IL

Metastatic non-small cell lung cancer (mNSCLC) is the leading cause of cancer-related death in the United States. Most patients with mNSCLC are treated with systemic agents, which prolong survival and improve symptoms, but are typically not curative. Although recent advancements in immune checkpoint inhibitors have revolutionized the management of mNSCLC lacking targetable driver mutations, only a fraction of mNSCLC patients benefit from immunotherapy. Emerging evidence suggests that ablative radiotherapy can augment immunotherapy responses in metastatic disease; however, strategies to optimize the synergy between local radiation and the immune system are not well defined. We are conducting a randomized phase I/II clinical trial designed to evaluate the safety and efficacy of combination immune checkpoint blockade (ipilimumab + nivolumab) plus multisite ablative radiotherapy as a first-line treatment for patients with mNSCLC. As a secondary analysis of the phase I trial, we propose to investigate biomarkers associated with treatment response. In Aim 1, we propose to compare the diagnostic accuracy of established clinical biomarkers, including PD-L1 immunohistochemistry (IHC), tumor mutational burden, gene expression profiles, and multiplex IHC in predicting response to combination ablative radiotherapy and immunotherapy. In Aim 2, we propose to characterize global transcriptional and genomic changes induced by radiation when given prior to or concurrently with immunotherapy and evaluate whether these changes are associated with treatment response. In addition, in Aim 3, we propose to validate a novel biomarker derived from alternative splicing as a predictor of radio-immunotherapy response. By elucidating the immunomodulatory properties of radiotherapy, we may be able to improve treatment responses and long-term survival in patients with mNSCLC.

The overarching goal of the project is to develop a new technology for accurate and cost-effective lung cancer screening in current/former smokers. Lung cancer is curable if detected early. However, there are no robust screening techniques with options such as CT scans fraught with cost, harms, and a high false positive rate. Dr. Backman and his group hope to transform the clinical practice of lung cancer screening by exploiting field carcinogenesis, the concept that the genetic/environmental milieu that results in lung tumor impacts upon the entire aerodigestive mucosa including the buccal mucosa, which was referred to as a “molecular mirror” of lung carcinogenesis.

Their data show that the alteration of nanoscale architecture of buccal cells is exquisitely sensitive to lung field carcinogenesis and may serve as a robust biomarker for lung cancer. These nanoarchitectural changes can be detected in a practical and highly accurate fashion via a new technology, partial wave spectroscopic (PWS) microscopy (‘nanocytology’).

In the proposed study, they will conduct a blinded validation case-control trial to determine the sensitivity and specificity of buccal nanocytology for lung cancer. They will evaluate the ability of the test to identify patients who have lung cancer and how many patients with lung cancer would be missed using this technique. They will perform a subgroup analysis for Stage I lung cancers. They will assess the potential confounding effects of smoking frequency and time of cessation and other aerodigestive malignancies.

This project will provide the requisite data for the future definitive multicenter validation trial followed by FDA submission.