THE NEOANTIGEN REVOLUTION
The advent of Next Generation Sequencing has now made it possible to sequence the entire genome or exome (coding regions) of tumor and matched normal cells to identify all of the mutations that have occurred (mutanome). The resultant mutanome will then be used to personalize each cancer immunotherapy based on the patient’s genomics to improve patient outcomes. Neoepitopes represent an untapped and promising therapeutic area for cancer treatment. Prior cancer vaccines target Tumor Associated Antigens, which are expressed on both healthy and cancerous cells and thus, leading to toxicities. Exploiting natural immune-surveillance, we direct the immune system into targeting the cancer cells specifically expressing neoepitopes.
Tumor Associated Antigens (TAAs)
TAAs are self-derived immune targets overexpressed on cancerous cells. While particular care is taken to find TAAs that are not expressed in healthy tissues, these antigens retain intrinsic safety issues which can lead to activating immune responses against normal tissues [1, 2]. Furthermore, breaking central tolerance to these self antigens can be challenging, limiting the efficacy of TAA-based therapies.
Tumor Specific Antigens (TSAs)
TSAs, on the other hand, are immune targets uniquely expressed by cancerous cells and they are ideal for developing precision cancer immunotherapies. Notably, TSAs are not affected by central tolerance mechanisms and avoid inadvertent targeting of healthy tissues, important factors for efficacy and safety.
SHARED VS PERSONALIZED:
The vast majority of neoepitopes are ‘private’ or unique to each patient’s tumors . A limited number of neoepitopes are shared across patients (‘shared’ neoepitopes) - the frequency of these shared neoepitopes varies by tumor type.
Shared neoantigens are attractive targets for development of an 'off-the-shelf' therapy, but only a subset of patients can benefit from this approach, and in any given subject, such therapies would target only a very narrow set of available tumor specific antigens, leading to tumor immunoediting and immune escape [4, 5].
In a bladder cancer study conducted by EpiVax Therapeutics, we found shared neoantigens in <40% of 400 patient samples tested, the most frequent shared neoantigen being detected in only 5% of samples. This suggests that an ‘off-the-shelf’ vaccine would have to include a significant number of shared neoantigens to be effective in even a minority (<40%) of patients.
Private, or personalized neoantigens offer the advantage of targeting each tumor specifically. This multiprong approach limits the tumor's ability to avoid immune detection, enhancing clinical outcomes.
EpiVax Therapeutics' uses a sophisticated, proprietary immunoinformatics platform, Ancer, to discover immunogenic, private neoantigens that are used for cancer immune therapy.
EVT-PCV-001 is a personalized cancer vaccine designed with Ancer. Our unique design and manufacturing process allows us to go from biopsy to vaccine administration in only 4 weeks, successfully positioning us in the neoadjuvant treatment setting, improving therapy outcome.
Safety of EVT-PCV-001 will be first evaluated in the muscle invasive bladder cancer setting, with Phase 1 trial in 2023.