Colorectal carcinoma (CRC) and pancreatic ductal adenocarcinoma (PDAC) are the second and third leading causes of cancer death, respectively, with standard locoregional treatment for resectable disease resulting in a 5-year survival rate of less than 20% and few effective treatments for recurrence. PD1/PDL1 checkpoint inhibitors alone or in combination with CTLA4 inhibitors are ineffective in PDAC and stable microsatellite carcinoma (MSS) due to the low number of antigen-specific tumour-infiltrating lymphocytes (TILs) and rare neoantigen mutations. However, the prevalent KRAS mutations (93% in PDAC and 50% in CRC) are considered ideal targets for immunotherapy as they are necessary for tumour survival. mKRAS-specific T cell-based therapies have shown positive responses, but are limited to certain mutations and HLA alleles and are associated with complicated logistical processes and high costs.
ELI-002 2P is a promising therapy, a three-element vaccine targeting the lymph nodes. The special formulation enables effective delivery to the lymph nodes, activation of antigen-presenting cells and stimulation of robust immune responses. Preclinical studies have shown increased efficacy of the vaccine with T-cell expansion and tumour infiltration leading to long-term eradication of solid tumours with reduced systemic toxicity.
The AMPLIFY-201 trial evaluated the efficacy of the ELI-002 2P vaccine in 25 patients with colorectal carcinoma (CRC) and pancreatic ductal adenocarcinoma (PDAC). Patients undergoing definitive locoregional treatment received the vaccine containing modified mKRAS G12D and G12R peptides and CpG-7909 Toll-like receptor 9 agonist DNA. The multicentre, open-label Phase I study was conducted between 4 October 2021 and 6 September 2023 in five cohorts at seven centres in the US.
The immune response was large, with an average 58-fold increase from baseline, indicating strong activation of mKRAS-specific T cells. The duration of the response was assessed at up to 8.5 months and showed robust persistence of the immune response.The efficacy of the vaccine was demonstrated by the significant reduction in tumour biomarkers in 84% of patients, with 44% showing a 30% reduction, 32% a 50% reduction and 24% complete elimination of biomarkers.
A significant improvement in relapse-free survival (RFS) was observed in patients with a T-cell response above the median. These results are particularly promising considering that the presence of ctDNA or persistently elevated CA19-9 levels after pancreatic cancer therapy are associated with rapid relapse and high mortality.
The link between the vaccine-induced increase in the mKRAS-specific immune response and clinical outcomes is clear. Patients with a T-cell response above the median had a significant reduction in tumour biomarkers and longer relapse-free survival compared to patients with a T-cell response below the median.
The recommended dose was 10mg, which was well tolerated and showed a consistent reduction in tumour biomarkers and induction of mKRAS-specific T cell responses. A reduction in tumour biomarkers and an induction of mKRAS-specific T-cell responses were also observed in patients receiving the highest dose (10mg).
The vaccine's safety was confirmed, with only grade 1-2 side effects and no serious events. Despite the strong cellular immune responses induced, no T-cell related adverse events, such as cytokine release syndrome, were observed. In addition, no autoimmunity-related safety events were reported. The main toxic effects were minor and localised, as is usual for vaccine administration.
The ELI-002 2P vaccine was designed to maximise T cell responses against mKRAS neoantigens. The broad antigen coverage and lack of HLA restriction suggest a potential advantage over adoptive T-cell therapy approaches. The study design included patients with MRD to optimise the T cell to tumour ratio. The vaccine was able to boost both existing and newly generated T cell responses, suggesting promising anti-tumour activity.
ELI-002 offers the practical advantage that it does not need to be specifically formulated for each individual and could potentially be used to develop T cell-specific neoantigens. Combination with targeted therapies or immunotherapies could further improve clinical outcomes. Despite the study limitations, the preliminary observations are promising and support progress towards randomised Phase II trials. ELI-002 is a potential option for various solid tumours and demonstrates the key role of T cell responses in cancer therapy.
In a nutshell, the ELI-002 2P vaccine has demonstrated safety, immunogenicity and anti-tumour activity in patients with CRC and PDAC, paving the way for further Phase II trials. The extensive data provides a detailed insight into the immunological response and clinical outcomes, and reinforces the enthusiasm for this new therapy's potential.