Cancer vaccines and immune monitoring: shaping the future of cancer treatment

Cancer remains one of the leading causes of mortality worldwide (1). It is characterized not only by aberrant and uncontrolled cellular proliferation, but also by the capacity of malignant cells to evade immune surveillance (2). Within the broad spectrum of therapeutic approaches, cancer vaccines have emerged as a promising strategy, offering the potential to generate durable and precisely targeted immune responses against tumors (3), as surgery, chemotherapy, and radiotherapy can be effective at reducing cancer burden, but may cause significant side effects. Targeted therapies and immune checkpoint inhibitors have improved outcomes in some cases; however, their effectiveness can be limited by tumor heterogeneity, development of resistance, or immune-related side effects.

Unlike conventional prophylactic vaccines against infectious diseases, cancer vaccines are almost exclusively therapeutic. Their main purpose is to stimulate adaptive immunity to recognize and destroy malignant cells by presenting tumor-specific antigens to the natural immune system (3). The critical step in this process is the priming of cytotoxic CD8⁺ T lymphocytes by antigen-presenting cells, mostly dendritic cells, displaying tumor-associated antigens or, preferentially, tumor-specific neoantigens (3). CD4⁺ helper T cells play a supportive role by sustaining CD8⁺ T-cell responses and promoting the establishment of long-term immune memory (3). Neoantigens, arising from somatic mutations unique to individual cancers, are especially attractive vaccine targets because they bypass central immune tolerance and are readily recognized as non-self (4). To this end, the therapeutic challenge in vaccinology is to induce a potent and sustained T-cell response rather than relying predominantly on humoral immunity, since tumors employ multiple strategies of immune escape that demand direct cytotoxic elimination (5).

Several vaccine platforms are under active clinical and preclinical investigation, each with its own advantages and limitations (Table 1) (6). Shared-antigen vaccines employ standardized antigens expressed across many patients with a given malignancy, allowing scalable, off-the-shelf production. Nonetheless, their efficacy may be strongly limited by tumor heterogeneity and immune tolerance to self-derived antigens. Contrarily, personalized neoantigen vaccines can exploit next-generation sequencing (NGS) to identify unique tumor mutations in each patient, which are then encoded, typically using messenger RNA (mRNA) constructs, and delivered by lipid nanoparticle carriers to elicit tailored T-cell responses that overcome interpatient variability. A leading example of this individualized approach is autogene cevumeran, an investigational mRNA-based vaccine co-developed by BioNTech and Genentech (7). In a phase I study of patients with resected pancreatic ductal adenocarcinoma, tumor exome sequencing was used to generate personalized vaccines encoding up to 20 neoantigens. Of 16 evaluable patients, half mounted strong neoantigen-specific T-cell responses. In these responders, the median recurrence-free survival (RFS) was not reached at 18 months, whereas non-responders experienced a median RFS of 13.4 months. Extended follow-up confirmed that several responders remained disease-free for over 3 years, while non-responders relapsed within a little more than a year, underscoring the link between vaccine-induced immunity and clinical outcome (8).

Another notable strategy involves dendritic cell vaccines, in which autologous dendritic cells are harvested, pulsed ex vivo with tumor antigens, and reinfused to prime antigen-specific T cells (9). Although technically more complex, this approach has demonstrated the capacity to elicit robust T-cell-mediated immunity in early-phase studies across multiple malignancies (9).

In situ vaccination represents a complementary approach, using interventions within the tumor microenvironment (e.g., local radiotherapy, oncolytic viruses, or immune adjuvants) for promoting the release of tumor antigens and activating dendritic cells in situ. This local priming may then translate into a systemic anti-tumor immune response (10).

