Therapeutic Cancer Vaccines: Are We There Yet?

Tumor heterogeneity is the key obstacle preventing consistent treatment responses in patients with cancer. Decades of research have led to significant progress in developing novel therapies, but they have also revealed the complex and adaptive nature of cancer.

At the European Society for Medical Oncology 2025 Congress, Catherine Wu, MD, lead of the Division of Stem Cell Transplantation and Cellular Therapies and Dana Farber Cancer Institute in Boston, discussed exciting advancements in therapeutic cancer vaccines, bringing attention to investigations involving personalized vaccines across cancer types.

What is tumor heterogeneity?

Tumor heterogeneity refers to the differences in genetic makeup and behavior among cancer cells within the same tumor or across different tumors in a patient. It remains a critical challenge in cancer treatment because it allows tumors to evolve and adapt, escape immune control, and develop therapeutic resistance.¹

“I think we have to confront ugly truth about the enemy,” Wu began, “that there is tumor heterogeneity and that we see [it] across different cancers. This is the fuel that kind of generates clonal evolution and therapeutic resistance."¹

Wu explained that this evolutionary process can be understood through what’s known as the “three E’s” model of cancer immunoediting—elimination, equilibrium, and escape. In the earliest stages, immune cells recognize and attack tumor cells expressing abnormal antigens, effectively keeping cancer in check. Over time, however, selective pressure from the immune system enables some tumor cells to survive by acquiring mutations that help them evade detection.¹

During the equilibrium phase, a fragile balance is maintained: the immune system continues to suppress tumor growth, but resistant cancer cell populations persist and slowly diversify. Eventually, this leads to the escape phase, in which the tumor has accumulated enough adaptive mutations to bypass immune surveillance altogether. These tumor cells may lose antigens that once made them visible to the immune system or alter antigen presentation and immune regulation pathways.¹

At the same time, the tumor microenvironment becomes increasingly immunosuppressive, as inhibitory cells and signaling molecules dampen the body’s anti-tumor defenses.¹

“Unfortunately,” Wu noted, “by the time we are diagnosing and treating our patients, we’re already on the right-hand side of that process—at the point of tumor escape—where multiple mechanisms have evolved to inactivate immune control.”¹

Can personalized vaccines overcome tumor heterogeneity?

Understanding and combating tumor heterogeneity is crucial for developing more effective cancer treatments. Personalized cancer vaccines represent a promising strategy designed to target the unique genetic mutations within an individual’s tumor. Through a multi-pronged attack, personalized vaccines can address tumor heterogeneity, target multiple tumor antigens simultaneously, and provide a comprehensive immune response strategy.¹

Cancer vaccines function through activation and enhancement of adaptive immune system interactions, leading to stronger T-cell activation, improved infiltration of immune cells into tumor tissue, and a broader, more effective T-cell response. They may also help reshape the immunosuppressive tumor microenvironment, enabling the immune system to sustain its attack on cancer cells.¹

These vaccines engage directly with the tumor immune microenvironment to promote immune activation and modify the soluble factor environment to support anti-tumor activity. Through these mechanisms, they can overcome immune evasion strategies by maintaining antigen presentation and promoting continuous T-cell priming.¹

The result is a therapy capable of expanding pre-existing anti-tumor T-cell populations, recruiting new de novo T cells, and supporting long-term immune surveillance and memory. By targeting multiple tumor neoantigens in parallel, personalized vaccines offer a promising avenue for overcoming tumor heterogeneity and preventing disease progression.¹

“I think cancer vaccines hold a very interesting therapeutic place, because at some level, we're fighting fire with fire heterogeneity, with an adaptive response that is hardwired and built to deal with heterogeneity in our environment.”¹

What factors shape the safe, effective cancer vaccines?

Wu emphasized that the success of therapeutic cancer vaccines relies on a delicate balance between efficacy, safety, timing, and accessibility. One of the foremost considerations is the careful selection of vaccine targets—ensuring that they are specific to tumor cells while minimizing off-target effects. The inclusion of strong adjuvants, such as poly-ICLC, can help amplify immune responses, but their use requires precision to avoid overstimulation or toxicity. Controlled dosing schedules and close monitoring of immune responses are essential to achieving the right level of activation while minimizing potential adverse reactions.¹

Timing also plays a critical role in maximizing vaccine effectiveness. The most promising outcomes are often seen when vaccines are administered during periods of minimal residual disease—such as in adjuvant settings or early stages of cancer—when the immune system is better positioned to eliminate microscopic disease and prevent relapse.¹

Despite, their clinical promise, personalized cancer vaccines face significant cost-related challenges. Each vaccine requires genomic sequencing, individualized tumor profiling, and specialized manufacturing processes tailored to the patient’s unique cancer mutations. These factors make current production both time- and resource-intensive.¹

“We should be able to call up our pharmacy and say, ‘Let’s order up a personal cancer vaccine,’ and that vaccine should be able to come back to clinic in a couple of weeks to be administered to our patients,” Wu said.¹

Overcoming these barriers will require advances in sequencing technologies, automation, and scalable manufacturing systems to bring down costs and make personalized vaccines more widely available.¹

Can new antigens unlock the next wave of cancer vaccines?

