Stroma penetrating and immune modulating nanoparticles for image-guided therapy of pancreatic cancer

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Project Summary Recent advances in targeted delivery of nanoparticle/drugs and CAR T cell therapy have shown promises in the development of novel approaches for overcoming resistance to chemo- and immunotherapy in pancreatic cancer. A major obstacle in CAR T therapy in pancreatic cancer is the presence of multiple barriers that prevent cytotoxic T cells reaching tumors and actively killing tumor cells. Dense tumor stromal cells and extracellular matrix create physical and biological barriers to trap T cells in the stroma and inhibit T cell function. There is an unmet need of effective approaches to improve delivery of CAR T cells in pancreatic cancer. Tumor targeted, stroma- penetrating theranostic iron oxide nanoparticles (IONPs) developed in the parent R01 project offer an opportunity to develop a combination therapy to improve targeted delivery and intratumoral distribution of CAR T cells and overall therapeutic responses. Our results showed that uPAR-targeted and stroma breaking ligand (ATFmmp14) can overcome stromal cellular and extracellular matrix barriers to enhance tumor delivery of nanoparticle-drugs and T cells in human pancreatic PDX and transgenic mouse tumor models. In this supplement research project, we hypothesize that the binding of uPAR targeted, stroma-penetrating IONPs carrying chemo- and immunotherapeutic agents to CAR T cells significantly enhances delivery of CAR T cells and chemotherapy drugs into pancreatic cancer. Immune checkpoint PD-L1 and CTLA4 blocking peptides conjugated on the IONPs further activate CAR T cell function. Those combined effects lead to a strong therapeutic response in pancreatic cancer and overcome therapy resistance. In the proposed study, we will first determine the effect of ATFmmp14- conjugated IONPs carrying a chemotherapy agent, SN38, on viability and cytotoxicity of anti-MUC16 and/or Mesothelin CAR T cells in vitro in human pancreatic cancer cell lines. Therapeutic effect of co-delivery of the targeted IONP/SN38 with CAR T cells will be evaluated in a pancreatic cancer PDX model in SCID mice (Aim 1). Next, we will develop a novel targeted and stroma-penetrating CAR T cell delivery system by backpacking with ATFmmp14-IONP/SN38 carrying PD-L1 and/or CTLA4 blocking peptides, mediated by a CXCR4 inhibitor (BL-8040), for overcoming resistance to chemo- and CAR T cell therapy in pancreatic cancer (Aim 2). The effect on targeted delivery of CAR T cells and therapeutic efficacy using the backpack system containing ATFmmp14- IONP/SN38/immune checkpoint inhibitors will be evaluated in the pancreatic cancer PDX model (Aim 2). We will then investigate the therapeutic effects of the targeted chemo- and immunotherapy IONP-CAR T cells on tumor cells, immune cells and tumor stroma immune microenvironment using a mouse anti-MUC16 CAR T cells in a transgenic mouse pancreatic cancer cell line derived mouse tumor model (Aim 2). Finally, the feasibility of MR imaging for tracking intratumoral delivery of targeted IONP backpacked CAR T cells will be determined in mouse tumor models (Aim 2). This supplement project will provide a diversity pre-doctoral candidate with multidisciplinary research training to develop a novel cancer immunotherapy and to complete PhD thesis study.