Targeting tumor microenvironment by nanoimmunodrugs for glioma treatment

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Glioblastoma (GBM) is the most lethal form of brain cancer. Treatment options are limited, in part because of inefficient drug delivery across the blood-brain barrier (BBB). GBM microenvironment contributes to malignant growth, invasion, and escape from immune surveillance. We will develop a radically new strategy of GBM treatment by simultaneous targeting of tumor microenvironment and activating brain cancer privileged immune system. This new combination approach aims to regulate tumor microenvironment components that are largely independent of heterogeneous genetic mutations in glioblastoma. It has potential advantage over conventional GBM treatment with small molecule drugs, radiation and targeted molecular marker(s) inhibition. In the frame of the FOA "Toward Translation of Cancer Nanotechnology Interventions", we will develop the translation of cancer interventions using novel nanomedicines able to cross biobarriers, such as BBB, cell and endosomal membranes, and modulate tumor microenvironment for effective therapy that may treat not only brain primary tumors (GBM) but other poorly treatable brain secondary/metastatic tumors. We plan to understand the interactions between extracellular matrix (ECM) protein laminin-411 (a4b1g1) expression and brain local immune system as parts of GBM-promoting immunosuppressive microenvironment. Our clinical data on 130 GBM patients showed that tumor laminin-411 correlated with tumor aggressiveness, poor patient survival and early recurrence. We developed nano drugs based on natural polymer, poly(β-L-malic acid), able to block the synthesis of trimer protein laminin-411 in vivo. We also used syngeneic mouse models treated with nano immuno drugs delivering to GBM checkpoint inhibitor antibodies anti-CTLA-4 or anti-PD-1 that in free form do not cross BBB, which increased animal survival. Nanodrugs were well characterized and non- toxic in mice and rabbits (collaboration with Nanotechnology Characterization Laboratory). Nano polymeric drugs production was scaled up to grams. Toxicity and PK studies were successfully performed on primates, male/female Cynomolgus macaques using therapeutic 1X and acute 10X intravenous dosages. We also developed a nano immuno delivery system on the same platform bearing anti-CTLA-4 or anti-PD-1 antibodies that traversed BBB, activated local brain immune system and prolonged animal survival. New preliminary data demonstrate that laminin-411 regulates Notch pathway and activation of NK, NKT, IFNg+ NKT, and macrophages, whereas checkpoint inhibitors delivered to the brain on nanoplatform regulate both innate and adaptive immune system. Our translational research is geared towards developing clinically suitable combinations of BBB-crossing nanomedicines for efficient glioma treatment. Aim 1. Synthesis of novel nano drug variants for combination brain cancer therapy. Aim 2. Lead nano drug testing for glioma treatment efficacy. Aim 3. Pharmacological (PK, PD) and toxicological examination of lead nano immunopolymers.