Anti-tumor vaccine against KRAS 'breakdown': first encouraging results in pancreatic and colon cancer

The final results of the phase 1 AMPLIFY-201 trial have been published in Nature Medicine: the “off-the-shelf” amphiphilic vaccine ELI-002 2P, targeting KRAS mutations (G12D and G12R) and delivered directly to the lymph nodes via albumin trafficking, induced potent and long-lasting T-cell responses in patients with pancreatic and colorectal cancer with minimal residual disease after local treatment. The strength of the immune response correlated with clinical outcomes: in patients with a “high” T-response, the median survival without radiological relapse and overall survival were not reached, while in “low” ones, it was 3.02 months and 15.98 months, respectively. No new safety signals were identified.

Background

• A large unmet need. After “radical” treatment, pancreatic cancer (PDAC) returns very often: in some series, ≈60–80% of patients experience a relapse in the first 1–2 years. In many cases, relapse can be detected by ctDNA-MRD earlier than by imaging — ctDNA-positive status consistently predicts rapid disease relapse and worse survival.
• Why KRAS? KRAS driver mutations are present in >85–90% of PDAC and approximately ~50% of colorectal cancers; in PDAC subtypes, the most common are G12D (~40–45%) and G12R (~10–17%). This means that targeting the immune response to these “public” neoantigens potentially covers a large proportion of patients.
• How is the vaccine different from “KRAS pills?” KRAS G12C inhibitors work only in a rare proportion of PDAC (~1–2%), and for G12D/G12R, chemical inhibitors are still in early trials (e.g., MRTX1133). Therefore, the vaccine strategy — stimulating T cells to recognize the most common KRAS variants — seems practical in PDAC/CRC.
• The window of application is “minimal residual disease.” The logic is that when the tumor is no longer visible, but ctDNA/biomarkers indicate traces of disease, it is easier for the immune system to “get” microscopic lesions. That is why AMPLIFY-201 included MRD+ patients after local treatment.
• Delivery to lymph nodes by means of “albumin lift”. In ELI-002, the KRAS peptide antigens (G12D/R) and the CpG-7909 adjuvant are made amphiphilic: the lipid “tails” cling to albumin and “deliver” the complex to the lymph nodes, where a more powerful T-response is formed than in conventional peptide vaccines. This platform (“albumin hitchhiking”) was validated preclinically and in early phases.
• Why “off the shelf” and not personalized. Personalized mRNA vaccines for PDAC have already shown immunogenicity, but require individual patient production and time. ELI-002 uses ready-made “public” KRAS epitopes, so it is potentially easier and faster to scale up — an important plus for adjuvant therapy.
• Where is the clinic now? Phase 1 AMPLIFY-201 (ELI-002 2P) in Nature Medicine showed high T-response and its association with outcomes in patients with PDAC/CRC after local treatment. Phase 1/2 AMPLIFY-7P (an expanded version with 7 peptides) is underway with randomization versus observation.

What is this vaccine and how does it work?

ELI-002 2P are amphiphilic peptide antigens to mutant KRAS (G12D, G12R) + amphiphilic adjuvant CpG-7909. The molecules have lipid tails “sewn” onto them, which bind to albumin and carry the complex away from the injection site to the lymph nodes, where the antigen is captured by dendritic cells — this is how a stronger CD4⁺/CD8⁺ response is formed than with conventional peptide vaccines. KRAS is a convenient target: driver mutations occur in ≈93% of PDAC and ≈50% of CRC, are recognized by many HLA alleles and are rarely “lost” during tumor evolution.

Design AMPLIFY-201

The study included 25 patients (20 PDAC, 5 CRC) after radical local treatment, who had no tumor signs on the images, but minimal residual disease (MRD⁺) remained - according to ctDNA and/or tumor markers (CA19-9, CEA). The vaccine was administered as monotherapy. As of the cutoff date (September 24, 2024), the median follow-up was 19.7 months; protocol visits were completed in August 2024.

Main results

• Immunogenicity. 84% (21/25) of patients generated mKRAS-specific T-cell responses; 100% responded to the two maximum doses of adjuvant. 71% induced both CD4⁺ and CD8⁺ responses; the majority showed a cytotoxic profile (granzyme B, perforin) and memory.
• Threshold of "effective" response. ROC analysis identified a threshold of 9.17-fold increase in T-response (vs baseline). In patients above the threshold, the median radiological relapse-free survival was not reached versus 3.02 months "below the threshold" (HR 0.12; p=0.0002); the median overall survival was not reached versus 15.98 months (HR 0.23; p=0.0099).
• Antigen "spreading." Antigen spreading was observed in 67% of cases — the appearance of T cells to individual tumor antigens that were not included in the vaccine. This is a sign that the primary attack on KRAS "swinged up" broader antitumor immunity.
• Safety: No new toxicity signals were identified during extended surveillance.

Why is this important?

Pancreatic cancer and some colorectal tumors with KRAS mutations respond poorly to immunotherapy and often relapse even after “radical” treatment. Here, a realistic strategy for maintenance therapy of MRD⁺ patients is shown: a standardized vaccine that does not require lengthy production, with clear delivery to lymph nodes and a biomarker of benefit (T-response amplitude ≥9.17×). This distinguishes ELI-002 from personalized neoantigen vaccines, which are effective but difficult to manufacture.

What this does not prove (limitations)

This is a small, non-randomized phase 1; some patients received subsequent therapy when biomarkers rose, which may have affected outcomes. The association of strong T-response → clinical benefit is compelling, but randomized phase 2/3 studies are needed, including in combination with chemo/immunotherapy and for other KRAS variants.

What's next?

The authors emphasize the potential of early intervention in the MRD window and testing of combinations (e.g. checkpoints) - especially since some patients without radiological relapse after vaccination underwent subsequent therapy. A further clinical program is underway (NCT04853017). In parallel, independent experts called for careful interpretation of the phase 1 results and waiting for randomized confirmation.

Source: Nature Medicine, August 11, 2025 - Lymph node-targeted, mKRAS-specific amphiphile vaccine in pancreatic and colorectal cancer: phase 1 AMPLIFY-201 trial final results.