US20160030497A1 - Oncolytic poliovirus for human tumors - Google Patents

Oncolytic poliovirus for human tumors Download PDF

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US20160030497A1
US20160030497A1 US14/646,233 US201314646233A US2016030497A1 US 20160030497 A1 US20160030497 A1 US 20160030497A1 US 201314646233 A US201314646233 A US 201314646233A US 2016030497 A1 US2016030497 A1 US 2016030497A1
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poliovirus
tumor
human
solid tumor
pharmaceutical preparation
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Matthias Gromeier
John H. Sampson
Darell D. Bigner
Annick DESJARDINS
Henry S. Friedman
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Duke University
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Duke University
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Assigned to DUKE UNIVERSITY reassignment DUKE UNIVERSITY ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: GROMEIER, MATTHIAS, SAMPSON, JOHN H., BIGNER, DARELL D., DESJARDINS, Annick, FRIEDMAN, HENRY S.
Publication of US20160030497A1 publication Critical patent/US20160030497A1/en
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    • C12N2770/00011—Details
    • C12N2770/32011—Picornaviridae
    • C12N2770/32711—Rhinovirus
    • C12N2770/32733—Use of viral protein as therapeutic agent other than vaccine, e.g. apoptosis inducing or anti-inflammatory
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    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • This invention is related to the area of anti-tumor therapy.
  • it relates to oncolytic virus anti-tumor therapy.
  • 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).
  • IRES is a cis-acting genetic element located in the 5′ untranslated region of the PV genome, mediating viral, m 7 G-cap-independent translation.
  • 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 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.
  • oncolytic viral therapy is the result of a complex, triangular relationship between (a) the infected malignant cells, (b) the non-malignant tumor microenvironment, and (c) the host immune system. A system of such complexity and intricacy has not been recreated in any animal model.
  • a chimeric poliovirus construct is administered directly to the tumor in the human.
  • the chimeric poliovirus comprises a Sabin type I strain of poliovirus with a human rhinovirus 2 (HRV2) internal ribosome entry site (IRES) in said poliovirus' 5′ untranslated region between said poliovirus' cloverleaf and said poliovirus' open reading frame.
  • HRV2 human rhinovirus 2
  • IRES internal ribosome entry site
  • FIGS. 1A-1B Intratumoral PVS-RIPO infusion induces gradual tumor regress.
  • FIG. 1A Tumor volumes upon mock ( ⁇ ) or PVS-RIPO ( ⁇ ) treatment.
  • FIG. 1B Average virus recovery from tumors at the indicated intervals.
  • FIG. 2 (formerly FIG. 12 ). MRI from Apr. 16, 2012. Axial, postcontrast, T1-weighted MRI showing disease progression.
  • FIG. 3 (formerly FIG. 13 ). MRI from May 9, 2012. Axial, postcontrast, T1-weighted MRI obtained pre-infusion of PVS-RIPO.
  • FIG. 4 (formerly FIG. 14 ). MRI from May 11, 2012. Axial, postcontrast, T1-weighted MRI showing distribution of Gd-DTPA contrast and -presumably- PVS-RIPO within the brain.
  • FIG. 5 (formerly FIG. 15 ). MRI from Jun. 6, 2012. Axial, postcontrast, T1-weighted MRI showing disease stability.
  • FIG. 6 (formerly FIG. 16 ). MRI from Jul. 9, 2012. Axial, postcontrast, T1-weighted MRI revealed concerns for disease progression.
  • FIG. 7 (formerly FIG. 17 ). 18-FDG PET scan from Jul. 11, 2012. The results suggest the absence of hypermetabolic activity in the area of concern on MRI.
  • the inventors have developed a viral construct for use in humans. Previously, laboratory grade preparations of the viral construct have been tested in cell culture and in animal models. But these tests are not sufficient to attribute any effect to the viral construct itself, rather than other elements in the crude, laboratory grade preparations. Moreover, as is well known in the art, cell culture and animal models are not predictive of efficacy in humans.
  • poliovirus is a potential disease agent
