Research Funded to Date

Lung cancer is the leading cause of cancer death and accounts for more than 160,000 deaths each year. Immunotherapy, aimed at improving the immune system’s response to cancer, has recently emerged as a profound breakthrough for patients with lung cancer. In particular, therapies targeting the programmed death-1 (PD-1) pathway have been successful. PD-1 is a molecule on immune cells, called T cells, that serves as the “brakes” of the immune system, and tumors can exploit this pathway to shut down the potentially effective anti-tumor immune response. PD-1 immunotherapy blocks this cancer-enabling pathway and allows the immune system to reject tumors. Recently, the FDA has approved PD-1 blockade in combination with traditional chemotherapy for the treatment of metastatic non-small cell lung cancer (NSCLC). This combination approach has resulted in significantly longer survival compared to chemotherapy alone. Despite this, many patients still do not achieve clinical benefit or extended survival. Prior studies have shown that tumors with a high number of genetic changes, called “mutations”, respond favorably to PD-1 immunotherapy, possibly because these mutations induce more immune activation that can then be unleashed following blockade of the PD-1 pathway. However, we are unsure how mutations play a role in the response to PD-1 blockade in combination with chemotherapy which, counter to PD-1 blockade, has traditionally been thought to dampen the immune system. It is therefore of immediate urgency that we understand how PD-1 blockade and chemotherapy work together to promote tumor regression and longer survival and to help clinicians better select patients most likely to benefit from these treatments. Here we propose to evaluate the effect of treatment on anti-tumor immune responses in patients receiving anti-PD-1 in combination with chemotherapy versus those receiving anti-PD-1 alone. The findings from this study will significantly advance our knowledge of the immune response to lung cancer and may result in a paradigm shift in how we select patients who are most likely to benefit from PD-1 immunotherapy.

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.

Lung cancer remains the leading cause of death related to cancer and the majority of lung cancer patients present with advanced disease that is for the most part incurable. Efforts to improve the early detection of lung cancer are crucial to help decrease the number of people who die from lung cancer. It has long been known that genetic information specific to cancer cells can be detected in the blood of cancer patients. Current technologies are enabling us to identify this cancer-specific genetic information directly from blood samples allowing for “liquid biopsies” that offer the potential of making cancer diagnoses directly from blood tests. However, the amount of cancer specific genetic information in the blood of patients with smaller tumors in early stages is often only present in very minute amounts that are difficult to detect. The development of new liquid biopsy technologies that can identify smaller amounts of genetic information more economically could potentially lead to blood tests that are able to detect smaller, more curable tumors and could be used for lung cancer screening. The recent identification of CRISPR-Cas systems, bacterial immune systems adapted to recognize specific genetic sequences, that can accurately detect very small quantities of specific genetic sequences are an attractive platform to develop liquid biopsy tests. The goal of the proposed project is to develop a CRISPR based blood test that can accurately identify genetic sequences specific to lung cancer and can accurately identify patients with early stage lung cancer.