Transluminal delivery of viruses for treatment of diseased tissue

Abstract

Methods are provided for treatment of cancer in a subject's body by intraluminal delivery of oncolytic viruses through a balloon catheter or alternative mechanism inserted in a blood vessel or duct leading to a target site of the cancer tissue, or for somatic cell gene therapy of single defective gene-caused other diseases or disorders by similar intraluminal delivery of non-oncolytic viruses to a target site of affected tissue and cells of the disease or disorder, wherein during delivery of the oncolytic or non-oncolytic virus, the designated vessel or duct is selectively occluded at both ends of the target site by two spaced-apart inflated balloons of the catheter to block perfusion therethrough and allow control of the volume of virus delivered to the target site so as to increase concentration and pressure of the virus thereat sufficient to enable viral penetration of an endothelial barrier of the vessel or duct without compromise thereof and into diseased cells in the vicinity of the target site toward achieving a desired therapy.

Claims

1. A method for treating a disease or disorder in the body of a subject by delivering effectively and with high concentration a selected virus locally to affected tissue at a target site of defective cells of the body responsible for the disease or disorder to be treated, the method including selecting the virus for its ability to infect the defective cells in the affected tissue so as to allay the defect therein while leaving normal cells unscathed; selecting a balloon catheter sized for advancement to the target site through a blood vessel or fluid duct of the subject's body in direct fluid communication with the target site, and having a discharge port of an infusion lumen situated between two spaced-apart inflatable balloons coupled by an inflation lumen of the catheter; advancing the catheter through the vessel or duct to position its distal end such that the target site is located between the two balloons, and inflating both balloons through the inflation lumen to maintain the catheter so positioned with the discharge port confronting the target site, thereby (i) forming an open space encompassed by the lining of the vessel or duct, the outer surface of the catheter, and confronting surfaces of the two inflated balloons, and (ii) blocking normal perfusion through the vessel or duct within that space; transluminally infusing therapeutically effective doses of the virus in containment fluid for discharge into said space through the infusion lumen and its discharge port; and selectively increasing pressure of the discharged virus by increasing the volume of fluid containing the virus in said space, to force the virus under an effective extravasation pressure through the natural endothelial barrier of the lining of the vessel or duct within said space, without removing or otherwise injuring the barrier, and into the defective cells of the affected tissue at the target site, sufficient for delivery of the effective doses of the virus thereto.

2. The method of claim 1, wherein the disease or disorder to be treated is cancer, the affected tissue is a malignant tumor, the selected virus is an oncolytic virus, and each of the therapeutically effective doses of the virus is contained within a pharmaceutically acceptable fluid carrier constituting the containment fluid.

3. The method of claim 1, wherein the disease or disorder to be treated is attributable to single-gene defects for treatment by somatic cell gene therapy, the affected tissue is selected from one of an immunodeficiency, cystic fibrosis, hemophilia, muscular dystrophy, and sickle cell anemia, the selected virus is an engineered non-oncolytic virus having incorporated therein therapeutic DNA integrated into its genome for delivery into a chromosome so as to administer a gene that causes expression of a needed protein and thereby replace or disrupt the defective gene to treat the disease or disorder.

4. A method for treating a disease or disorder in the body of a subject, said method comprising the steps of selecting a balloon catheter having two distally spaced-apart inflatable balloons coupled by an inflation lumen for simultaneous inflation or deflation thereof, and having an infusion lumen with at least one discharge port situated between the two balloons; advancing the balloon catheter transluminally into a vessel or duct of the body in direct fluid communication with affected tissue of the body containing defective cells attributable to or responsible for the disease or disorder to be treated, until a target site of the affected tissue is situated between the two balloons; inflating the two balloons through the inflation lumen while injecting through the infusion lumen of the catheter a body-compatible fluid containing a predetermined quantity of a virus selected for its ability to infect the defective cells so as to allay the defect therein while leaving normal cells unscathed, to discharge the quantity of virus in the fluid from the discharge port into a chamber at the target site formed by the space encompassed by the lining of the vessel or duct and the outer surface of the catheter between opposing surfaces of the two inflated balloons; and selectively increasing pressure of the discharged virus and fluid in the chamber to force the virus under an effective extravasation pressure through an endothelial barrier presented by the lining of the vessel or duct, without removing or otherwise injuring the endothelial barrier or the lining, for delivery of an effective dose of the virus into the defective cells of the affected tissue at the target site.

5. The method of claim 4, wherein the disease or disorder to be treated is cancer, the affected tissue is a malignant tumor, the selected virus is an oncolytic virus, and delivery of the virus is performed by placing the desired quantity thereof in a pharmaceutically acceptable fluid carrier before infusion thereof to the target site.

