Infectious Diseases | Immuno-Oncology | Rare Diseases
mRNA-Based Personalized Cancer Vaccines
We are also applying our mRNA technology to the emerging field of immuno-oncology, also often referred to as immunotherapy. This therapeutic area involves harnessing the body’s immune system to identify and kill cancer cells in the same way the immune system identifies and targets infection from pathogens.
Recent breakthroughs in cancer immunotherapy have demonstrated that powerful antitumor responses can be achieved by activating antigen specific T cells in a variety of cancer settings. Despite these advances, many patients' cancer responds only partially or does not respond at all all to these anti-cancer therapies. One approach is to administer a cancer vaccine that encodes for peptides containing mutations found in their cancer, i.e., to create a personalized cancer vaccine composed of neoantigens unique to a patient’s tumor. Moderna’s Immuno-Oncology programs are currently focused on two main areas: therapeutic vaccines and intratumoral immuno-oncology therapeutics.
Therapeutic Vaccines – Personalized Cancer Vaccines
Moderna is creating individualized, mRNA-based personalized cancer vaccines to deliver one custom-tailored medicine for one patient at a time. Through next-generation sequencing, we identify mutations found on a patient’s cancer cells, called neoepitopes. Neoepitopes can help the immune system distinguish cancer cells from normal cells. Using algorithms developed by our in-house bioinformatics team, we predict 20 neoepitopes present on the patient’s cancer that should elicit the strongest immune response, based on unique characteristics of the patient’s immune system and the cancer's particular mutations. We then create a vaccine that encodes for each of these mutations and load them onto a single mRNA molecule.
Once injected into the patient, the vaccine has the potential to direct the patient’s cells to express the selected neoepitopes. In turn, this may help the patient’s immune system better recognize cancer cells as foreign and destroy them.
Leveraging our rapid cycle time, small-batch manufacturing technique and digital infrastructure, we work to manufacture and supply each individually manufactured personalized cancer vaccine to the patient rapidly.
mRNA-4157 also has the potential to enhance clinical outcomes associated with checkpoint inhibitor therapies. In 2016, Moderna and Merck formed a strategic alliance to develop mRNA-4157 in combination with Merck’s anti-PD-1 therapy, KEYTRUDA. We are currently conducting a Phase 1 study evaluating the safety, tolerability, and immunogenicity of mRNA-4157 alone in subjects with resected solid tumors and in combination with KEYTRUDA in subjects with unresectable solid tumors (KEYNOTE-603).
Therapeutic Vaccines – KRAS Cancer Vaccine
Although monotherapy checkpoint inhibitors can provide significant benefit for some cancer patients, many patients have incomplete or no response to therapy, presenting a need for alternative approaches to stimulate antitumor immunological responses. We are developing an mRNA-based approach with Merck to advance a cancer vaccine that encodes for the four most common KRAS mutations. KRAS is a frequently mutated oncogene in epithelial cancers, primarily in non-small cell lung cancer (NSCLC), colorectal, and pancreatic cancers.
We have designed an mRNA vaccine to generate and present KRAS neoantigens to the immune system, which we intend to test alone and in combination with Merck’s KEYTRUDA. Given that a T cell response against a single antigen has the potential to eradicate cancer cells, we believe that delivering multiple neoantigens could increase the probability of a successful treatment outcome for a patient. We are advancing this program through clinical trials in collaboration with Merck, which will lead the clinical development program.
Intratumoral Immuno-Oncology Therapeutics
There have been several advances in the treatment of cancer through immune-mediated therapies in recent years. However, the outlook for many patients with advanced cancer remains poor, especially in tumors that have little immune system engagement and are therefore termed immunologically “cold.” We aim to activate the tumor microenvironment with our mRNA therapeutics, in conjunction with a checkpoint inhibitor, to activate the immune system against these otherwise immunologically cold tumors.
Our intratumoral immuno-oncology efforts are focused on driving robust, specific anti-cancer T cell responses, transforming cold tumors with an immunosuppressive microenvironment into one that is immunologically “hot” thereby resulting in a productive anti-cancer immune response. Our goal is to discover and develop locally administered, or intratumoral, immune-mediated therapies to deliver mRNA encoding for potent immunestimulatory proteins that can act at the site of the injected tumor, reduce systemic toxicities, and potentially create an “abscopal effect” where distal tumor sites are also impacted. These may be combined with checkpoint inhibitors to boost the response. All of the mRNAs utilized in this modality are designed to decrease the amount of protein that could be made in hepatocytes through incorporation of microRNA binding sites, thus potentially reducing off-target effects and resulting in better tolerability.