Neoantigen-based cancer immunotherapies
We are witnessing one of the most accelerated scientific efforts in response to the COVID-19 pandemic. Among these efforts that include sequencing the virus, designing the very first prophylactic vaccines, conducting clinical trials, demonstrating efficacy, and getting regulatory approvals in record time, many companies have leveraged their vaccine technology and infrastructure to help combat the current pandemic. While a 30,000 bp virus is relatively simple in nature to understand in terms of structure, function, and immunogenicity, applying the same technology and lessons learned to design vaccine therapeutics for complex diseases like cancer is a much more demanding task.
Indeed, the oncology field has been investigating cancer vaccines for years, investing specifically in neoantigen-based designs targeting solid tumors. The concept of packaging immunogens from the patient tumor into a vaccine to mount an immune response against the tumor has materialized in the form of numerous designs and approaches currently in clinical trials. To name a few examples below:
- Moderna is exploring its mRNA technology as a therapeutic modality for personalized neoantigen-based cancer vaccines, mRNA-4157. The mRNA encodes 20-34 neoantigens unique to each patient’s tumor. Preliminary data from the Phase 1 dose escalation study [Burris III et al, poster presented at ASCO 2019] demonstrates safety, tolerability and immunogenicity of the vaccine evidenced by CD8+ T cell responses to the selected neoantigens. Results from the dose expansion study [Bauman et al., poster presented at SITC 2020] point to a favorable clinical outcome in HPV-negative HNSCC patients and supports expansion of this patient cohort. There is also an ongoing randomized Phase 2 clinical trial in combination with pembrolizumab, an immune checkpoint inhibitor.
- BioNTech has also developed an mRNA platform for individualized cancer immunotherapy targeting up to 20 neoantigens, RO7198457. Results from the Phase 1b study [Braiteh et al, poster presented at AACR 2020] indicate a lower-than-expected response rate albeit with 49% of patients achieving stable disease. The vaccine is also reported to have elicited CD8+ T cell responses specific to the selected neoantigens. Similarly, a randomized Phase 2 clinical trial is ongoing in combination with pembrolizumab.
- Neon Therapeutics (currently BioNTech-US) recently published major findings from its Phase 1b study investigating NEO-PV-01, a peptide vaccine consisting of up to 20 neoantigens [Ott et al, 2020]. The vaccine had demonstrated safety, tolerability and immunogenicity, and leads to neoepitope spreading associated with progression-free survival. The company has also expanded programs to include a neoantigen-specific T cell product for adoptive cell therapy, NEO-PTC-01, currently in the dose-finding part of the Phase 1 clinical trial.
- Genocea also shared recent results from its Phase 1/2a clinical trial of GEN-009, a neoantigen peptide vaccine candidate that consists of up to 20 peptides and recently published on their ATLAS bioassay for neoantigen selection [Lam et al, 2021]. The data demonstrates that the vaccine is safe, well tolerated, and immunogenic. Results from GEN-009 are now informing a follow-up neoantigen T cell therapy program, GEN-011.
Challenges of Neoantigen identification and selection
Somatic mutations are a hallmark of cancer and result in mutant peptides, that are called neoantigens. These neoantigens are immunogens considered tumor-specific and foreign such that they can be recognized and efficiently eliminated by the host’s immune system. Therefore, neoantigens became ideal targets for therapy design including cancer vaccines and cell therapies. The first step in building an efficacious neoantigen-based cancer vaccine is to accurately identify, select, and prioritize immunogenic neoantigens. This is achieved partly through whole exome and transcriptome sequencing of the tumor to detect various source mutations including single nucleotide variants, insertions, deletions, fusions, and others. It also requires accurate HLA typing from whole exome sequencing of the germline sample to derive the patient’s HLA genotype for neoantigen predictions. This is followed by complex computational methods to characterize the neoantigens and synthesize the top candidates for vaccine development.
There are a number of parameters that can be considered in defining an immunogenic neoantigen and these are related to each step of neoantigen biology. Integrated bioinformatic pipelines and predictive models can provide information on peptide cleavage site, predicted binding affinity of the peptide to patient specific HLA alleles, binding stability, peptide presentation, expression abundance, clonality, alterations in the antigen presenting machinery, and others. There is also significant variability in these pipelines in terms of which parameters and neoantigen features scientists decide to include in the prioritized list of potential neoantigen candidates.
The Parker Institute brought together a team of researchers from academia, industry and non-profit centers working in the field of neoantigen characterization for therapy design. They formed the Tumor Neoantigen Selection Alliance (TESLA) with the objective of standardizing the process of accurately and reproducibly identifying neoantigens capable of eliciting an immune response, and creating a validated dataset that the community can use for effective benchmarking. TESLA designed a study for comparing key parameters to better predict neoepitope immunogenicity [Wells et al, 2020]. The study included six tumor and normal samples from melanoma and non-small cell lung cancer. All samples were sequenced and analyzed using a single source. The same genomic information which consisted of whole exome sequencing data from the tumor and normal, whole transcriptome sequencing data from the tumor, and HLA typing was provided to twenty-eight participants in this exercise. Participants were asked to generate a list of ranked neoantigens from this data using their own algorithms. TESLA then took the top neoantigens as defined by each participant, a list of ~600 neoantigens in total, synthesized these peptides, and performed in vitro testing to validate whether these selected neoantigens are able to bind to the patient’s HLA alleles and form a multimer. They found that only 6% of the top ranked peptides were actually immunogenic and observed substantial diversity in the features used by each participant in defining what is an immunogenic neoantigen. They then looked at the overlapping features enriched in the immunogenic set of peptides and identified key essential metrics that defined immunogenicity.