New Hope on the Horizon: KRAS Vaccine Ignites Promise for Cancer Vaccines

The immune system is always in a constant battle against varieties of pathogens. Sometimes, they win by themselves, sometimes, they need a push to attain victory. Among various means to do so, one way is to provide them with a vaccine push, where the goal is to recognize specific pathogens, like viruses or bacteria, well before an infection occurs. However, this concept of vaccination has now expanded beyond interventions that prevent disease to treat or ameliorate ongoing pathology. Along with eliciting new immune responses in naive individuals, vaccines can now be used to enhance pre-existing immunity and modulate its type to better tackle the targeted disease. Therapeutic cancer vaccines fall into this category, where they identify proteins produced by cancer cells, known as antigens, to provoke a powerful immune response to existing tumours. The preventive vs therapeutic comparisons of vaccines can be visualized in a battleground scenario, while the former’s goal is to identify the enemy's enemy's banners (pathogens) so the army can prepare for a specific battle, the latter is more akin to sending in scouts to gather intelligence on a hidden enemy encampment (the tumour).  A key difference between these two types of cancer vaccines is that the former focuses mainly on activating antibody-producing B cells, while the latter focuses on generating a strong T-cell response. Dendritic cells loaded with tumour antigens bind and activate CD8+ cytotoxic T cells, which can then mount an attack on the tumour.

  

While decades of research have yielded a growing arsenal of cancer vaccine candidates currently undergoing clinical trials, only a handful have been approved for use in patients. The effectiveness of these vaccines hinges on a complex interplay of factors, including the specific antigens chosen, the tumour's surrounding microenvironment, the unique immune response within the tumour itself, and the precise formulation of the vaccine.

KRAS, a highly mutated gene in pancreatic, colorectal, and lung cancers, has become a focal point in the relentless pursuit of a universal cancer vaccine.  The current landscape of cancer immunotherapy boasts a diverse arsenal, yet KRAS has proven a formidable foe for existing treatments due to its intracellular nature. Recently, there has been a buzz about a KRAS vaccine (ELI-002 2P) doing remarkably well in a phase 1 trial involving 25 patients whose pancreatic or colorectal cancer had KRAS G12D or G12R mutations and were at high risk of cancer returning after surgery (ClinicalTrials.gov identifier: NCT04853017). The vaccine demonstrated a good safety profile and, crucially, its ability to stimulate the immune system.  84% of patients mounted the desired immune response, with their T cells specifically recognizing and proliferating in response to cancer cells harbouring the KRAS mutation. Activating the immune system's foot soldiers is a key indicator of potential efficacy. The study observed a positive trend in another critical marker – tumour burden.  84% of patients showed reduced circulating tumour DNA, a marker for residual cancer cells. Notably, 24% of patients achieved complete clearance of detectable tumour DNA, suggesting a potential for eradicating the minimal residual disease. Perhaps the most compelling evidence is the observed correlation between a robust T-cell response and relapse-free survival. Patients who mounted a stronger immune response after vaccination exhibited a longer period without disease recurrence.

ELI-002 2P represents a novel three-pronged approach to cancer immunotherapy. This lymph node-targeted vaccine leverages amphiphile (Amph) modification to enhance delivery and efficacy. It comprises Amph-modified long peptides derived from the G12D and G12R mutations of the KRAS oncogene, alongside an Amph-modified CpG-7909 DNA sequence that agonizes Toll-like receptor 9 (TLR9). Conventional soluble vaccines often face limitations due to the small size (<20 kDa) of peptide and adjuvant components. This hinders their ability to effectively reach lymph nodes, where specialized antigen-presenting cells (APCs) orchestrate immune responses. In contrast, ELI-002 2P utilizes a clever strategy. By modifying vaccine components (both antigens and adjuvants) with amphiphilic molecules, the vaccine leverages "hitchhiking" on endogenous albumin (∼65 kDa) after injection. This approach exploits fatty-acid-binding pockets on albumin, leading to enhanced accumulation within lymph nodes and efficient delivery to APCs, triggering their activation. This robustly reprogrammed the immune microenvironment, fostering the development of high-magnitude and functionally active T-cell responses. 

The ELI-002 2P administration follows a straightforward approach. Patients receive four injections, one in each limb (arm and leg). These injections deliver peptide fragments derived from the KRAS mutation directly to nearby lymph nodes. Lymph nodes act as training centres for the immune system, housing immune cells called lymphocytes crucial for mounting an effective response. 

While these are early days, the findings from this phase 1 trial offer a glimpse of hope. The vaccine's ability to trigger a targeted immune response and potentially eliminate minimal residual disease warrants further investigation in larger clinical trials. Future studies will determine the vaccine's long-term efficacy and potential for improving patient outcomes.

Figure: Design of ELI-002 2P Amph mechanism of action and study participant disposition.

(Pant, Shubham, et al, Nature medicine (2024))

Read the article published in Nature Medicine here, ‘https://www.nature.com/articles/s41591-023-02760-3#Sec2’