The proposal addresses Lung Cancer Research Program 2018 Areas of Interest, “Understanding predictive markers to identify responders and non-responders” and “Understanding mechanisms of resistance to treatment (primary and secondary).” This project is relevant to military Service members, Veterans, and their families because lung cancer is the leading cause of cancer death in men and women. Service members and Veterans exhibit a higher rate of tobacco use relative to civilian populations where tobacco smoking is the major cause of lung cancer incidence. While this proposal focuses on lung cancers driven by oncogenic forms of EGFR and ALK that are more frequent in non-smokers, these cancers are still observed, albeit at lower frequency in smokers. Importantly, non-smoking related lung cancers still ranks within the top 10 based on number of cancer deaths and is thus relevant to military Service members that don’t use tobacco. If successful, the project is predicted to exert a significant impact on the health and well-being of Service members, Veterans, and their families.

The most effective precision medicines for treatment of lung cancers driven by oncogenic forms of epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) induce pronounced tumor shrinkage and increased patient survival, but some cancer cells invariably remain. This is important because these remaining tumor cells, termed “residual disease,” serve as a reservoir from which lethal, drug-resistant cancers will inevitably develop. While new therapies that unleash the patient’s immune system to participate in attacking the cancer have greatly impacted some cancers, lung cancers bearing EGFR and ALK exhibit relatively weak responses to these drugs. Thus, identifying rational, evidence-based approaches to improve the overall survival of these lung cancer patients is a major priority of the field.

The overall objective of this project is to thoroughly characterize residual disease, the tumor remaining after 2 to 6 weeks of therapy, in EGFR and ALK-driven lung cancer patients. In parallel, experiments with human and murine lung cancer cell lines will be completed to identify therapy-induced vulnerabilities that can be attacked in the residual disease state. The central hypothesis is that drugs targeting oncogenic EGFR and ALK initiate activation of signal pathways that increase the presentation of tumor-specific antigens on lung tumor cells to immune cells. Also, the therapy-induced signal pathways increase secreted factors that actively recruit specific immune cells into the tumor, a potential vulnerability, such that combinations of existing and still emerging immune therapies and oncogene-targeted drugs will increase the degree of tumor shrinkage relative to either class of agents alone. The EGFR and ALK inhibitors to be tested have clearly established clinical benefit and are Food and Drug Administration (FDA)-approved as single agent therapies. While EGFR and ALK positive lung cancers are not as responsive to emerging immune therapies as other types of lung cancers, these therapies have already gained FDA approval in lung cancer despite reduced response rates. We anticipate that positive findings could lead to novel and evidence-based strategies for improving the therapeutic outcome for patients bearing EGFR- and ALK-driven lung cancers through combination with existing and emerging agents that enhance engagement of the patient’s immune system in the attack on their lung cancer.