Project Title: Development of Personalized Therapeutic Cancer Vaccines to Effectively Mobilize Anti-Tumor T Cell Immunity in Non-Small Cell Lung Cancer
Immunotherapies harness the body’s own natural defenses to fight cancer and can lead to durable responses in some patients, but clinical benefit has remained limited. Therapeutic vaccines derived from whole tumor lysates are a promising treatment strategy that are well tolerated and have shown promising results in early clinical trials, stimulating neoantigen-specific immune responses in a subset of patients. Yet the majority of patients are poorly responsive to vaccine treatment, underscoring the need to devise improved strategies for stimulating anti-tumor activity, and thereby preventing tumor escape. To induce robust cellular immunity against non-small cell lung cancer (NSCLC), the leading cause of cancer-related death in the US, our strategy is to optimally prime neoantigen-reactive T cells from individual NSCLC patients. We propose an innovative priming method to induce neoantigens in tumor cells prior to lysate generation, thereby enhancing the immunogenicity of each vaccine preparation. Importantly, as mice are poor models for human NSCLC we will use a novel, human cell-based vascularized microtumor (VMT) platform to assess the sensitivity of tumor cells to T-cell mediated attack at the individual patient level. Single-cell RNA sequencing (scRNAseq) will then be used to uncover mechanisms of therapeutic success vs. failure. Our goal is to advance novel approaches to effectively mobilize anti- tumor immunity, improve therapeutic vaccine efficacy and overcome resistance in NSCLC.