  • extra precautions must be taken to ensure that disease-causing agents are not introduced to the subjects. Using good manufacturing procedures and purifications, a preparation was made that was sufficiently pure to permit introduction into humans in a trial.
  • Any technique for directly administering the preparation to the tumor may be used. Direct administration does not rely on the blood vasculature to access the tumor.
  • the preparation may be painted on the surface of the tumor, injected into the tumor, instilled in or at the tumor site during surgery, infused into the tumor via a catheter, etc.
  • One particular technique which may be used is convection enhanced delivery.
  • Any human tumor can be treated, including both pediatric and adult tumors.
  • the tumor may be in any organ, for example, brain, prostate, breast, lung, colon, and rectum, Various types of tumors may be treated, including, for example, glioblastoma, medulloblastomas, carcinoma, adenocarcinoma, etc.
  • tumors include, adrenocortical carcinoma, anal cancer, appendix cancer, grade I (anaplastic) astrocytoma, grade II astrocytoma, grade III astrocytoma, grade IV astrocytoma, atypical teratoid/rhabdoid tumor of the central nervous system, basal cell carcinoma, bladder cancer, breast sarcoma, bronchial cancer, bronchoalveolar carcinoma, cervical cancer, craniopharyngioma, endometrial cancer, endometrial uterine cancer, ependymoblastoma, ependymoma, esophageal cancer, esthesioneuroblastoma, Ewing's sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct cancer, fibrous histiocytoma, gall bladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor, gestation
  • patients may be stratified on the basis of NECL5 expression. This can be assayed at the RNA or protein level, using probes, primers, or antibodies, for example.
  • the NECL5 expression may guide the decision to treat or not treat with the chimeric poliovirus of the present invention.
  • the NECL5 expression may also be used to guide the aggressiveness of the treatment, including the dose, frequency, and duration of treatments.
  • Treatment regimens may include, in addition to delivery of the chimeric poliovirus construct, surgical removal of the tumor, surgical reduction of the tumor, chemotherapy, biological therapy, radiotherapy. These modalities are standard of care in many disease states, and the patient need not be denied the standard of care.
  • the chimeric poliovirus may be administered before, during, or after the standard of care.
  • the chimeric poliovirus may be administered after failure of the standard of care.
  • the clinical pharmaceutical preparation of the chimeric poliovirus has admirable genetic stability and homogeneity. This is particularly advantageous as the poliovirus is known to be highly mutable both in culture and in natural biological reservoirs.
  • Any suitable assay for genetic stability and homogeneity can be used.
  • One assay for stability involves testing for the inability to grow at 39.5 degrees C.
  • Another assay involves bulk sequencing.
  • Yet another assay involves testing for primate neurovirulence.
  • PVS-RIPO 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 )
  • 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).
  • a follow-up MRI was obtained on May 9, 2012 ( FIG. 13 ), before the patient underwent infusion of PVS-RIPO on May 11, 2012 with the FDA-approved max. starting dose (10e8) by the intended clinical delivery method (convection-enhanced, intratumoral infusion of 3 mL of virus suspension containing the contrast Gd-DTPA over 6 hrs; see Example 4) and experienced no neurologic or other complications related to this.
  • An MRI obtained immediately after completion of the infusion documents the distribution of the infusate ( FIG. 14 ).
  • the 18-FDG PET scan demonstrated hypometabolic activity in the area of concern on the MRI, suggestive of a necrotic process (treatment response effect; FIG. 17).
  • the PET scan from July 9 suggests the absence of viable tumor.
  • An MRI/PET overlay demonstrates the absence of signal from the general area of the tumor recurrence.
  • the BrainLab iPlan Flow system is used to plan catheter trajectories based on predicted distributions using information obtained from a preoperative MRI.
