A peptide vaccine targeting 6 common KRAS mutations (mKRAS-VAX) demonstrated durable T-cell responses and was safe in patients with hereditary pancreatic ductal adenocarcinoma (PDAC) predisposition and a radiographic pancreatic abnormality, according to findings from a first-in-human phase 1 study (NCT05013216) published in Cancer Discovery.1
What were the key immunogenicity and safety findings?
Patients mounted a median 18.2-fold increase (range, 1.8-167.1) in their pooled average mKRAS-specific T-cell response within 17 weeks of vaccination, as measured by ex vivo IFNγ ELISpot assay. Investigators classified 18 of 20 patients (90%) as immune responders, defined as at least a 2.5-fold increase in the pooled response over baseline. Responses spanned a diverse range of HLA alleles, and 10 of 20 patients (50%) mounted a significant response against all 6 mKRAS antigens included in the vaccine.
Antigens G12A (median, 43.9; range, 0.2-169.3), G12V (median, 33.7; range, 1.8-242.7), and G12R (median, 21.8; range, 2.4-336.0) elicited the greatest T-cell responses, while G12D (median, 8.3; range, 0.4-104.4) and G13D (median, 9.1; range, 0.2-139.3) were the least immunogenic. Vaccination induced both CD4-positive and CD8-positive effector and memory T-cell responses, with CD4-positive responses generally larger in magnitude.
Regarding safety, mKRAS-VAX had a favorable safety profile. All adverse events (AEs) were grade 1 or 2 in severity; injection site reactions occurred in 85% of patients. The most common vaccine-related AEs were fatigue (70%), chills (40%), and flu-like symptoms (40%), and all were self-limiting. No new safety signals were identified.
How was the study designed?
The phase 1 study was conducted at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center to evaluate the safety and immunogenicity of mKRAS-VAX in patients at high risk of developing PDAC. Those eligible for the study met the criteria of at least 1 of 3 predefined high-risk groups based on familial and/or germline predisposition to PDAC.
mKRAS-VAX consists of 21-mer synthetic long peptides corresponding to 6 of the most common KRAS mutations in PDAC (G12D, G12V, G12R, G12A, G12C, and G13D), formulated with the adjuvant poly-ICLC. Patients received the vaccine subcutaneously across 5 injection sites during a prime phase (weeks 1, 3, and 5) followed by a single booster at week 13.
The median age of patients enrolled was 66.5 years (range, 46.0-81.0). The majority of patients (85%) had at least 1 first-degree relative diagnosed with PDAC and had a germline mutation (60%); the most common germline mutations were ATM (20%), BRCA2 (15%), BRCA1 (10%), APC (10%), and CDKN2A (10%).
What happened to pancreatic cysts after vaccination?
Over a median follow-up of 16.5 months, no vaccinated patients developed PDAC or a high-risk lesion requiring surgical resection. In a post hoc exploratory imaging analysis of 16 of 20 patients, 3 patients had a cyst resolve radiographically, and 3 additional patients had a partial regression of at least 2 mm in the longest cyst axis. The remaining cysts were stable. The vaccinated cohort showed a higher rate of cyst reduction or resolution (37.5%) compared with an independently monitored, unvaccinated cohort with similar clinical characteristics (6.8%; P = .01).
How durable were the vaccine-induced T-cell responses?
Longitudinal TCRβ sequencing showed that vaccine-induced, putative mKRAS-specific T-cell clonotypes persisted for up to 2 years after initial vaccination. A median of 18.6% (range, 7.4%-45%) of clonotypes that emerged during the prime phase retained reactivity against mKRAS antigens at 1- or 2-year follow-up. In vitro expansion of banked PBMCs also identified low-frequency circulating mKRAS-specific T cells that fell below the limit of detection of the standard ex vivo assay, suggesting that immune responses may persist longer than peripheral blood monitoring alone would indicate.
What else has happened with KRAS-directed vaccines in pancreatic cancer?
Other mKRAS-directed vaccine platforms are also in active development for PDAC. CancerNetwork® previously reported that ELI-002 7P, a lymph node–targeted amphiphile vaccine, induced mKRAS-specific T-cell responses in 99% of evaluable patients in the ongoing phase 2 AMPLIFY-7P trial (NCT05726864), with responses observed across diverse HLA backgrounds.2
References
- Haldar SD, Huff AL, Wang HH, et al. First-in-human testing of a mutant KRAS vaccine for pancreatic cancer interception in high-risk cohorts. Cancer Discov. Published online July 16, 2026. doi:10.1158/2159-8290.CD-25-2245
- Elicio Therapeutics reports ELI-002 7P achieved robust mKRAS-specific T cell responses in 99% of evaluable patients in ongoing phase 2 AMPLIFY-7P trial. News release. Elicio Therapeutics. September 17, 2025. Accessed July 20, 2026. https://tinyurl.com/3b4f6fd9
