Summary Patients with extrabronchial tumors that induce malignant central airway obstruction (MCAO) face significant morbidity and only 1-7 months median overall survival. An estimated 20-30% of patients with lung cancer will have MCAO during the course of their disease, but other malignancies that metastasize to the airway can induce central airway obstruction. We have recently reported, in a Phase I study, that Photofrin® mediated image- guided interstitial photodynamic therapy (I-PDT) with our novel treatment planning and light dosimetry platform is safe, with promising outcomes. Three out of 10 treated patients are alive at 26.5, 12 and 8.3 months. Our image-based treatment planning was used to guide the administration of the light dose rate (irradiance) and light dose (fluence) to the target tumor while sparing adjacent normal tissue. Our goal is to improve the rate of complete and partial tumor response of extrabronchial MCAO to I-PDT. To that end we propose to increase tumor blood oxygenation that will increase laser light transmission and oxygen supply known to improve the efficacy of PDT. Murine studies reported that palliative x-ray radiotherapy (p-XRT) can increase tumor oxygenation and alter vasculature. We therefore explore the use of p-XRT to improve tumor response to I-PDT. Our preliminary data demonstrate that p-XRT followed by I-PDT (p-XRT/I-PDT) significantly increases (p<0.05) complete response of locally advanced mouse tumors, in comparison to either I-PDT or p- XRT. Under compassionate care exemption we showed that I-PDT delivered 48 ± 4h after 8Gy x1 p-XRT can provide control of extrabronchial MCAO in two patients. There are no effective treatments for extrabronchial MCAO. Thus, the overriding significance of our proposal is its responsiveness to an unmet clinical need. We hypothesize that standard of care p-XRT (8Gy x1) followed by I-PDT is safe and will improve treatment outcomes in patients with extrabronchial MCAO, and that this improvement is due to changes in the tumor microenvironment. To test our hypothesis, we propose to accomplish the following aims. Aim 1. To conduct a Phase I/II study to test the safety and efficacy of p-XRT followed by I-PDT in patients with extrabronchial MCAO. We define success as demonstrating that this treatment is safe and result in ≥50% of participants having partial or complete tumor response and/or significant improvement in quality of life and physical performance at 3 months post treatment. We will transmission and immune markers with tumor response. evaluate the relationship of changes in light Aim 2. To define the mechanisms by which p-XRT improves tumor response to I-PDT in mouse models. We will define how changes in tumor microenvironment impact light transmission and tumor response, as well as the contribution of anti-tumor immunity to tumor control and tumor-free survival. These data will inform the design of a future randomized Phase II trial of p-XRT/I-PDT versus standard of ca...