Immunogenic peptide priming of dendritic cells for RET+ NSCLC
This project will explore the use of neoantigens to evaluate immunogenic priming of dendritic cells (DC) in RET+ NSCLC. Neoantigens are short protein fragments present only in cancer cells that bind to genetically encoded proteins known as human leukocyte antigens (HLA). Dr. Cummings will use features of HLA to predict which cancer-specific protein fragments best match an individual’s immune system, utilizing a biobank of RET-rearranged NSCLC biospecimens. This approach could help identify optimal immunogenic targets, that could be translated into a pathway for clinical use of personalized DC vaccines.
- Research Summary
RET-rearranged non-small cell lung cancer (NSCLC) is a rare subtype of lung cancer that is driven by growth signals triggered by RET activation. RET-specific inhibitors are effective initially, but most benefit from this treatment for only 1-2 years before additional treatment is needed. Chemotherapy is a widely-available option but typically provides less than six months of benefit, and it is unclear whether immunotherapy alone or in combination with chemotherapy is a better option. Findings from other gene-rearranged NSCLC studies, particularly those on ALK-rearranged NSCLC, suggest that immunotherapy works better when the immune system is better exposed to abnormalities created by the gene-rearrangement. These are neoantigens, or short protein fragments present only in cancer cells that bind to human leukocyte antigen (HLA), a scaffold that displays these protein fragments to the immune system. One issue with this approach is that these fragments have to be specifically matched to the immune system of an individual, and even the most common forms of HLA are only found in 20% of people. This means that these types of approaches would be applicable to at most 1 out of 5 people with RET-rearranged NSCLC. Our techniques broaden this approach by using features of HLA to predict which cancer-specific protein fragments best match an individual’s immune system (motif neoepitopes), including neoantigens from RET rearrangements and those predicted from the individual’s tumor. We propose to use our biobank of RET-rearranged NSCLC biospecimens, which have not been previously analyzed, to determine whether we can detect and elicit enhanced immune responses with motif neoepitopes, neoantigens related to RET-rearrangements, or other predicted neoantigens. We can then offer this approach in a currently open clinical trial investigating immune system optimization through an application to the FDA.
- Technical Abstract
RET-rearranged non-small cell lung cancer (NSCLC) presents challenges in management following progression on selective tyrosine kinase inhibitors (TKIs). Platinum-based chemotherapy and docetaxel are available options but are without durable benefit. Real world data with single-agent and combination chemo-immunotherapy suggests modest benefit and possible efficacy if immunotherapy-based approaches are appropriately optimized. For the past decade, our group has meticulously curated hundreds of NSCLC biospecimens including matched tissue and blood from multiple timepoints, including 7 RET-rearranged NSCLC cases that have not previously been analyzed. We have extensive expertise in neoepitope prediction and personalized immunotherapy through dendritic cell (DC)-based vaccination. Our most recent collaboration enabled functional assessments of T-cells through nanovial-based affinity repertoires, further enhancing our ability to predict and translate immunogenic peptides through a personalized vaccine-based program. We propose to use our RET-rearranged NSCLC biospecimens to systematically study T-cell-specific responses to identify optimal immunogenic peptide targets, an approach that could be translated in our currently open and approved DC vaccination trial (NCT03546361) through single patient exemptions.
