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Oncolytic poliovirus for human tumors

a technology of human tumors and oncolytic poliovirus, applied in the field of antitumor therapy of oncolytic virus, can solve problems such as unpredictable efficacy

Inactive Publication Date: 2016-02-04
DUKE UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent describes a method for treating tumors in humans that express NECL5, a protein found in solid tumors. The method involves administering a chimeric poliovirus construct directly to the tumor. This chimeric poliovirus has a particular genetic material that allows it to specifically target and destroy NECL5-positive tumors. This method can provide an effective treatment for brain tumors and other solid tumors that express NECL5.

Problems solved by technology

Because of the differences between tissue culture, animal models, and humans, efficacy is unpredictable.
Moreover, viral preparations used in pre-clinical studies are often impure, so that any activity cannot be attributed to the agent under investigation.

Method used

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  • Oncolytic poliovirus for human tumors
  • Oncolytic poliovirus for human tumors
  • Oncolytic poliovirus for human tumors

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0025]Animal tumor models. An IND-directed efficacy trial of PVS-RIPO was conducted in the HTB-15 GBM xenograft model in athymic mice. PVS-RIPO (from the clinical lot) was administered at the ‘mouse-adjusted’, FDA-approved max. starting dose [the FDA-approved max. starting dose (10e8 TCID) was adjusted for the reduced tumor size in mice (to 6.7×10e6 TCID)]. Delivery mimicked the intended clinical route, i.e., slow intratumoral infusion. Under these conditions, PVS-RIPO induced complete tumor regress in all animals after 15 days (FIG. 8A). While virus was recovered from treated tumors until day 10, the levels were modest at best, indicating that direct viral tumor cell killing alone cannot account for the treatment effect (FIG. 8B)

[0026]Evidence from animal tumor models suggests that intratumoral inoculation of PVS-RIPO causes direct virus-induced tumor cell killing and elicits a powerful host immunologic response against the infected / killed tumor (3, 7, 10). The response to virus in...

example 2

[0027]Clinical trials. IND no. 14,735 ‘Dose-finding and Safety Study of PVSRIPO Against Recurrent Glioblastoma’ was FDA-approved on Jun. 19, 2011 and IRB-approved on Oct. 27, 2011. A phase I / II clinical trial in patients with recurrent glioblastoma (GBM) (NCT01491893) is currently enrolling patients.

[0028]Two human subjects have so far been treated with PVS-RIPO per IRB-approved protocol. Preliminary findings from the first subject are described in Example 3.

example 3

[0029]Preliminary findings with first human subject. The patient is a 21-year-old female nursing student diagnosed with a right frontal GBM (WHO grade IV). She was first diagnosed in June 2011, at the age of 20 years, following a history of severe headaches and unsuccessful treatment for a suspected sinus infection. Brain imaging was obtained on Jun. 17, 2011 and showed a large right frontal mass, measuring ˜5×6 cm. She underwent a subtotal resection of the right frontal mass on Jun. 22, 2011, with pathology confirming GBM (WHO grade IV). Given the young age of the patient, her excellent performance status and the subtotal tumor resection, it was decided to treat her aggressively with a combination of six weeks of radiation therapy with concurrent Temodar chemotherapy at 75 mg / m2 by mouth daily and bevacizumab (antiangiogenic agent) administered every 2 weeks. The patient completed six weeks of treatment on Sep. 18, 2011. On Oct. 3, 2011, the patient initiated adjuvant therapy with ...

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Abstract

Human clinical use of a chimeric poliovirus construct has demonstrated excellent anti-tumor effect. The mechanism of action is believed to involve both viral oncolysis as well as immune recruitment, both of which lead to necrosis in the area of the tumor. No adverse effects have been observed.

Description

[0001]This invention was made using funds provided by the United States government. The U.S. government retains certain rights according to the terms of grants from the National Institutes of Health R01 CA87537, P50 NS20023, R01 CA124756, and R01 CA140510.TECHNICAL FIELD OF THE INVENTION[0002]This invention is related to the area of anti-tumor therapy. In particular, it relates to oncolytic virus anti-tumor therapy.BACKGROUND OF THE INVENTION[0003]PVS-RIPO is an oncolytic poliovirus (PV) recombinant. It consists of the live attenuated type 1 (Sabin) PV vaccine containing a foreign internal ribosomal entry site (IRES) of human rhinovirus type 2 (HRV2). The IRES is a cis-acting genetic element located in the 5′ untranslated region of the PV genome, mediating viral, m7G-cap-independent translation.[0004]PVS-RIPO oncolytic therapy has been reported in tissue culture assays (6, 7, 10, 15-17) and in animal tumor models, but not in clinical trials in humans. Because of the differences betw...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K35/768A61K9/00A61K41/00A61K45/06A61K51/08A61N5/10C12N7/00
CPCA61K35/768C12N7/00A61K9/0085A61K41/00C12N2770/32733A61K45/06A61N5/10C12N2770/32632C12N2770/32611A61K51/081C12N2770/32671A61P1/00A61P11/00A61P13/08A61P15/08A61P25/00A61P35/00Y02A50/30
Inventor GROMEIER, MATTHIASSAMPSON, JOHN H.BIGNER, DARELL D.DESJARDINS, ANNICKFRIEDMAN, HENRY S.
Owner DUKE UNIV
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