Technological advances, particularly in sequencing and prediction tools, have been crucial in making personalized cancer vaccines a viable approach. Next-generation sequencing (NGS) will play a critical role through identification of cancer drivers and pathways and personalized antigen discovery. Compared with other tools, NGS is relatively cost-effective, making it more accessible to a wider patient population.¹

There are also HLA predictive tools, which can scan mutation repertoires and select peptides with good binding capacity to predict potential immunogenic targets. These innovations have paved the way for the discovery of neoantigens—new antigens created by somatic mutations that are unique to each individual’s tumor.¹

Neoantigens stand apart from shared tumor antigens due to their tumor-specific expression, high immunogenicity, and lack of T-cell tolerance. Because they are unique to each tumor, they enable a level of precision targeting that was previously unattainable. Together, NGS and predictive modeling have transformed cancer vaccine development, opening new therapeutic opportunities and advancing personalized treatment strategies.¹

What does the research show?

The field has seen significant progress, with numerous studies demonstrating the ability of vaccines to generate new epitope immune responses and target tumor neoantigens. Wu highlights the most pivotal trial in this space, which was published in The Lancet by Jeffrey S Weber, MD PhD, who was the deputy director of the Perlmutter Cancer Center at NYU Langone, co-leader of its Clinical Melanoma Program, and professor of oncology at NYU Grossman School of Medicine.¹

The study (NCT03897881) represents the first large-scale study evaluating therapeutic vaccines in cancer therapy. Weber and his team conducted an open-label, randomized, phase 2b, adjuvant study of mRNA-4157 (Moderna, Merck) plus pembrolizumab (Keytruda; Merck) versus pembrolizumab monotherapy in 150 patients with completely resected melanoma (stage 3B–4). mRNA-4157 was given intramuscularly for up to 9 doses, while pembrolizumab was administered intravenously for up to 18 doses, both on 3-week cycles.^2,3

mRNA-4157 plus pembrolizumab extended recurrence-free survival compared with monotherapy, with a hazard ratio of 0.56 (95% CI 0.31–1.02; p = 0.053). Recurrence or death occurred in 22% of combination patients versus 40% on pembrolizumab alone, translating to 18-month recurrence-free survival rates of 79% versus 62%.³

Most adverse events were mild (grade 1–2). Grade 3 or higher events were reported in 25% of combination patients and 18% of monotherapy patients, with no grade 4 or 5 events linked to mRNA-4157. Immune-mediated adverse events occurred at similar rates in both groups (36%).³

the study demonstrates that mRNA-4157 plus pembrolizumab is not only effective in extending recurrence-free survival but also generally well tolerated, supporting further investigation across a range of cancers. As of 2025, there over 1200 other ongoing clinical trials investigating therapeutic vaccinations in cancers such as ovarian cancer, pancreatic adenocarcinoma, and gliosarcoma, and other difficult to treat tumors.¹

“This has really driven a lot of the excitement in the field,” said Wu. “And this is just a small snapshot.”¹

Are we there yet?

Continued research is needed to overcome the persistent challenges of mutation levels across cancer types, complex tumor microenvironments, and mechanisms of tumor escape. Advanced disease treatment is complex due to difficulty targeting heterogeneous tumors, highlighting the need for combination therapies. In diseases with low mutational burdens, identifying targets is a major barrier to personalized vaccine development due to their limited immunogenic potential.¹

Advances in antigen selection are poised to improve the effectiveness of personalized cancer vaccines. Expanding the range of targeted antigens and developing more comprehensive, multi-antigen strategies can help overcome tumor heterogeneity, while combining multiple targeting approaches may further enhance therapeutic efficacy. Optimizing vaccine administration is another key focus, including identifying the most effective treatment settings, exploring early intervention approaches, and integrating vaccines into adjuvant therapy regimens.¹

Emerging research continues to explore combinations of vaccines with other immunotherapies, the use of adjuvants such as Montanide to amplify immune activation, deep molecular tracking of immune responses, and a better understanding of tumor escape mechanisms. Together, these developments offer a roadmap for more effective, durable, and personalized cancer vaccine strategies in the years ahead.¹

REFERENCES

1. Ascierto P, Wu C. Therapeutic cancer vaccines: Clinical perspectives. Presented at: European Society for Clinical Oncology. October 17, 2025 to October 21, 2025. Berlin Germany.

2. An efficacy study of adjuvant treatment with the personalized cancer vaccine mRNA-4157 and pembrolizumab in participants with high-risk melanoma (KEYNOTE-942). Clinicaltrials.gov. June 8, 2025. October 20, 2025. https://clinicaltrials.gov/study/NCT03897881

3. Weber J, Carlino M, Khattak A, et al. Individualised neoantigen therapy mRNA-4157 (V940) plus pembrolizumab versus pembrolizumab monotherapy in resected melanoma (KEYNOTE-942): a randomised, phase 2b study. The Lancet. February 17, 2025. Accessed October 20, 2025. doi: 10.1016/S0140-6736(23)02268-7