ABSTRACT Lung cancer is the leading cause of death in the United States and worldwide. In 2015, an estimated 221,200 adults will be diagnosed with lung cancer and 158,040 will die from the disease in the United States. The rate of recurrence after initial treatment ranges between 30% to 63%, depending on the stage at initial diagnosis. The death rate is very high within one year after recurrence, approximately 48% to 80% depending on stage. It is generally acknowledged that earlier detection of recurrence before it is detectable by imaging may help improve the effectiveness of salvage therapy. The goal of this Phase I SBIR is to evaluate a non-invasive biomarker in the blood of cancer patients for early detection of lung cancer recurrence. The standard of care to monitor for recurrence is CT, or PET/CT imaging. There are two drawbacks to imaging: 1) lack of specificity, which may not accurately identify tumor recurrence (for example, inflammation mimics tumor regrowth), and 2) insufficient sensitivity, requiring tumors to be large enough for visual identification. Typically, tumors must show growth over serial imaging analyses and be larger than 5 mm to become suspicious. We propose that the newly characterized cancer-associate macrophage-like cell (CAML), which is found circulating in the blood of patients with cancer, may be a candidate for aiding earlier detection of lung cancer recurrence. Preliminary clinical data has shown that CAMLs are found in >85% of stage I, and >90% of stages II-IV, in numerous cancer types (breast, prostate, lung and pancreatic cancers), but not found in people without cancer. CAMLs have been shown to be more sensitive in detecting cancer than circulating tumor cells, or circulating tumor DNA, and are specifically present in progressing malignancies. In this Phase I SBIR, blood will be collected from 30 stage II and III unresectable patients treated by chemoradiation at three time intervals: at last treatment and at the time of imaging 3 months and 6 months after treatment. The specific aims are to show that the presence of CAMLs is correlative with early recurrence in lung cancer and further that CAMLs can detect disease recurrence earlier than standard surveillance imaging methods.