U.S. patent application number 14/646233 was filed with the patent office on 2016-02-04 for oncolytic poliovirus for human tumors.
The applicant listed for this patent is DUKE UNIVERSITY. Invention is credited to Darell D. BIGNER, Annick DESJARDINS, Henry S. FRIEDMAN, Matthias GROMEIER, John H. SAMPSON.
Application Number | 20160030497 14/646233 |
Document ID | / |
Family ID | 50776674 |
Filed Date | 2016-02-04 |
United States Patent
Application |
20160030497 |
Kind Code |
A1 |
GROMEIER; Matthias ; et
al. |
February 4, 2016 |
ONCOLYTIC POLIOVIRUS FOR HUMAN TUMORS
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.
Inventors: |
GROMEIER; Matthias; (Durham,
NC) ; SAMPSON; John H.; (Durham, NC) ; BIGNER;
Darell D.; (Durham, NC) ; DESJARDINS; Annick;
(Durham, NC) ; FRIEDMAN; Henry S.; (Durham,
NC) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
DUKE UNIVERSITY |
Durham |
NC |
US |
|
|
Family ID: |
50776674 |
Appl. No.: |
14/646233 |
Filed: |
November 21, 2013 |
PCT Filed: |
November 21, 2013 |
PCT NO: |
PCT/US13/71246 |
371 Date: |
May 20, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61729021 |
Nov 21, 2012 |
|
|
|
Current U.S.
Class: |
424/1.69 ;
424/93.2; 600/1 |
Current CPC
Class: |
A61K 51/081 20130101;
A61P 13/08 20180101; C12N 2770/32611 20130101; A61P 15/08 20180101;
C12N 2770/32733 20130101; A61K 41/00 20130101; A61P 35/00 20180101;
Y02A 50/30 20180101; A61K 35/768 20130101; A61K 45/06 20130101;
C12N 2770/32632 20130101; A61K 9/0085 20130101; C12N 2770/32671
20130101; A61P 11/00 20180101; C12N 7/00 20130101; A61N 5/10
20130101; A61P 25/00 20180101; A61P 1/00 20180101 |
International
Class: |
A61K 35/768 20060101
A61K035/768; A61K 9/00 20060101 A61K009/00; A61N 5/10 20060101
A61N005/10; A61K 51/08 20060101 A61K051/08; A61K 45/06 20060101
A61K045/06; C12N 7/00 20060101 C12N007/00; A61K 41/00 20060101
A61K041/00 |
Claims
1. A method of treating a human harboring a solid tumor which
expresses NECL5 (nectin-like protein 5), said method comprising the
steps of: administering directly to the tumor in the human a
chimeric poliovirus construct comprising 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.
2. The method of claim 1 wherein convection enhanced delivery is
used to administer the chimeric poliovirus construct.
3. The method of claim 1 wherein the solid tumor is a
glioblastoma.
4. The method of claim 1 wherein the solid tumor is a prostate
tumor.
5. The method of claim 1 wherein the administration is
intracerebral.
6. The method of claim 1 wherein the solid tumor is a
medulloblastoma.
7. The method of claim 1 wherein the solid tumor is a breast
tumor.
8. The method of claim 1 wherein the solid tumor is a lung
tumor.
9. The method of claim 1 wherein the solid tumor is a colorectal
tumor.
10. The method of claim 1 wherein the administration is
intracerebral infusion with convection enhanced delivery.
11. The method of claim 10 wherein the administration is
stereotactically guided.
12. The method of claim 1 wherein the human is an adult.
13. The method of claim 1 wherein the human is a child.
14. The method of claim 12 wherein concurrent or serial
chemotherapy is administered to the human.
15. The method of claim 13 wherein concurrent or serial
radiotherapy is administered to the human.
16. The method of claim 1 wherein the solid tumor is subjected to
surgical removal before or after administering the nonpathogenic,
oncolytic, poliovirus.
17. The method of claim 1 wherein prior to the step of
administering the solid tumor is tested for expression of
NECL5.
18. A method of treating a human harboring a solid tumor which
expresses NECL5 (nectin-like protein 5), said method comprising the
steps of: testing a solid tumor to ascertain that it expresses
NECL5; administering directly to the tumor in the human a chimeric
poliovirus construct comprising 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,
wherein the administering is stereotactically guided, intracerebral
infusion with convection enhanced delivery.
19. A clinical pharmaceutical preparation of a chimeric poliovirus
construct, comprising: 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; and
gadolinium.
20. The clinical pharmaceutical preparation of claim 19 wherein the
gadolinium is chelated with diethylene triamine pentaacetic acid
(DPTA).
21. The clinical pharmaceutical preparation of claim 19 further
comprising human serum albumin.
22. The clinical pharmaceutical preparation of claim 21 wherein the
human serum albumin is radiolabeled.
