Development of markers to predict response to immunotherapy in NSCLC

2018

Jeffrey Thompson, MD

University of Pennsylvania

Philadelphia

Currently, three immune checkpoint inhibitors are approved by the FDA for the treatment of a subset of advanced-stage NSCLC. However, immunotherapy is a costly treatment regimen and comes with a unique side effect profile because of the inhibitors’ ability to cause inflammatory tissue damage. At present, the PD-L1 protein is used as a biomarker to predict which patients may respond to immunotherapy. Unfortunately, presence or absence of PD-L1 protein may not be an accurate predictor of response. Dr. Jeffrey Thompson is studying how we can develop more accurate biomarker signatures that may not only predict response to immunotherapy but may also determine which patients will develop treatment-related side effects. He will develop a novel blood-based liquid biopsy approach that will enable doctors to predict which patients will respond to immunotherapy drugs.

Research Summary

Lung cancer is the leading cause of cancer-related death in both men and women worldwide. The majority of patients initially present with late-stage disease with a 5-year survival rate as low as 5%. Improved understanding of how the immune system interacts with tumor cells has enabled the development of specific drugs that release the brakes off of the immune system allowing these immune cells to attack and kill cancer cells. These immunotherapeutic drugs have shown great promise for the treatment of lung cancer, but in the majority of clinical trials, only about 20-50% of patients respond. To date, measurement of a protein called PDL1 that is expressed on the tumor cell surface has been the most commonly used marker to predict which patients will respond to these therapies. However, even when high expressers of PDL1 are selected to receive immune targeted agents, less than half of patients respond. In addition, these novel drugs have significant economic costs and are associated with drug-related toxicities in 20-30% of patients. Thus, the goal of this proposal is to develop better predictors of response to immunotherapy in patients with lung cancer in order to avoid unnecessary toxicities, reduce costs, and enable a more appropriate therapy to be delivered. We will accomplish this goal in two complimentary specific aims. In Specific Aim 1, we have developed a novel method to quantitate a number of proteins expressed on immune and tumor cells present in the tumor microenvironment from late-stage lung cancer patients using a technique called multi-parametric flow cytometry. We hypothesize that quantifying these proteins will provide a more comprehensive view of the function of these immune cells with the tumor and be able to predict which patients will respond to immunotherapy. In Specific Aim 2, we will focus on a newly developed blood-based biomarker, exosomal PDL1 expression, to predict response to immunotherapy. We will enroll late-stage non-small cell lung cancer patients scheduled to receive an immunotherapeutic agent who will undergo additional tumor biopsies and blood draws for analysis, and patients be followed over time to monitor for response and outcome data.

Technical Abstract

This project describes a 3-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 two complementary specific aims. In Specific Aim 1, 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 2, 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, 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.

Key words

Biomarker or biomarker testing

Immune checkpoint inhibitors

Immunotherapy

Metastatic

Non-small cell lung cancer (NSCLC)

Stage III

Stage IV

Development of markers to predict response to immunotherapy in NSCLC

LUNGevity Foundation

CHICAGO OFFICE

BETHESDA OFFICE

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