More recently, off-the-shelf vaccines designed to target common oncogenic driver mutations have shown promise. The phase I AMPLIFY-201 trial investigated ELI-002 2P, an amphiphile-peptide vaccine directed against mutant KRAS (G12D and G12R), prevalent in pancreatic and colorectal cancers (11). This vaccine combines amphiphile-modified KRAS peptides with a CpG-7909 adjuvant engineered for lymph node targeting. Among 25 patients treated in the adjuvant setting, 84% (21/25) mounted ex vivo detectable T-cell responses, including both CD4⁺ and CD8⁺ T cells in 59% (15/25). Clearance of circulating tumor DNA biomarkers was achieved in 24% (6/25). Treatment was well tolerated, and the regimen achieved a median RFS of 16.3 months and an overall survival of 28.9 months across the cohort (12). Importantly, patients who exhibited robust T-cell responses, defined as an over 9.2-fold expansion from baseline (17/25; 68%), experienced significantly better RFS [hazard ratio (HR): 0.12; 95% confidence interval (CI): 0.02–0.61] and median overall survival not reached (HR: 0.23; 95% CI: 0.06–0.85) compared with nearly 16 months in weaker responders. The so-called “antigen spreading” (i.e., the diversification of immune response to antigens beyond those specifically included in the vaccine), was observed in approximately two-thirds of evaluable patients (12). These findings highlight the potential of mutation-specific, off-the-shelf vaccines to provide scalable and broadly applicable therapeutic options, with distinct manufacturing and accessibility advantages over fully personalized platforms.

Additional evidence of clinical relevance has emerged from the KEYNOTE-942 study (13). This phase 2b, open-label trial investigated whether the addition of the individualized mRNA-based neoantigen vaccine mRNA-4157 (V940) to pembrolizumab could improve outcomes compared with pembrolizumab monotherapy in patients with completely resected high-risk cutaneous melanoma. A total of 157 patients were randomized to receive the combination or monotherapy. After a median follow-up of approximately 23 months, RFS was improved with the combination, with an 18-month RFS rate of 79% vs. 62% with pembrolizumab alone. Another phase I trial investigated the efficacy of the RNA-lipoplex vaccine encoding four melanoma-associated antigens FixVac (BNT111) alone or with PD-1 blockade in patients with advanced melanoma (14). A total of 89 patients were included in an interim analysis. Vaccine-induced immune responses were observed in over 75% of patients, with robust CD8⁺ and CD4⁺ T cell activation. The combination therapy achieved a 50% objective response rate, with durable immune response.

The clinical progress achieved to date has been made possible by innovations in vaccine delivery systems. Lymph node-targeted formulations, including albumin-binding amphiphiles and lipid nanoparticle-based mRNA vaccines, are designed to enhance antigen uptake by dendritic cells and optimize T-cell priming (15). Still, the immunosuppressive tumor microenvironment remains a central obstacle, as tumors recruit regulatory T cells and myeloid-derived suppressor cells while upregulating inhibitory checkpoint molecules such as programmed death-ligand 1 (PD-L1). Consequently, combination strategies integrating vaccines with immune checkpoint inhibitors (anti-PD-L1 antibodies) are being actively pursued to boost vaccine efficacy (16). The genetic and immunologic heterogeneity of tumors also necessitates multi-antigen or patient-specific vaccine designs to ensure broad coverage.

Parallel progress in immune monitoring technologies represents one of the most critical enablers for the advancement of cancer vaccines. The ability to precisely measure, characterize, and predict immune responses not only informs whether a given vaccine is immunogenic, but also provides insight into which patients are more likely to obtain clinical benefits. Multiparametric T-cell assays, for example, allow for simultaneous evaluation of multiple functional aspects of T-cell responses, including cytokine production, cytotoxic activity, memory formation, and exhaustion profiles. By capturing this functional diversity, researchers can build a more comprehensive picture of vaccine-induced immunity and its relationship to tumor control (17). Equally important is the use of T-cell receptor (TCR) sequencing, which enables the identification and tracking of clonal T-cell populations specific to tumor neoantigens. TCR sequencing offers unprecedented resolution in determining the breadth and depth of antigen-specific T-cell repertoires, as well as the persistence of these clones over time, allowing investigators to assess whether successful long-term tumor control correlates with expansion of certain TCR clonotypes or with a more diverse polyclonal repertoire (18). Predictive biomarkers are emerging as another cornerstone of vaccine optimization. Expression of checkpoint molecules such as PD-1 or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), tumor mutational burden, the degree of antigen presentation machinery integrity, and immune gene expression signatures all provide valuable clues about which patients are most likely to respond to treatment. Integrating these biomarkers into clinical trial design makes it possible to stratify patients, identify non-responders earlier, and adapt therapy accordingly. In such a way, immune monitoring does not simply function as a passive measure of efficacy but actively shapes the next generation of cancer vaccine design.