6. The method of claim 4, wherein the disease or disorder to be treated is attributable to single-gene defects for treatment by somatic cell gene therapy, the affected tissue is selected from one of an immunodeficiency, cystic fibrosis, hemophilia, muscular dystrophy, and sickle cell anemia, the selected virus is an engineered non-oncolytic virus having incorporated therein therapeutic DNA integrated into its genome for delivery into a chromosome so as to administer a gene that causes expression of a needed protein and thereby replace or disrupt the defective gene to treat the disease or disorder.

7. The method of claim 4, wherein the disease or disorder to be treated is attributable to a gene defect for treatment by gene therapy, the affected tissue is selected from one of an acquired or inborn disease such as HIV, immunodeficiency, cystic fibrosis, hemophilia, muscular dystrophy, or sickle cell anemia, the selected virus is an engineered non-oncolytic virus having the ability to induce therapeutic RNA, mRNA, iRNA, shRNA, DNA, or CRISPR Cas9 constructs, integrated into its genome for delivery into the target site so as to induce a genetic modification that causes expression of a needed protein to modify, replace or disrupt the defective gene for treatment of the disease or disorder.

8. A method for treating a disease or disorder in the body of a subject, said method comprising the steps of selecting a balloon catheter with an inflatable balloon separated from the distal end and coupled to an inflation lumen of the catheter, and with an infusion lumen having a discharge port situated between the balloon and the distal end of the catheter, and a separate central lumen having an outlet port at the distal end of the catheter; advancing the balloon catheter transluminally into a vessel or duct of the body in direct fluid communication with affected tissue of the body containing defective cells attributable to or responsible for the disease or disorder to be treated, until the balloon is positioned such that a target site of the affected tissue lies between the balloon and the distal end of the catheter; inflating the balloon through the inflation lumen and dispensing body-compatible soluble beads through the central lumen for ejection from the outlet port, and injecting through the infusion lumen of the catheter a body-compatible fluid containing a predetermined quantity of a virus selected for its ability to infect the defective cells so as to allay the defect therein while leaving normal cells unscathed, to discharge the quantity of virus in the fluid from the discharge port into a chamber at the target site formed by the space encompassed by the lining of the vessel or duct and the outer surface of the catheter between the surface of the inflated balloon and the surface presented by a wall formed by the beads ejected from the distal end; and selectively increasing pressure of the discharged virus and fluid in the chamber by increasing the volume thereof to force the virus under an effective extravasation pressure through a barrier presented by the endothelial lining of the vessel or duct, without removing or otherwise injuring the endothelial lining, for delivery of an effective dose of the virus into the defective cells of the affected tissue at the target site.

9. The method of claim 8, wherein the disease or disorder to be treated is cancer, the affected tissue is a malignant tumor, the selected virus is an oncolytic virus, and the containment fluid of the virus is a pharmaceutically acceptable fluid carrier.

10. The method of claim 8, wherein the disease or disorder to be treated is attributable to single-gene defects for treatment by somatic cell gene therapy, the affected tissue is selected from one of an immunodeficiency, cystic fibrosis, hemophilia, muscular dystrophy, and sickle cell anemia, the selected virus is an engineered non-oncolytic virus having incorporated therein therapeutic DNA integrated into its genome for delivery into a chromosome so as to administer a gene that causes expression of a needed protein and thereby replace or disrupt the defective gene.

11. The method of claim 8, wherein the disease is attributable to a gene defect for treatment by gene therapy, the affected tissue is selected from one of an acquired or inborn disease including HIV, immunodeficiency, cystic fibrosis, hemophilia, muscular dystrophy, or sickle cell anemia, the selected virus is an engineered non-oncolytic virus having the ability to induce therapeutic RNA, mRNA, iRNA, shRNA, DNA, or CRISPR Cas9 constructs, integrated into its genome for delivery into defective cells at the target site so as to induce a genetic modification that causes expression of a needed protein to modify, replace or disrupt the defective gene.

12. A method for treating a disease or disorder in the body of a subject, said method comprising the steps of occluding a blood vessel or duct of the body bounding a target site of defective cells of affected tissue of the disease or disorder with two spaced-apart balloons of a balloon catheter inflated to create a chamber therebetween at the target site and to block normal perfusion through the vessel or duct at the chamber, infusing an effective dose of a virus selected for its ability to infect the defective cells and contained in a body-compatible fluid carrier under pressure through an infusion lumen of the catheter and into the chamber, and controlling the volume of the selected virus and its containment carrier delivered into the chamber and thereby the pressure therein so as to reach an effective extravasation pressure sufficient to force the effective dose of the virus through a natural endothelial barrier lining the vessel or duct within the chamber, without inflicting damage thereto, to penetrate and induce a desired therapeutic effect in defective cells of the affected tissue in the vicinity of the target site.

13. The method of claim 12, wherein the disease or disorder to be treated is cancer, the affected tissue is a malignant tumor, the selected virus is an oncolytic virus, and delivery of the virus into the chamber is performed by infusing the effective dose thereof in a pharmaceutically acceptable fluid carrier through the infusion lumen of the balloon catheter inserted in the vessel or duct to position the chamber at the target site.

