Pursuing More Potent and Durable Immune Responses Through Vaccine Innovation

State-of-the-art artificial intelligence platform (EDGE™) to identify critical T cell targets

Next-gen vectors, ChAd and self-amplifying mRNA*, to drive potent and durable immune responses suited to the clinical context

In-house GMP manufacturing enables personalized and off-the-shelf products (clinical stage and scale-up)

Immunogen design is key component of novel vaccine formats – must be studied in clinical trials

Bench-to-bedside-to-bench: innovative product development pushes scientific boundaries

1. Identification

EDGE™ (Epitope Discovery for GEnomes)

The first platform of our immunotherapy is our understanding of antigens and neoantigens, and specifically which ones will be transcribed, translated, processed and presented on a cell surface by human leukocyte antigen (HLA) molecules; and therefore will be visible to T cells. We accomplish this through our proprietary artificial intelligence-based platform, EDGE™ (Epitope Discovery for GEnomes).

Developing cancer immunotherapies that include tumor-specific neoantigens presents a challenge due to their nature – tumors typically have hundreds of mutations, but only a small percentage of those mutations result in true tumor-specific neoantigens that are leverageable. To address this challenge, we trained EDGE’s novel integrated neural network model architecture with millions of datapoints from hundreds of tumor and normal tissue samples from patients of various ancestries. This enables us to use sequence data from a patient’s routine biopsy to predict which mutations will generate tumor-specific neoantigens most likely to be presented on the tumor cell surface by the HLA. EDGE has shown a significant improvement in accuracy for predicting tumor presented peptides in comparison with publicly available approaches. We believe that mutations selected by our EDGE platform have a much higher likelihood of being useful targets for immunization than mutations selected using previous methods.

Vaccines against viruses ideally generate both neutralizing antibody responses to whole proteins on the virus surface, and also T cell responses to the short fragments of viral proteins which are displayed on the surface of virus-infected cells (once inside a cell, a virus is invisible to antibodies which operate outside the cell). All viral proteins are foreign to the human immune system, but only short fragments of proteins (called peptides) are displayed on the cell surface by HLA and visible to T cells. The specific fragments presented will vary between subjects depending upon the HLA type of the subject (conceptually similar to someone’s blood type but more complex). Identification of key viral protein fragments that can drive strong T cell responses is an output of Gritstone’s EDGE platform.

View Publication in Nature Biotechnology: Deep Learning Using Tumor HLA Peptide Mass Spectrometry Datasets Improves Neoantigen Identification

2. Delivery

Proprietary Vaccine Platform

The second platform is our ability to embed the immunogen within our proprietary delivery systems or vectors to drive generation of T cells and neutralizing antibodies (nAbs), and stimulate the immune system to attack and destroy diseased cells. Gritstone uses these proprietary vectors, chimpanzee adenovirus (ChAd) and self-amplifying mRNA (samRNA), independently and in combination across our clinical programs.

Approach To Cancer

With the development and commercialization of immunotherapy drugs such as checkpoint inhibitors, the field of immuno-oncology is transforming the treatment of patients with cancer. However, cures remain elusive, and many cancer patients experience only modest clinical benefit.

A challenge facing the field of immuno-oncology is to develop new approaches to drive potent, tumor-specific immune responses that provide therapeutic benefit to a large number of patients.

Gritstone’s scientific founders published an important discovery in immuno-oncology: in patients with solid tumors who respond to checkpoint inhibitors, mutations in the tumor’s DNA produce critical new targets. These targets, called tumor-specific neoantigens, are unique to tumor cells and can be recognized and targeted for destruction by the patient’s own immune system.

Neoantigens represent a novel class of targets for advancing cancer immunotherapy and have been validated in cancer patients as critical T cell targets. However, the identification of neoantigens presents a key therapeutic challenge. Some tumors have hundreds of mutations, but only a minority result in true tumor-specific neoantigens found on the surface of tumor cells – making them difficult to find and target appropriately.

Neoantigens can be classified as either individualized, meaning each patient has their own unique neoantigens, or shared, in which common driver mutations are found across some patients.

Watch how Gritstone Hopes to Cure Cancer

Infectious Disease Treatment

Given the well-established role of T cells in the elimination of virally infected cells, Gritstone’s technologies may also prove highly beneficial in the treatment of infectious diseases. Our vaccine platform can accommodate a large cassette payload capacity, enabling the inclusion of multiple viral antigens as immune targets. Additionally, our platform has been clinically validated, with demonstrated safety and clinical benefit in immunocompromised cancer patients. Together, these attributes, as well as preclinical data showing the induction of potent and durable immune responses (including memory) to simian immunodeficiency virus (SIV) epitopes, make this a potentially potent treatment approach in the fight to cure human immunodeficiency virus (HIV) and other infectious diseases.


Infectious Disease Prevention

Today’s vaccines have demonstrated the ability to generate a strong antibody responses against viruses, including SARS-CoV-2. However, antibody responses may wane and viruses mutate over time, reducing clinical protection.

In multiple studies against COVID-19, data has been generated demonstrating that inducing immune responses against epitopes in conserved regions of the virus can lead to broader immune response and potentially broader protection. Additionally, analysis of blood from convalescent COVID-19 patients show that recovered patients have both antibody immune and T cell responses.

Within our CORAL program, Gritstone is developing multiple vaccine candidates designed to deliver Spike and additional SARS-CoV-2 T cell epitopes against COVID-19 using its novel vector, self-amplifying mRNA (samRNA). We believe approach could offer the potential for more durable protection and broader immunity against SARS-CoV-2, and could serve as proof-of-concept for application of this approach against a variety of other infectious diseases.

Scientific Publications

View Publications