  • This invention uses one mM of gadolinium, along with 124 I-labeled human serum albumin to a surrogate tracer to identify the distribution of the poliovirus. This could be used for other drug infusions as well.
  • the gadolinium and radio-labeled albumin is co-infused with the drug and various MRI sequences and PET imaging are used to quantify the distribution.
  • the entire volume of the agent to be delivered will be pre-loaded into a syringe by the investigational pharmacist and connected to the catheter under sterile conditions in the operating room or the NICU just prior to beginning of infusion. Due to the complexity of scheduling all of the necessary components for the infusion (operating room time, pharmacy time, and radiology appointments), a +1 day window has been built in to the study for the study drug infusion. This means that the infusion is allowed to start the following day after the biopsy/catheter placement. This will still be considered “day 0” in regards to the protocol and the timing of the subsequent events. At the time of virus injection, emergency drugs, including epinephrine and diphenhydramine will be available and the neurologic status, oxygen saturation, and cardiac rhythm will be monitored.
  • emergency drugs including epinephrine and diphenhydramine will be available and the neurologic status, oxygen saturation, and cardiac rhythm will be monitored.
  • Drug infusion will occur in the Neuro-Surgical Intensive Care Unit (NSCU) so that all other emergency facilities will be available.
  • Patients will be treated with a prophylactic antibiotic such as nafcillin, a second-generation cephalosporin or vancomycin starting with the induction of anesthesia for the catheter placement.
  • a Medfusion 3500 infusion pump will be pre-programmed to a delivery rate of 500 ⁇ L/hr.
  • the agent (which will be in a total volume of 10 mL to account for ‘dead-space’ of 3.3723 mL in the infusion system) will be loaded in a 20 mL syringe into the syringe pump at the initial onset to avoid any interruptions in the infusion.
  • the total amount of the inoculum delivered to the patient will be 3 mL.
  • the catheter itself (30 cm length, 1 mm interior diameter) cannot be preloaded with virus suspension. Therefore, the initial ⁇ 250 ⁇ L of infusion will be preservative-free salinein the ‘dead-space’ of the indwelling catheter.
  • the infusion pump will be programmed for delivery of 3.250 mL.
  • the infusion will be performed using a Medfusion 3500 (Medex, Inc., Duluth, Ga.) syringe infusion pump.
  • the virus injection procedure will be completed within 6.5 hrs.
  • the catheter will be removed immediately following the delivery of PVSRIPO.
  • the infusion catheter (PIC 030) and infusion tubing (PIT 400) will be supplied by Sophysa, Inc. (Crown Point, Ind.).
  • the Infusion Catheter Kit is a 30 cm clear, open-ended catheter (1.0 mm ID/2.0 mm OD) with 1 cm markings for 20 cm. The catheter comes with a 30 cm stainless steel stylet, a barbed female luer lock with cap and a stainless steel trocar.
  • the Infusion Tubing Kit consists of a 3-way stopcock connector with air filter, 4 m of microbore tubing with antisiphon valve, a red, vented cap and a white luer lock cap.
  • the catheter products are packaged sterile and non-pyrogenic and are intended for single (one-time) use only.
  • the infusion will be performed using a Medfusion 3500 (Medex, Inc. Duluth, Ga.) syringe infusion pump.

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US16/505,771 Active US10799543B2 (en) 2012-11-21 2019-07-09 Oncolytic poliovirus for human tumors
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Cited By (2)

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Publication number Priority date Publication date Assignee Title
WO2017197207A1 (en) * 2016-05-11 2017-11-16 Ohio State Innovation Foundation Oncolytic viruses comprising esrage and methods of treating cancer
EP3773650A4 (de) * 2018-04-02 2021-12-29 Duke University Neoadjuvante krebsbehandlung

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EP2922564B1 (de) 2012-11-21 2018-07-04 Duke University Onkolytisches poliovirus für menschliche tumoren
WO2016201224A1 (en) 2015-06-10 2016-12-15 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Processes for production and purification of nucleic acid-containing compositions
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