Evaluation of a therapeutic vaccination strategy with motif neoepitope peptide-pulsed autologous dendritic cells for non-small cell lung cancer patients harboring a charged HLA-B binding pocket.

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PROJECT SUMMARY Lung cancer is the leading cause of cancer related deaths in the United States and the World. Inefficient prediction of functional tumor neoantigens and insufficient understanding of host anti-tumor immune responses limit optimization of immunotherapeutic approaches. We recently demonstrated that programmed cell death 1 (PD-1) inhibitors, which lead to durable responses in a minority of non-small cell lung cancer (NSCLC) patients, have greater efficacy in patients with charged human leukocyte antigen (HLA)-B binding pockets whose tumors harbor mutation(s) leading to what we have designated as “motif neoepitopes”. Motif neoepitopes lead to an amino acid substitution in the second position of a nonamer (anchor for HLA-binding), generating a change in charge from the wild type peptide in which the resultant amino acid has a charge opposite to the HLA-B binding pocket. This substitution leads to enhanced binding affinity to the corresponding HLA-B supertype demonstrated by in vitro competition assays. These data suggest that optimal presentation of motif neoepitopes by corresponding charged HLA supertypes results in effective host anti-tumor immune responses in vivo. Dendritic cell (DC)-based vaccination has emerged as a potential component for immunotherapy due to both its favorable toxicity profile and its essential role in antigen-specific T cell priming and activation. We have expertise in clinical studies evaluating a DC in situ vaccination strategy in NSCLC. In this proposal, we intend to combine DCs as functional antigen presenting cells (APCs) with putative motif neoepitopes as an innovative vaccination approach to enhance host systemic tumor-specific T cell responses and potentiate clinical benefits of current immunotherapies. We hypothesize that 1) peptides derived from motif neoepitopes are functional neoantigens in vivo that are capable of inducing host tumor-specific immune responses, and 2) autologous DCs pulsed with motif neoepitope-derived peptides, particularly at optimal conditions, will induce systemic activation of motif neoepitope-specific T cells. As part of this proposal, we are analyzing multiple biospecimens collected from our ongoing phase I trial of intratumoral injection of autologous DCs combined with PD-1 inhibition in advanced NSCLC. Collected specimens include serial blood and tumor biopsies as well as autologous DCs. We will evaluate whether exposing DCs to peptides derived from motif neoepitopes can induce tumor-specific T cell activation in co-culture experiments. We will assess the binding affinity of these peptides and the corresponding wild type peptides to their respective HLA-B supertype. We will further optimize conditions, including addition of PD-1 blockade, to achieve optimal T cell activation by autologous DCs pulsed with motif neoepitope-derived peptides. These studies will greatly enhance our understanding of the potential function of motif neoepitopes in inducing host anti-tumor immune responses, and lay the foundation for future clinical investigations of motif neoepitope-pulsed autologous DCs as a novel treatment strategy for NSCLC.