PROJECT SUMMARY/ABSTRACT This project describes a 5 year training program for a career as a physician-scientist with the long term goal of establishing a research program within the field of translational thoracic oncology. The applicant is currently an Instructor of Medicine in the Section of Interventional Pulmonology and Thoracic oncology conducting research in developing biomarkers for the treatment selection and monitoring of patients with lung cancer. The research focus of this proposal is to develop molecular markers to better identify the subgroup of patients that will respond to PD1/PDL1 therapies in order to avoid unnecessary toxicities, reduce costs, and enable more appropriate therapies to be delivered. This goal will be accomplished in three complementary specific aims. In Specific Aim 1, mRNA expression analyses will be performed on tumor tissue from advanced lung cancer patients treated with anti-PD1 therapy to determine the association of specific gene signatures with treatment response. In Specific Aim 2, a novel approach to acquire fresh tissue samples for immunophenotyping will be utilized to prospectively determine the ability of deep T cell phenotyping and functional assays to predict response to anti-PD1/PDL1 therapy using multi-parametric flow cytometry. In Specific Aim 3, a newly developed technique that enables the quantitative measurement of circulating PDL1 exosomes will be utilized to determine the association of pretreatment and on-treatment exosomal PDL1 expression levels to predict clinical outcomes in non-small cell lung cancer patients receiving checkpoint blockade. The training component of this proposal includes formal coursework, participation in a rich environment of post-doctoral lectures in thoracic oncology/tumor immunology, acquisition of advanced laboratory techniques (with a focus on bioinformatics and advanced flow cytometry), and individual mentoring. This project will take place under the supervision of Dr. Steven Albelda who is the Director of the Thoracic Oncology Laboratory at the University of Pennsylvania and Co-Director of the Abramson Cancer Center’s Translational Center of Excellence for Lung Cancer Immunobiology, and Dr. Anil Vachani who is the Director of Clinical Research for the Section of Interventional Pulmonology and Thoracic Oncology at Penn. Dr. Albelda and Dr. Vachani have mentored over 100 trainees. In addition, an advisory committee of distinguished scientists will provide experimental assistance, intellectual guidance, and career advice throughout the duration of this award.

PROJECT NARRATIVE The development of immune checkpoint inhibitors has ushered in a new era of antineoplastic therapy for the treatment of non-small cell lung cancer. However, in the majority of trials, response rates were limited to ~20- 50% of patients. In this application, the candidate outlined a detailed scientific plan to develop molecular markers to better identify the subgroup of patients that will respond to immunotherapeutic agents in order to avoid unnecessary toxicities, reduce costs, and enable a more appropriate therapy to be delivered.