Mechanisms of Caspase-1 Mediated Schwannoma Regression

Massachusetts General Hospital, Boston MA

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Abstract

DESCRIPTION (provided by applicant): While schwannoma tumors are typically benign (non-malignant) they can have devastating consequences for patients. As for an individual patient there is often no efficacious treatment. Thus, schwannoma therapy represents a major unmet clinical need. We have developed a new therapeutic approach to these nerve-associated tumors that involves intra-tumoral injection of an adeno-associated virus (AAV) vector carrying the pro-apoptotic gene caspase-1 (ICE) under a Schwann-cell specific promoter (P0); the vector is denoted AAV-P0-ICE. Our pre-clinical studies have shown a remarkable ability of the AAV-P0- ICE vector to produce a prolonged reduction in tumor volume with no nerve damage (manuscript submitted). Our preliminary data suggests that AAV-PO-ICE not only directly kills infected caspase-1-expressing tumor cells (presumably by inducing apoptosis), but also kills non-infected tumor cells through a bystander effect. It is hypothesize that this bystander killin is mediated by both tumor- and host-specific mechanisms that involve humoral- and cell-mediated pathways. The overriding goal is to investigate the biology of AAV-P0-ICE mediated tumor destruction in the human and mouse schwannoma models we have developed in nude and immunocompetent mice, respectively, and to identify the molecular and cellular pathways mediating the killing of non-vector-infected tumor cells that is associated with apoptotic death of infected tumor cells. In brief, the specific aims are to 1) investigate the parameters of tumor regression in two schwannoma models in mice - a human schwannoma in nude mice and a mouse schwannoma in immune competent animals, 2) investigate whether caspase-1 bystander killing involves apoptotic death of uninfected cells, and 3) analyze whether host immune mechanisms are involved in AAV-P0-ICE initiated bystander killing. In vivo tumor growth will be monitored via bioluminescent imaging and MRI for the human and mouse schwannoma models, respectively; both techniques allow serial assessment over time in a given animal. A variety of biochemical and cell biological techniques will be used to determine whether caspase expressing tumor cells produce factors - both humoral and microvesicle contained - that can be transferred to and cause apoptotic death of uninfected tumor cells. Histological analysis and a variety of fundamental immunological assays will be used to investigate host mechanisms of bystander killing after AAV-P0-ICE injection. This application is novel and innovative in that it utilizes the first viral vector we know of that is restrictively expressed in Schwann-lineage cells hence allowing targeting of schwannomas without neurotoxicity, and proposes investigation of the pathways - tumor and host specific - which underlie induction of bystander tumor killing. Mechanistic understanding of the extensive and specific tumor killing induced by AAV-P0-ICE injection into schwannomas has the potential lead to novel treatment strategies for NF1, NF2 and schwannomatosis, as well as, a variety of other neoplasms.