A New Class of
Cancer Immunotherapy Requires New Approaches
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 Oncology’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. Gritstone is currently in the final preclinical stages of developing immunotherapy product candidates to target both patient-specific neoantigens and shared neoantigens and plans to introduce these candidates through clinical trials in the near future.
Our unique approach to neoantigen immunotherapy rests on two key pillars
Superior identification of tumor-specific neoantigens, using EDGE™, our proprietary artificial intelligence platform, trained on extensive data generated from human tumors; and
Delivery of these neoantigens to patients in a highly immunogenic context that is designed to drive the patient’s immune system to attack and destroy the tumor.
The first pillar of our immunotherapy is our understanding of tumor-specific neoantigens and our application to predict the presence of a patient’s unique neoantigens on tumor cells. The identification of these 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 transcribed, translated, processed and presented on the cell surface. Furthermore, these rare neoantigens are usually unique to each individual patient’s tumor. To address this challenge, Gritstone Oncology has developed a proprietary artificial intelligence platform, EDGE, using extensive data from real human tumor samples. EDGE was trained on this large dataset and 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. EDGE has shown a nine-fold 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 industry standard methods.
The second pillar of our immunotherapy platform is our ability to develop and manufacture a potent immunotherapy utilizing a patient’s tumor specific neoantigens to drive the patient’s immune system to attack and destroy tumors. Gritstone’s immunotherapy platform uses a two-part heterologous prime-boost system to accomplish this robust immune response. Grounded in traditional infectious disease vaccine immunology, this two-step immunization utilizes a viral prime and a self-amplifying mRNA boost, which has been demonstrated in preclinical studies to educate T cells to detect target neoantigens and destroy tumor cells.
Patient selection depends upon whether the tumor
displays patient-specific or shared neoantigens
*We believe that our personalized immunotherapy product candidate will have an addressable population of 70-80% of patients within common solid tumor types such as colorectal cancer and lung cancer.
For each patient, our personalized immunotherapy will start with a routine clinical biopsy. We then utilize our in-house sequencing capabilities with the tumor sample and apply our proprietary EDGE™ platform to derive a set of predicted patient-specific neoantigens likely to be presented on the patient’s tumor. Using these predicted neoantigens, we will then design a personalized immunotherapy containing the relevant neoantigens to be administered by simple intramuscular injection. We intend to deliver the immunotherapy in a community oncology setting where a vast majority of cancer patients are treated.
Routine FFPE clinical biopsy as input material
AI model for tumor antigen prediction trained on human tumor data
Patient specific predicted neoantigens inserted into Gritstone immunotherapy
Immunotherapy administered in conjuction with checkpoint inhibitors
The routine clinical biopsy used to identify personalized patient mutations can also identify patients that have common mutations within their tumor from commercially available genomic panel sequencing. These common driver mutations have been shown to produce shared neoantigens as identified by Gritstone’s EDGE platform in a subset of patients. Similar to patient-specific neoantigens, shared neoantigens are a class of immune targets that present mutated peptides on the surface of the tumor cell. Because these neoantigens are shared, an “off-the-shelf” therapy may be able to treat additional patients across multiple tumor types.
Gritstone’s EDGE™ antigen discovery platform has also identified other non-mutated immune targets, enabling opportunities for additional therapeutic modalities. These novel targets identified by EDGE™ can be addressed therapeutically using several different formats, such as adoptive T cell therapy, bispecific antibody approaches, and vaccination. We believe these discovery-stage programs have the potential to enhance the response to cancer drug therapies for many patients across multiple tumor types.Our Pipeline