23. The clinical pharmaceutical preparation of claim 22 wherein the
human serum albumin is radiolabeled with .sup.124I.
24. A method of delivering a clinical pharmaceutical preparation to
a solid tumor in a human, comprising: administering via convection
enhanced infusion through a single intratumoral catheter, a dose of
a poliovirus construct within 6.5 hours, wherein said poliovirus
construct is in a clinical pharmaceutical preparation comprising 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; and gadolinium.
25. The method of claim 24 wherein the tumor is a brain tumor.
26. The method of claim 24 wherein the tumor is a glioblastoma
multiforme.
27. The method of claim 24 wherein the tumor is a pancreatic
tumor.
28. The method of claim 24 wherein the tumor is a prostate
tumor.
29. The method of claim 24 wherein the dose is delivered over a 6
hour period.
30. The method of claim 24 wherein the tumor expresses NECL5.
31. The method of claim 24 further comprising the step of testing
the solid tumor to ascertain that it expresses NECL5.
32. The method of claim 1 wherein the chimeric poliovirus construct
is in a clinical pharmaceutical preparation comprising
gadolinium.
33. The method of claim 18 wherein the chimeric poliovirus
construct is in a clinical pharmaceutical preparation comprising
gadolinium.
34. The method of claim 1 wherein the method further comprises
administering a biological therapy.
35. The method of claim 18 wherein the method further comprises
administering a biological therapy.
36. The method of claim 24 wherein the method further comprises
administering a biological therapy.
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, m.sup.7G-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
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.
[0005] The art provides no examples of oncolytic viral agents in
which biological activity in tumor models correctly predicted
efficacy in patients. The reason for this is that 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.
[0006] There is a continuing need in the art to identify and
develop effective anti-cancer treatments for humans, particularly
for patients with brain tumors.
SUMMARY OF THE INVENTION
[0007] According to one aspect of the invention a method is
provided for treating a human harboring a solid tumor which
expresses NECL5 (CD155, HVED, Nec1-5, PVS, TAGE4; nectin-like 5;
nectin-like protein 5). 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.
[0008] These and other embodiments, which will be apparent to those
of skill in the art upon reading the specification, provide the art
with methods of treating tumors, including brain tumors.
BRIEF DESCRIPTION OF THE DRAWINGS
[0009] FIGS. 1A-1B (formerly FIG. 8.) Intratumoral PVS-RIPO
infusion induces gradual tumor regress. FIG. 1A. Tumor volumes upon
mock (.quadrature.) or PVS-RIPO (.box-solid.) treatment. FIG. 1B.
Average virus recovery from tumors at the indicated intervals.
[0010] FIG. 2 (formerly FIG. 12). MRI from Apr. 16, 2012. Axial,
postcontrast, T1-weighted MRI showing disease progression.
[0011] FIG. 3 (formerly FIG. 13). MRI from May 9, 2012. Axial,
postcontrast, T1-weighted MRI obtained pre-infusion of
PVS-RIPO.
[0012] 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.
[0013] FIG. 5 (formerly FIG. 15). MRI from Jun. 6, 2012. Axial,
postcontrast, T1-weighted MRI showing disease stability.
[0014] FIG. 6 (formerly FIG. 16). MRI from Jul. 9, 2012. Axial,
postcontrast, T1-weighted MRI revealed concerns for disease
progression.
[0015] 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.
DETAILED DESCRIPTION OF THE INVENTION
[0016] 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.
[0017] Because the 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.
[0018] 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.
[0019] 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. Other examples of
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, gestational trophoblastic tumor,
gestational trophoblastic tumor, glioma, head and neck cancer,
hepatocellular cancer, Hilar cholangiocarcinoma, hypopharyngeal
cancer, intraocular melanoma, islet cell tumor, Kaposi sarcoma,
Langerhans cell histiocytosis, large-cell undifferentiated lung
carcinoma, laryngeal cancer, lip cancer, lung adenocarcinoma,
malignant fibrous histiocytoma, medulloepithelioma, melanoma,
Merkel cell carcinoma, mesothelioma, endocrine neoplasia, nasal
cavity cancer, nasopharyngeal cancer, neuroblastoma, oral cancer,
oropharyngeal cancer, osteosarcoma, ovarian clear cell carcinoma,
ovarian epithelial cancer, ovarian germ cell tumor, pancreatic
cancer, papillomatosis, paranasal sinus cancer, parathyroid cancer,
penile cancer, pharyngeal cancer, pineal parenchymal tumor,
pineoblastoma, pituitary tumor, pleuropulmonary blastoma, renal
cell cancer, respiratory tract cancer with chromosome 15 changes,
retinoblastoma, rhabdomyosarcoma, salivary gland cancer, small cell
lung cancer, small intestine cancer, soft tissue sarcoma, squamous
cell carcinoma, squamous non-small cell lung cancer, squamous neck
cancer, supratentorial primitive neuroectodermal tumor,
supratentorial primitive neuroectodermal tumor, testicular cancer,
throat cancer, thymic carcinoma, thymoma, thyroid cancer, cancer of
the renal pelvis, urethral cancer, uterine sarcoma, vaginal cancer,
vulvar cancer, and Wilms tumor.
