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Gritstone's Proprietary Technologies

Our unique approach to immunotherapy rests on two key pillars

1.

Target
Identification

Gritstone EDGE™:
Accurate identification of antigens that can be recognized by the immune system on tumor or virally-infected cells; and

2.

Antigen
Delivery

Immunogenic vaccine platform:
Develop and manufacture potent immunotherapies containing these antigens to potentially drive the patient’s immune system to specifically attack and destroy disease-causing cells.

What is a Tumor Antigen?

A small protein on the surface of a tumor cell that functions as the target for T cell mediated tumor death.

1.
Lineage
Specific

Antigens restricted to a certain normal cell type or lineage

2.
Shared Tumor-Associated Antigens

Antigens present in normal cells and overexpressed in cancer cells

3.
Shared Tumor-Specific Antigens

Antigens found in testis and tumor tissue that are functionally tumor specific

4.
Tumor-Specific Neoantigens

Antigens derived from mutated proteins in tumor cells

Increasing Tumor Specificity
1. Identification

Gritstone EDGE™

The first pillar 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 the use of Gritstone EDGETM, our proprietary machine learning-based platform.

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. 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, but 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 Drives Potent Immune Response

The second pillar is our ability to develop and manufacture potent immunotherapies utilizing (neo)antigens to drive the patient’s immune system to attack and destroy diseased cells. Gritstone’s vaccine platform uses a two-part heterologous prime-boost system to accomplish this robust immune response. Grounded in infectious disease vaccine immunology, this two-step immunization utilizes a viral prime and a self-amplifying mRNA boost. Our immunotherapies are designed to educate the patient’s T cells to recognize and attack diseased cells displaying the encoded antigens.


Approach Towards Cancer Therapeutics

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 new 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 patient-specific, 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

 

Approach Towards COVID-19

First generation COVID-19 vaccines generate a strong antibody response against SARS-CoV-2, the virus that causes COVID-19. These vaccines elicit neutralizing antibodies that can recognize the surface Spike protein of the virus and attack it before it infects cells. However, antibody responses may wane over time and long-term durability of protection remains unknown. Additionally, mutations in SARS-CoV-2 continuously arise, including in the Spike protein, and may further reduce clinical protection derived from vaccine-induced neutralizing antibodies to Spike.

Analysis of blood from convalescent COVID-19 patients show that recovered patients have both T cell and antibody immune responses. This is expected since T cells play a fundamental role in protective immunity against viruses. If a virus successfully evades neutralizing antibodies and infects a cell, the cell displays pieces of the virus on its surface, which T cells can recognize. Since T cells remember what viruses look like, they may provide longer, more robust immunity, complementing antibody-based immunity. Mutations in the Spike protein may reduce protection by antibodies (since the antibody target has changed its shape) and T cell immunity to different viral proteins may provide a second layer of clinical protection.

Gritstone is developing a COVID-19 vaccine, CORAL, that has the potential to maximize both T cell and antibody responses to Spike and other viral proteins. Additionally, by using multiple viral targets in our vaccine, some of which are conserved between different viral strains (e.g. SARS and SARS-CoV-2) it may have pan-SARS/coronavirus potential to protect against future coronavirus pandemics.

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Approach Towards HIV

Gritstone’s prime-boost vaccine platform is designed to elicit a significant T-cell response (particularly CD8+ cytotoxic T cells) against disease-specific targets that are engineered into the vaccine. Given the well-established role of CD8+ T cells in the elimination of virally infected cells, this approach may prove highly beneficial in the treatment of infectious diseases, such as HIV. The vaccine platform can accommodate a large cassette payload capacity, enabling the inclusion of multiple viral antigens as immune targets. Additionally, the 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).

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