personalized vaccine] is great to see… [it] puts us in a strong position to enter Phase 3 and then regulatory discussions.” onclive.com That sentiment echoes across the major players in this space.

From the vantage point of late 2025, we are witnessing a convergence of cutting-edge science and medicine: the individual patient’s genome directing the assembly of a bespoke therapy that enlists their own immune system to seek and destroy cancer cells. It’s the embodiment of precision oncology and immunotherapy rolled into one. There are challenges to iron out – manufacturing, cost, and the biological complexity of tumor-immune interactions – but the momentum is undeniable. As a recent Lancet commentary remarked, “cancer vaccines and the future of immunotherapy” are now intertwined, and the question is no longer if a personalized cancer vaccine can work, but rather when and for how many types of cancer trial.medpath.com. The Phase 3 trials in melanoma and NSCLC will be our first major yardsticks. If they succeed, the floodgates may open for personalized mRNA vaccines in oncology, turning what once sounded like science fiction into a life-saving reality for patients around the world.

Sources:

1. Merck & Moderna Press Release (Oct 2024) – Phase 3 trial of V940 (mRNA-4157) in NSCLC after neoadjuvant therapy merck.com
2. Merck & Moderna Press Release (Dec 2023) – Initiation of INTerpath-002 Phase 3 in adjuvant NSCLC merck.com
3. Merck & Moderna Press Release (Dec 2022) – Phase 2b melanoma trial (KEYNOTE-942) results merck.com
4. Journal of Hematology & Oncology (2025) – Review: Cancer vaccines status and directions jhoonline.biomedcentral.com
5. Targeted Oncology (Apr 2024) – Interview: Global Phase 3 melanoma vaccine trial targetedonc.com
6. Memorial Sloan Kettering – Trial summary: INTerpath-002 NSCLC vaccine trial mskcc.org
7. MedPath News (Aug 2025) – Russia’s personalized mRNA vaccine program (Gamaleya) trial.medpath.com
8. Labiotech.eu (2023) – 11 cancer vaccine companies to watch (Nouscom’s neoantigen vaccines) labiotech.eu
9. OncLive (Apr 2024) – Gritstone’s GRANITE personalized vaccine in colorectal cancer onclive.com
10. MDPI Molecules (2025) – Progress and Future of RNA Cancer Vaccines (Sarfaraz K. Niazi et al.) pmc.ncbi.nlm.nih.gov
11. UK Government Press Release (July 2023) – NHS-BioNTech partnership for personalized cancer vaccines gov.ukgov.uk
12. Targeted Oncology (July 2024) – BNT111 Phase 2 in melanoma (BioNTech) labiotech.eu