Project 3: Immune Checkpoint Inhibition Therapy Enhanced by Integrated Photodynamic Treatment and Image Guidance in Preclinical Models of Pancreatic Cancer

点击翻译按钮获取中文摘要

The statistics for pancreatic ductal adenocarcinoma (PDAC) remain dismal despite advances in combination chemotherapies. It is largely chemo and radiation resistant, and surgery, the only curative option, is available to only ~20% of patients. Immune checkpoint inhibition (ICI) has brought hope but in PDAC even the modest success (anti-PD1: Pembrolizumab) is limited to only 1-3% of patients displaying microsatellite instability. The majority of tumors lack the immune infiltration necessary for effective ICI. Based on our data and the literature, we hypothesize that Photodynamic Priming (PDP), a process that is a fallout of photodynamic therapy (PDT) and our main research focus, alters the tumor microenvironment to sensitize it to enhance ICI therapy. PDP induces immunogenic cell death and enhances tumor infiltrating lymphocyte (TIL) migration, augmented by PDP-induced higher tumor permeability.. We capture this priming effect for designing a non-empiric approach for a PDT-ICI combination. We are greatly helped in this by our recent innovation of hyperspectral imaging capable, for the first time, of monitoring 6 biomarkers simultaneously in live tumor bearing animals; it allows us to quantify TILs (and subsets) along with PD1/PD-L1 expression changes to generate an immunoscore (IS). We posit that ICI administration will be most beneficial when the tumor has been PDP-stimulated to be the “hottest” thus minimizing ICI dose and associated toxicities, similar to that observed for PDP-chemotherapy combinations. The hypothesis will be tested in 3 aims. Aim 1 will identify, in orthotopic murine tumors, PDP- dosimetry and optimal timing for IS modulation to establish the time for maximal benefits of anti-PD1 therapy (increased survival, decreased metastasis) and increased tolerability. Aim 2, informed by aim 1, will use both orthotopic and a bilateral subcutaneous PDAC murine model to determine abscopal effects of PDP-ICI therapy. A comparison of optimally timed, single dose ICI therapy with multiple dosages along with a comparison of single immune checkpoint blockade (anti-PD1) with dual blockade (anti-PD1/anti-PD-L1) will also be established. Aim 3 will utilize patient derived tumor immune organoids (PDIO), to recapitulate heterogeneity and evaluate the combination therapy outcomes. PDP induced IS will inform optimally timed anti-PD1/anti-PD-L1 therapy guidance for PDIOs. Relevance and Impact 1) it sensitizes non-immune responsive tumors to responsive ones and expands the eligible PDAC patients (currently only at 3%). 2) A non-empiric approach is introduced. 3) Combined with imaging-enabled dose reduction of anti-PD1 it reduces toxicities of immune drugs as reported with chemotherapy and receptor tyrosine kinase inhibitors. 4) It provides a broad imaging platform for in vivo real-time multiple-marker information at cellular resolution and serves as a general point-of-care tool by enabling simultaneous visualization of several molecular targets (e.g., tumor immune cell phenotypes and cytokines/stromal/metabolic signatures) for designing new therapies for many other diseases, and with potential to expand the use of fine needle aspirate biopsy for PDAC ICI dosimetry.