Johns Hopkins University

Verena Staedtke

Renyuan Bai

Gregory J Riggins

Bert Vogelstein

Kenneth W Kinzler

Nickolas Papadopoulos

Shibin Zhou

Avadhut D Joshi

Tara Williamson

Ren-Yuan Bai

Provided herein are methods for increasing the therapeutic efficiency of oncolytic bacterial therapeutics. Bacterial oncolytic therapies, especially the ones targeting tumor hypoxia such as-NT, often encounter incomplete tumor clearance in less hypoxic tumoral areas and severe inflammatory reactions. In this study, we explored immune-modulating preconditioning to suppress the host neutrophils and significantly enhanced the antitumor efficacy of-NT in animal models, including an orthotopic brain tumor model in rabbits. The optimized preconditioning agent, hydroxyurea, is clinically approved and-NT has demonstrated manageable safety and promising antitumor responses in clinical trials. Thus, the proposed preconditioning of neutrophil suppression is readily translatable to patients undergoing-NT trials or other oncolytic biologic therapies and could improve outcome.

Neutrophil suppression as preconditioning to increase oncolytic bacterial therapy

The invention provides methods of delaying or preventing NF1-related malignancies or tumors using mebendazole. The administration of mebendazole results in decreased Ras activation in NF1-related tumor cells. Invention methods include the use of a cyclooxygenase-2 inhibitor such as celecoxib in combination with mebendazole. The methods include methods of treatment and methods of prevention or delaying of neurofibromatosis type 1-related malignancies or tumors.

Preventative effect of mebendazole against malignancies in neurofibromatosis

This document provides methods and materials for preventing cytokine release syndrome (CRS). For example, methods and materials for using one or more catecholamine inhibitors to prevent a mammal from developing CRS are provided.

Preventing cytokine release syndrome

Mebendazole is an antiparasitic drug with over 40 years of safe use. Recently mebendazole was repurposed for glioblastoma therapy. Three polymorphs of mebendazole exist, but the relative polymorph content for existing drugs varies, and the therapeutic anti-cancer relevance of the different polymorphs was unknown. As an oral drug mebendazole polymorph C is a superior form, and it reaches the brain and brain tumors in effective concentrations. Efficacy is further improved by combining mebendazole with a P-glycoprotein inhibitor. Mebendazole may also be used for therapy of other cancers, as well as a chemo-preventative agent.

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Baltimore, MD, United States of America

Verena Staedtke