In a first-in-human phase I study, the AMPLIFY-201 researchers demonstrated that lymph node directed ELI-002 2P vaccination targeting KRAS driver oncogenes present in one-quarter of solid tumours is immunogenic in 84% of patients with minimal residual disease (MRD)-positive relapse after locoregional treatment. T cell responses required no selected human leukocyte antigen (HLA) patient restrictions and correlated with reduction and clearance of tumour biomarkers and a significantly improved relapse-free survival (RFS) in patients with above-median T cell responses (not reached versus 4.01 months).
ELI-002 2P cancer vaccine was safe and induced considerable T cell responses in patients with immunotherapy-recalcitrant KRAS mutated tumours. The findings are published by Dr. Shubham Pant of The University of Texas MD Anderson Cancer Center in Houston, TX, US, Dr. Eileen M. O’Reilly of the Memorial Sloan Kettering Cancer Center in New York, NY, US, and study colleagues on 9 January 2024 in the Nature Medicine.
PD1/PD-L1 checkpoint inhibitors alone or in combination with CTLA4 inhibitors are ineffective in pancreatic ductal adenocarcinoma and microsatellite stable (MSS) colorectal cancer, consistent with low numbers of antigen-specific tumour-infiltrating lymphocytes and infrequent neoantigen mutations. However, widely expressed KRAS driver mutations that are present in 93% of cases of pancreatic ductal adenocarcinoma and 50% of colorectal cancers, are attractive immunotherapy targets required for tumour survival with uniform expression throughout disease progression.
The authors explained in the background that T cells targeting KRAS mutation are not limited by immune tolerance, and on-target, off-tumour toxicity is unlikely as normal tissues lack expression. Adoptive therapy with HLA C*08:02-restricted KRAS G12D-specific T cells has resulted in responses in patients with pancreatic ductal adenocarcinoma or MSS colorectal cancer. However, KRAS mutated directed T cell therapy is restricted to select mutations and HLA alleles, requires complicated logistics, is costly to manufacture and is accompanied by potential cytokine release syndrome and neurotoxicity. In contrast, vaccination offers potential to expand endogenous KRAS mutated directed T cells across diverse HLA backgrounds, with simplified manufacturing and off-the-shelf availability.
ELI-002 2P is a three-component lymph node targeted vaccine comprising amphiphile (Amph)-modified G12D and G12R KRAS mutated long peptides as well as Amph-modified Toll-like receptor 9 (TLR9) agonistic CpG-7909 DNA. Preclinically, Amph vaccination delivered vaccine components to and activated resident antigen-presenting cells, robustly reprogramming the immune microenvironment to develop high-magnitude, functional T cell responses. Amph vaccine therapy enhanced efficacy with increased T cell expansion and tumor infiltration, leading to long-term eradication of solid tumors alongside decreased systemic toxicity.
The study team hypothesized that administration of ELI-002 2P after tumour resection in MRD setting would induce expansion of functional tumour directed KRAS mutated specific T cells, increase the potential for antitumour activity by avoiding HLA loss in late-stage disease and allow T cell action to support destruction of micro-metastatic disease, resulting in reduced tumour biomarkers and delayed radiographic recurrence.
In the latest article published in the Nature Medicine, the authors report the safety, efficacy, immunogenicity, and recommended phase 2 dose (RP2D) of ELI-002 2P in a phase I multi-cohort AMPLIFY-201 study conducted in patients who had received definitive locoregional therapy, but who were positive for MRD with high risk for radiographic relapse due to the presence of circulating tumour DNA (ctDNA) or serum tumour antigen biomarkers.
The study team treated 25 patients of whom 20 with pancreatic and 5 with colorectal cancer, and who were positive for KRAS mutated MRD based on ctDNA and/or serum tumour antigen after locoregional treatment in a phase I study of fixed-dose Amph-Peptides-2P and ascending-dose Amph-CpG-7909. The study enrolment is complete with patient follow-up ongoing. Primary endpoints included safety and RP2D. The secondary endpoint was tumour biomarker response, with exploratory endpoints including immunogenicity and RFS.
No dose-limiting toxicities were observed, and the RP2D was 10.0 mg of Amph-CpG-7909. Direct ex vivo KRAS mutated specific T cell responses were observed in 21 of 25 patients (84%) of whom 59% both CD4-positive and CD8-positive. Tumour biomarker responses were observed in 21 of 25 patients (84%); biomarker clearance was observed in 6 of 25 patients (24%) of whom in 3 with pancreatic and in 3 with colorectal cancer; and the median RFS was 16.33 months.
Efficacy correlated with T cell responses above or below the median fold increase over baseline (12.75-fold): median tumour biomarker reduction was −76.0% versus −10.2% (p < 0.0014), and the median RFS was not reached versus 4.01 months (hazard ratio 0.14; p = 0.0167).
Despite the limitations noted for the single-arm, signal-seeking phase I design, which precludes assessment of causality, the preliminary signals observed warrant a randomised phase II study according to the study team. Development of ELI-002 is proceeding with a phase I and randomised phase II study of a 7-peptide formulation. This will offer additional opportunities to evaluate the activity of Amph vaccines in malignancies driven by a broad spectrum of KRAS mutations.
The study was sponsored and funded by Elicio Therapeutics.
Pant S, Wainberg ZA, Weekes CD, et al. Lymph-node-targeted, mKRAS-specific amphiphile vaccine in pancreatic and colorectal cancer: the phase 1 AMPLIFY-201 trial. Nature Medicine; Published online 9 January 2024. DOI: https://doi.org/10.1038/s41591-023-02760-3