Johns Hopkins University

Dsm IP Assets B.v.

Renyuan Bai

Verena Staedtke

Gregory J Riggins

Markus Wyss

Bert Vogelstein

Kenneth W Kinzler

Nickolas Papadopoulos

Shibin Zhou

Martin Lehmann

Avadhut D Joshi

Rual Lopez-Ulibarri

Markus Huembelin

Tara Williamson

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.

Mebendazole polymorph for treatment and prevention of tumors

The present invention relates to modified mevalonate kinases that are less sensitive to feedback inhibition, and to polynucleotides encoding them. The invention further pertains to vectors comprising these polynucleotides and host cells containing such vectors. The invention provides a process for producing the modified enzyme and for producing isoprenoid compounds using the modified enzymes.

Modified mevalonate kinase with reduced feedback inhibition

The present invention relates to modified mevalonate kinases that are less sensitive to feedback inhibition, and to polynucleotides encoding them. The invention further pertains to vectors comprising these polynucleotides and host cells containing such vectors. The invention provides a method for producing the modified enzyme and a method for producing isoprenoid compounds.

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Baltimore, MD, United States of America

Renyuan Bai