Every tumor is unique. The mutations that drive cancer growth create abnormal proteins—neoantigens—that exist nowhere else in the body. These molecular fingerprints offer an extraordinary opportunity: train the immune system to recognize and destroy cancer cells using personalized peptide vaccines tailored to each patient's specific tumor.
This isn't science fiction. In late 2025, researchers at Mount Sinai published 5-year follow-up data from a Phase 1 trial of PGV001, a personalized multi-peptide neoantigen vaccine. Of 13 patients with various advanced cancers, six survived to the 5-year mark, and three of those six are now completely tumor-free.
The Science of Neoantigens
Cancer cells accumulate mutations as they grow and divide. Some of these mutations alter the proteins the cell produces, creating neoantigens—peptide sequences that are completely foreign to the immune system. Unlike tumor-associated antigens (which are normal proteins overexpressed by cancer cells), neoantigens are truly tumor-specific, making them ideal targets for immunotherapy.
The challenge has been identifying which mutations create immunogenic neoantigens. Not every mutation produces a peptide that can be presented by the patient's MHC (major histocompatibility complex) molecules, and not every presented peptide generates a strong T-cell response.
The Manufacturing Pipeline
Creating a personalized neoantigen vaccine involves several complex steps:
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Tumor sequencing: DNA and RNA from both tumor tissue and normal cells are sequenced to identify tumor-specific mutations
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Neoantigen prediction: Computational algorithms predict which mutated peptides will bind to the patient's specific HLA (human leukocyte antigen) molecules and potentially trigger immune responses
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Peptide synthesis: Selected neoantigen peptides (typically 15-30 amino acids long) are manufactured under GMP conditions
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Vaccine formulation: Peptides are combined with adjuvants to enhance immunogenicity, often alongside checkpoint inhibitors like pembrolizumab
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Administration: Patients receive multiple injections over several months to build and maintain immune memory
The entire process from biopsy to first injection currently takes 4-8 weeks—a timeline that researchers are working to compress.
Landmark Clinical Results
Mount Sinai's PGV001 Trial
The Phase 1 trial at Mount Sinai tested PGV001 in patients with advanced cancers including non-small cell lung cancer, head and neck cancer, urothelial cancer, breast cancer, and multiple myeloma. The vaccine contained up to 20 personalized peptides per patient, formulated with the adjuvant poly-ICLC.
The results, published in 2025, were remarkable for a first-in-human study:
- No serious side effects were attributed to the vaccine
- 6 of 13 patients survived to the 5-year follow-up
- 3 of 6 surviving patients are completely tumor-free
- All patients developed detectable T-cell responses against at least some vaccine peptides
While these numbers are small, they're extraordinary for patients with advanced, previously treated cancers. The fact that some achieved complete responses suggests the approach can work.
Renal Cell Carcinoma: Zero Recurrences
A separate Phase 1 trial (NCT02950766) published in Nature in early 2025 tested personalized neoantigen vaccines in patients with high-risk, fully resected clear cell renal cell carcinoma. These patients had a significant risk of recurrence despite surgery.
The results after 40 months of follow-up:
- None of the 9 patients experienced cancer recurrence
- All patients generated T-cell responses against vaccine peptides
- Responses were detected against driver mutations in genes including VHL, PBRM1, BAP1, KDM5C, and PIK3CA
This trial is particularly compelling because it targeted high-risk patients in the adjuvant setting, where preventing recurrence is the goal. The 0% recurrence rate, while preliminary, far exceeds historical expectations.
The Technology Platforms
Neoantigen vaccines can be delivered through several platforms, each with advantages and limitations:
Peptide-Based Vaccines
The most established approach uses synthetic long peptides (typically 20-30 amino acids) that contain the mutated sequences. These peptides are taken up by dendritic cells, processed, and presented to both CD4+ and CD8+ T cells.
Advantages:
- Proven manufacturing processes
- Stable and easy to store
- Can target multiple neoantigens simultaneously
- Good safety profile
Limitations:
- Requires adjuvants for optimal immunogenicity
- Manufacturing takes several weeks
- Some peptides are difficult to synthesize
Peptide vaccines represent 64.8% of all neoantigen vaccine clinical trials, making them the dominant platform.
mRNA Vaccines
Following the success of COVID-19 mRNA vaccines, companies like Moderna and BioNTech are applying the technology to cancer. mRNA encoding multiple neoantigens is delivered via lipid nanoparticles.
Merck and Moderna are currently running a clinical trial testing mRNA-4157, a personalized neoantigen vaccine, as adjuvant therapy in patients with operable kidney cancer. Genentech and BioNTech are testing a similar approach in pancreatic cancer.
Dendritic Cell Vaccines
Patient dendritic cells are loaded with neoantigen peptides ex vivo and then reinfused. This approach consistently generates the highest per-epitope CD8+ T-cell response rates in clinical trials, though it's more complex and expensive to manufacture.
