ABSTRACT The Biological Models, Multiplexed Optical Biopsy, Molecular Pathology, and Biostatistics Core, Core B, integrates novel biological models with newly developed biochemical and imaging assay platforms to enable the development of the treatments envisioned in the Program Projects. The objective of Core B is to provide a service and research platform to increase the efficiency of microscopy, biostatistics and pathology techniques used by all four Program Projects. Core B will also coordinate centrally communicating biostatistics and pathological services to support experimental design and the interpretation of preclinical and clinical results. Collectively, the Core aims to develop new flexible and scalable technologies for skin and pancreatic cancer in partnership with the Program Projects to move the field further towards personalized and individualized therapies by informing the timing of immune checkpoint inhibition. This could have a tremendous impact with implications in the long run for customized, precision immune checkpoint inhibition treatments that maximize efficacy while reducing toxicity. This research and development component of Core B will provide novel cancer models and tumor imaging technologies for the advancement of the Program Projects. Core B is interactive with all of the Program Projects and each Project will leverage Core B resources and services, as follows: newly developed patient-derived in vitro organoid models from skin biopsies (Project 1) and pancreatic cancer discarded surgical tissue (Project 3); previously established in vivo immunocompetent mouse models of skin cancer (Project 1) and pancreatic cancer (Project 3); and, novel video multiplexed in vivo microendoscopy (Projects 1, 2, and 3) that was developed and validated during the previous funding cycle. In addition, the Core provides biostatistics and molecular pathology services to Projects 1, 2, and 3, with guidance from expert biostatisticians as well as pathologists with expertise in skin and pancreatic cancer. The strong infrastructure at MGH and the Mayo Clinic available at no costs makes this ambitious plan for Core B possible within the minimal resources of the P01. The microscopy support includes unique hardware and software, with rigorous validations, for hyperspectral multiplexing and this use of operational, custom-designed systems also introduces not only unique capabilities but also cost savings compared to commercial solutions. Collectively, Core B has the necessary infrastructure and personnel to maximize the success of the Program Projects in the discovery of novel combination regimens for photodynamic priming of immune checkpoint inhibition with potential to provide durable treatment outcomes and to improve quality of life for both skin and pancreatic cancer patients.

PROJECT NARRATIVE Core B interacts with each of the Program Projects to provide biological models, multiplexed in vivo optical biopsy, molecular pathology, and biostatistics support that are essential for the Projects to be successful in optimizing photodynamic priming of cancer immunotherapy to suppress the primary tumor (local control) as well as to shrink distal metastatic tumors while reducing costs and lowering the toxic side-effects of immune checkpoint inhibitors. The Core integrates newly developed biological models of the tumor immune microenvironment of skin and pancreatic cancer with novel tools and approaches for in vivo imaging, ex vivo microscopy, and ex vivo biochemical assays to enable therapeutic discovery and precise timing for administration of immune checkpoint inhibitors. Because the in vivo imaging technologies are conducive to integration with clinical endoscopy, the long-term impact of Core B is not only to stimulate and to support new research but also there is real potential to produce clinical translation of these precision medicine approaches.