Besides scientific hurdles, practical considerations remain. Personalized vaccines require complex pipelines involving tumor sequencing, neoantigen prediction, and individualized manufacturing, which collectively restrict scalability and increase costs. Contrarily, vaccines targeting shared oncogenic drivers, such as KRAS mutations, may overcome these barriers and expand accessibility by offering an off-the-shelf alternative.

While highlighting the successes of cancer vaccines is important, examining the lessons from unsuccessful cases is equally important. Many vaccine trials have failed due to a combination of biological, technological, and clinical factors. For example, low immunogenicity of the vaccine can limit the ability to mount a strong and durable immune response. Tumor immune evasion mechanisms, such as expression of immune checkpoint molecules or creation of an immunosuppressive tumor microenvironment, can prevent effective anti-tumor activity. In some cases, patient heterogeneity, including differences in genetic background or tumor mutational profiles, reduces overall efficacy. Additionally, suboptimal adjuvant selection, dosing schedules, or delivery platforms can contribute to trial failure, as can safety concerns or unforeseen adverse effects. Analyzing these setbacks provides valuable insights that can inform target selection, optimize vaccine design, and guide more rational clinical trial strategies.

Looking to the future, several trends are converging. Combination regimens that integrate vaccines with established immunotherapies, radiotherapy, chemotherapy, or targeted agents are expected to provide synergistic benefits (19). Expanding antigen targets beyond KRAS to other recurrent driver mutations and tumor-specific proteins remains a priority. Advances in mRNA engineering, nanoparticle delivery, and synthetic biology continue to improve vaccine immunogenicity and safety profiles, along with development of a next-generation of vaccines designed to also engage natural killer (NK) cells. Importantly, administering vaccines in the adjuvant setting, when disease burden is minimal and immune surveillance may be more effective, offers an alternative strategy to prevent relapse. The AMPLIFY-201 trial, which specifically enrolled patients with molecular evidence of minimal residual disease after surgery, exemplifies this rationale (12). In the longer term, tailoring vaccine regimens according to immune biomarkers and tumor profiles may herald in a more personalized and adaptive framework for immunotherapy.

In conclusion, cancer vaccines are moving steadily from theoretical promise to clinical reality. By engaging both CD8⁺ and CD4⁺ T-cell immunity against tumor-specific antigens, these therapies have the capacity to reshape the immunotherapeutic landscape. Evidence from individualized mRNA vaccines in pancreatic ductal adenocarcinoma and mutation-targeted KRAS vaccines in gastrointestinal cancers demonstrates that vaccine-induced immune responses can translate into tangible clinical benefit, including delayed recurrence and extended survival. Continued technological innovation, robust clinical validation, and thoughtful integration into combination regimens will be critical to overcome the remaining challenges (Table 1). With these advances, cancer vaccines have the potential to become a cornerstone of precision oncology and broaden the therapeutic armamentarium for patients across diverse malignancies.

Finally, the successful clinical translation of cancer vaccines will not only depend on continued innovation in vaccine platforms and delivery systems but also on the parallel development of robust laboratory monitoring strategies. By integrating multiparametric testing, clinicians will be able to better identify patients who are most likely to benefit, optimize treatment regimens in real time, and refine vaccine design for broader efficacy. To this end, immune monitoring is not merely an adjunct to vaccine therapy, but an indispensable tool that will shape patient selection, guide adaptive treatment strategies, and accelerate the realization of cancer vaccines as a transformative modality in precision oncology.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Journal of Laboratory and Precision Medicine. The article has undergone external peer review.

Peer Review File: Available at https://jlpm.amegroups.com/article/view/10.21037/jlpm-25-44/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jlpm.amegroups.com/article/view/10.21037/jlpm-25-44/coif). G.L. serves as the Editor-in-Chief of Journal of Laboratory and Precision Medicine from November 2025 to October 2027. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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