Combination Strategies
Neoantigen vaccines rarely work alone. The tumor microenvironment contains immunosuppressive factors that can neutralize even strong T-cell responses. That's why most current trials combine vaccines with:
Checkpoint Inhibitors
PD-1/PD-L1 inhibitors like pembrolizumab remove the "brakes" on T cells, allowing vaccine-induced immune responses to persist and function in the tumor microenvironment. Many trials use pembrolizumab in combination with personalized vaccines.
Unusual Radiotherapy Dosing
The iNATURE Phase II trial is evaluating how different radiation doses synergize with peptide vaccination. Low-dose radiation may help expose tumor antigens and create a more inflammatory microenvironment, enhancing vaccine effectiveness.
Chemotherapy
Some cytotoxic agents can induce immunogenic cell death, releasing tumor antigens and danger signals that boost vaccine-induced responses.
Challenges and Limitations
Despite promising results, significant hurdles remain:
Time Constraints
The 4-8 week manufacturing timeline can be problematic for patients with rapidly progressing disease. Companies are working on platform technologies that could reduce this to days.
Prediction Accuracy
Current algorithms predict HLA binding reasonably well, but predicting which peptides will actually generate strong T-cell responses remains imperfect. Many vaccine peptides fail to generate detectable immunity.
Tumor Heterogeneity
Tumors evolve. By the time a vaccine is manufactured, the tumor may have changed. Targeting multiple neoantigens helps, but cancer can still escape by losing expression of targeted antigens.
Cost and Scalability
Personalized medicine is inherently expensive. Each patient requires individual sequencing, prediction, synthesis, and formulation. Scaling this to treat large patient populations remains challenging.
Regulatory Pathway
How do you conduct Phase 3 trials for a therapy that's different for every patient? Regulators and companies are still working out the appropriate frameworks.
The Pancreatic Cancer Frontier
Pancreatic cancer, with its dismal prognosis and resistance to immunotherapy, represents both a major challenge and opportunity for neoantigen vaccines. Several trials are underway:
- Merck/Moderna: mRNA-4157 + pembrolizumab in resected pancreatic cancer
- Genentech/BioNTech: Autogene cevumeran in pancreatic cancer
- Multiple academic centers: Various peptide-based approaches
The rationale is compelling: pancreatic cancers have relatively high mutation burdens, creating numerous potential neoantigens. And for a disease with few good options, even modest improvements would be meaningful.
What This Means for Cancer Treatment
Personalized neoantigen vaccines represent a fundamental shift in how we approach cancer immunotherapy. Rather than targeting generic tumor markers shared across patients, we're attacking what makes each tumor unique.
The early clinical data is genuinely exciting:
- Safety: These vaccines appear remarkably safe, with minimal side effects beyond injection site reactions
- Immunogenicity: Most patients generate measurable T-cell responses against multiple vaccine peptides
- Clinical activity: Tumor regressions and prolonged survival have been observed across multiple cancer types
- Durability: Responses can last years, suggesting true immunological memory
But we're still in early days. Most data comes from small Phase 1 trials. Larger randomized trials are needed to confirm efficacy and identify which patients benefit most.
The Road Ahead
The next few years will be pivotal. Multiple Phase 2 and 3 trials are underway, and we should have more definitive data by 2027-2028. Key questions that need answers:
- Which cancers respond best to neoantigen vaccines?
- What's the optimal combination strategy?
- Can we improve neoantigen prediction algorithms?
- How can we accelerate manufacturing?
- What biomarkers predict response?
For now, personalized neoantigen peptide vaccines remain experimental, available only through clinical trials. But the concept has been validated: we can train the immune system to recognize and attack cancer using the tumor's own mutations against it.
That's a powerful idea—and one that may reshape cancer treatment in the years to come.
Key Takeaways
- Neoantigens are tumor-specific: Unlike other cancer targets, neoantigens arise from mutations unique to each patient's tumor
- Manufacturing is complex: Creating a personalized vaccine requires sequencing, prediction, synthesis, and formulation—taking 4-8 weeks
- Early results are promising: Phase 1 trials show 5-year survival in some advanced cancer patients and zero recurrences in high-risk kidney cancer patients
- Peptides dominate: About 65% of neoantigen vaccine trials use peptide-based approaches
- Combinations are key: Most trials combine vaccines with checkpoint inhibitors like pembrolizumab
- Challenges remain: Cost, manufacturing time, prediction accuracy, and tumor heterogeneity are ongoing hurdles
- This is still experimental: Larger trials are needed, and these vaccines are only available through clinical trials
This article is for informational purposes only and does not constitute medical advice. Cancer treatment decisions should be made in consultation with qualified oncologists. Clinical trials for neoantigen vaccines are actively enrolling—patients interested in these approaches should discuss options with their care team.