Core A: Administration, Integration, Education and Career Development

Abstract public domain (NIH RePORTER)

OVERALL PROGRAM SUMMARY For optimal cancer therapy, combination approaches that are mechanistically complementary and directed at non-overlapping molecular targets are needed. Strategically, combinations should be selected such that the first treatment primes the tumor for the second treatment. Building upon our own findings and work on photodynamic therapy (PDT) in pancreatic adenocarcinoma (PDAC) and nonmelanoma skin cancer (NMSC), along with recent advances in immunotherapy, we hypothesize that the damage-related processes triggered by PDT can form the basis for Photodynamic Priming (PDP) to promote an immune-based combination therapy. PDP induces immunogenic cell death, enhances influx of tumor infiltrating lymphocytes (TILs), and sensitizes the tumor microenvironment to immune checkpoint inhibition (ICI). We will capture the PDP effect to design a non-empiric approach for PDT-ICI combination therapy. We will be helped in this effort by our recent innovation of hyperspectral confocal imaging that can monitor 6 biomarkers simultaneously in live tumor bearing animals, and allow quantification of TIL subsets along with PD1/PD-L1 expression changes. We posit that ICI will be most beneficial when immunologically “cold” tumors can first be converted to “hot” tumors via PDP treatment, thereby minimizing the ICI dose required and reducing toxicity. Our Program has 3 Research Projects and 2 scientific Cores, plus an Administrative Core. Projects 1 and 2 are largely clinical while Project 3 is exclusively pre-clinical, driving fundamental findings that form the basis of the hypothesis. Project 1 introduces a double-priming strategy for the treatment of NMSC; the tumor is first treated pharmaco- logically with 5-fluorouracil or Vitamin D to enhance PDT priming, which in turn increases the efficacy of ICI. Project 2 focuses on PDP in pancreatic cancer patients who are unresponsive to chemotherapy. PDT is delivered under endoscopic ultrasound (EUS) guidance, and timing of ICI delivery is informed by findings from Project 3 and by examining subpopulations of TILs in metastatic lymph nodes in some patients. Project 3 looks in-depth at PDP induction of TILs in a PDAC murine model, and in patient-derived immune organoids (PDIO’s). Cores are critical. Core B will assist Projects 1 and 3 with high resolution imaging in preclinical models and PDIOs, and Core C will support all projects with dosimetry techniques to monitor tumor treatment response, including radiomics to garner new information from CT scans in PDAC patients. We propose t h a t new combinations o f PDT with immune checkpoint inhibition (ICI), if done in a rational way that is informed by optical imaging to monitor molecular responses at the cellular level and in real time, will reduce a major barrier to ICI therapy (the lack of effective immune cell infiltration into the tumor). Impact and Relevance: This program positively impacts the treatment of two cancers, PDAC and NMSC, at opposite ends of the spectrum of high mortality/morbidity and high incidence. Both cancers inflict a heavy societal burden of cost and suffering. Findings from this work could also be translatable to other types of cancer.

Public health relevance public domain (NIH RePORTER)

NARRATIVE - OVERALL This P01 aims to improve therapy for Pancreatic cancer, one of the most lethal of cancers, and nonmelanoma skin cancer, the most ubiquitous cancer in the United States. We use visible light activation to not only destroy the cancer itself, but also to increase the efficacy of other treatments such as chemotherapy and immunotherapy while minimizing the toxicity associated with the latter. Our overall strategy includes two clinical trials (in Projects 1 and 2), and preclinical studies (Project 3) which together will ultimately allow patient customized combination treatments that will benefit even those patients whose disease has stopped responding to any of the conventional treatments.