[0020] Optionally, 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.
[0021] 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.
[0022] Applicants have found that 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.
[0023] While applicants do not wish to be bound by any particular
mechanism of action, it is believed that multiple mechanisms may
contribute to its efficacy. These include lysis of cancer cells,
recruitment of immune cells, and specificity for cancer cells.
Moreover, the virus is neuro-attenuated.
[0024] The above disclosure generally describes the present
invention. All references disclosed herein are expressly
incorporated by reference. A more complete understanding can be
obtained by reference to the following specific examples which are
provided herein for purposes of illustration only, and are not
intended to limit the scope of the invention.
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.times.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
infusion is characterized by a strong, local inflammatory response,
leading to immune infiltration of the tumor. Eventually the slow
tissue response to PVS-RIPO infusion leads to the demise of the
tumor mass and its replacement by a scar.
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 .about.5.times.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/m.sup.2 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 monthly,
five-day Temodar chemotherapy in addition to bevacizumab 10 mg/kg
every two weeks.
[0030] On Apr. 16, 2012, the patient presented to clinic after
having experienced her first generalized seizure, which occurred in
her sleep. By that time, she had completed six months of the
combination of Temodar and bevacizumab. She had attributed the
seizure to increased stress at school, as she was completing a
degree to become a pediatric oncology nurse, despite her diagnosis
of GBM and ongoing chemotherapy treatment. The brain MRI obtained
on that day showed tumor recurrence, with a new nodular enhancement
along the medial aspect of the resection cavity (FIG. 12).
[0031] The patient was offered multiple treatment options, but
elected to pursue the PVS-RIPO clinical trial. Following her first
generalized seizure, she was initiated on Keppra, but forgot to
take it on occasion and because of this and the known tumor
recurrence, the patient experienced a second generalized seizure in
her sleep on May 6, 2012. She went back to her baseline neurologic
condition and was worked up to enroll on protocol.
[0032] 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.
[0033] An MRI obtained immediately after completion of the infusion
documents the distribution of the infusate (FIG. 14).
[0034] Our research team followed up on the patient on a weekly
basis and she was seen in clinic two weeks post infusion, at which
time she denied any new neurologic symptoms, seizure recurrence,
fatigue, shortness of breath or weakness. She again was evaluated
in clinic on Jun. 7, 2012 and her physical and neurological
conditions remained normal. The brain MRI obtained at that visit
showed stability of the disease (FIG. 15).
[0035] The patient was seen in clinic on Jul. 9, 2012. Once more,
she denied any new neurologic symptoms, including the absence of
any recurrent seizure activity since the seizure observed on May 6,
2012, prior to PVS-RIPO infusion. She also reported that her mood
was good, that she was content with her progress in nursing school,
feeling that she is able to focus in school much better since after
her infusion. She was also excited by her move with two roommates
and by the fact that she is able to exercise regularly. Her brain
MRI obtained on that day showed a slightly increased mass effect
and minimal increase in superior linear enhancement, concerning for
progression of disease (FIG. 16).
[0036] In view of worrisome radiographic changes with no clinical
worsening, we decided to obtain an 18-FDG PET scan. 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. After discussion with the patient and her mother, it
was decided to continue to follow the patient from a clinical and
radiographic standpoint.
[0037] In check-ups on August 27 and October 22 the patient denied
any new neurologic symptoms, including the absence of any seizure
activity since the seizure on May 6, 2012 (prior to PVS-RIPO
infusion). The patient reports improved cognitive/memory function,
motor function (exercise). As of October 26, the patient is
neurologically normal.
[0038] Because of the favorable radiographic presentation at August
27, a PET scan was not ordered. The patient was re-scanned on
October 22 and there was a quantifiable radiographic response.
[0039] An MRI/PET overlay demonstrates the absence of signal from
the general area of the tumor recurrence.
EXAMPLE 4
[0040] Convection infusion. Preoperatively the BrainLab iPlan Flow
system is used to plan catheter trajectories based on predicted
distributions using information obtained from a preoperative
MRI.
[0041] This invention uses one mM of gadolinium, along with
.sup.124I-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.
[0042] 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. 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.
[0043] Based on our own experience, previously published reports
(19) and IRB- and FDA-approved trials using similar infusion
techniques (IRB# 4774-03-4R0), patients will be infused at a rate
of 500 .mu.L/hr. A Medfusion 3500 infusion pump will be
pre-programmed to a delivery rate of 500 .mu.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 .about.250 .mu.L of infusion
will be preservative-free salinein the `dead-space` of the
indwelling catheter. To account for this, 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.
[0044] 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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