Dr. Grippin will investigate how mRNA vaccines can be combined with radiation therapy to improve lung cancer treatment outcomes. Preliminary data shows that NSCLC patients who received mRNA vaccines alongside radiation and immune checkpoint inhibitors had better survival rates. The study aims to optimize this combination therapy to overcome resistance in immune-refractory lung cancer as well as develop enhanced mRNA vaccine formulations. The findings will provide additional data for clinical trials integrating mRNA vaccines into standard lung cancer care, potentially making immunotherapy more effective.
- Research Summary
Immune checkpoint inhibitors (ICIs) help the immune system fight cancer, but many tumors still resist these therapies. mRNA vaccines, like those originally developed for COVID-19, may help boost the immune system’s response to cancer, but scientists don’t fully understand how to use them effectively. We have spent a decade studying mRNA vaccines, and recently discovered a new way that they generate immune responses against tumors. On a high level, we found that mRNA vaccines, even when they are directed against infectious diseases like COVID, activate the immune system to be on high alert for cancer. Since radiation acts in a similar way, we hypothesize that both of those therapies will synergize to help each other work more effectively.
Our early research in both patients and mice supports this hypothesis, demonstrating that patients who received radiation prior to mRNA vaccines had improved survival relative to their peers. To confirm this hypothesis further, we will study how the timing of radiation therapy affects the ability of mRNA vaccines to shrink tumors. We will also experiment with different mRNA vaccine formulations that we think will make them stronger immune stimulants. By combining mRNA vaccines and radiation, we hope to create more effective, accessible, and long-lasting cancer immunotherapies for patients who need them most.
- Technical Abstract
Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, yet many tumors remain resistant. mRNA vaccines have emerged as a promising strategy to enhance antitumor immunity, but their optimal integration with radiation therapy is not well understood. Our recent clinical findings suggest that mRNA vaccines potentiate ICI responses through mechanisms linked to Type I interferon (IFN), a key mediator of radiation-induced immune activation. Notably, we found that patients with non-small cell lung cancer (NSCLC) and metastatic melanoma who received an mRNA vaccine within 100 days of ICI initiation had nearly double the median overall survival (OS), with the most pronounced benefit observed in those receiving pre-vaccine radiation therapy (Grippin, Nature, In Revision). Based on this data, we hypothesize that methods to increase Type I IFN signaling including pre-vaccine radiation will augment responses to mRNA vaccines. To investigate this hypothesis, we propose the following Specific Aims:
1. Interrogate the interactions of radiation and mRNA vaccines. Mice will receive mRNA vaccines, ICIs and radiation therapy before, concurrently, or after vaccination. Tumor growth and immune responses will be analyzed to assess whether pre-vaccine radiation enhances mRNA vaccine efficacy via Type I IFN signaling.
2. Engineer next-generation mRNA cancer vaccines that maximize Type I IFN production. This aim will test the hypothesis that modifications to mRNA vaccines that enhance Type I IFN stimulation will enhance their antitumor effects.
This work will provide critical mechanistic insights into how radiation therapy synergizes with mRNA vaccines and guide the development of more effective cancer immunotherapy strategies. These findings will lay the foundation for clinical trials integrating mRNA vaccines into radiation regimens, with the potential to overcome resistance and improve patient outcomes in immune-refractory cancers.