14. The method of claim 12, wherein the disease or disorder to be treated is attributable to single-gene defects for treatment by somatic cell gene therapy, the affected tissue is from one of an immunodeficiency, cystic fibrosis, hemophilia, muscular dystrophy, and sickle cell anemia, the selected virus is an engineered non-oncolytic virus having incorporated therein therapeutic DNA integrated into its genome for delivery into a chromosome so as to administer a gene that causes expression of a needed protein and thereby replace or disrupt the defective gene in cells of the affected tissue in the vicinity of the target site.

15. The method of claim 12, wherein the disease or disorder to be treated is attributable to a gene defect for treatment by gene therapy, the affected tissue is from one of an acquired or inborn disease including HIV, immunodeficiency, cystic fibrosis, hemophilia, muscular dystrophy, or sickle cell anemia, the selected virus is an engineered non-oncolytic virus having the ability to induce therapeutic RNA, mRNA, iRNA, shRNA, DNA, or CRISPR Cas9 constructs, integrated into its genome for delivery into the chamber for penetration of cells of the affected tissue in proximity to the target site so as to induce a genetic modification that causes expression of a needed protein to modify, replace or disrupt the defective gene in the penetrated cells.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0049] For a more complete understanding of the present invention, including its various features and advantages, reference will now be made to a detailed description of the invention in conjunction with the accompanying figures, in which:

[0050] FIG. 1A is a simplified partial cut away cross-sectional view of a preferred embodiment of a two-balloon catheter positioned-in-place in a vessel or duct of the body, to be used in performing methods of infusing selected infecting viruses, whether engineered or unmodified, into defective cells of affected tissue attributable to a disease or disorder suffered by the subject.

[0051] FIG. 1B is a simplified partial cut away cross-sectional view of an alternative, but less preferred embodiment of a balloon catheter positioned-in-place as was the embodiment of FIG. 1A, to be used in performing methods of infusing such selected infecting viruses into defective cells.

[0052] FIG. 2 depicts a balloon catheter of the type shown in FIG. 1A, inserted into an arterial tree leading to targeted affected tissue in the body of a subject for administering a selected infecting virus into tissue of a malignant tumor or into affected tissue attributable to a different disease or disorder.

[0053] FIG. 3A is a transparent front view of a subject illustrating an exemplary procedure for injecting a prescribed quantity of virus contained in body-compatible fluid into the cerebral circulation of a patient, and FIGS. 3B and 3C are companion simplified views of syringes used in the course of such procedure.

[0054] FIG. 4 is a transparent front view of a subject illustrating an exemplary procedure for administering a prescribed quantity of selected virus in body-compatible fluid intraluminally through a duct of the subject's body via a balloon catheter installed in the duct, to infect targeted tissue of the body attributable to or responsible for a disease or disorder under treatment.

[0055] It should be noted at the outset that the figures are not intended to be to scale, nor to do more than serve as a visual aid to the description. In those figures representing the human body or body parts, certain components may be exaggerated relative to others for the sake of emphasis or clarity of the respective accompanying description. Also, it will be understood that the individual elements of the virus delivery system are not necessarily intended to reflect the specific shape(s) of those elements. Individual elements common to several Figures are in most instances designated by the same or closely related reference number.

DESCRIPTION OF PRESENTLY PREFERRED EMBODIMENTS AND METHODS

[0056] Certain embodiments of the present invention are directed to improvements in the method(s) and apparatus(es) utilized for prior local and regional delivery techniques, by administering viral agents with a multi-balloon catheter of various advantages.

[0057] In the instance of treating malignant tumors, for example, the methods disclosed herein exploit the abnormal structure of tumor vasculature. Although small clumps of nascent tumor cells are able to acquire oxygen and nutrients by diffusion, solid tumors require formation of new blood vessels for growth. The tumor thus rapidly induces the formation of a dedicated vasculature able to support progression. However, this vasculature features structural and functional abnormalities including decreased vessel density, heterogeneous microvessel distribution, increased sinusoids, dead ends and arterio-venous anastomosis, and vessels having incomplete basement membranes and absence of smooth muscle. In short, tumor vasculature is characterized by immature, highly-permeable, chaotic vessels with heterogeneous blood flow. The present invention, in its embodiments and methods for treating cancer, applies pressure-mediated delivery of oncolytic viruses to the tumor via vessels and ducts leading to the body tissue bearing the tumor.

[0058] Use of a balloon catheter provides several advantages in the treatment of cancers with oncolytic infecting viruses, and, as will be more fully understood from the detailed description herein, in the treatment of other diseases and disorders with prescribed infecting viruses, whether engineered or natural. These advantages include selectively local increases in viral concentration, isolation of the delivered viruses from normal fluid flow pressures in the target tissue in order to increase contact time and minimize interaction with systemic antibodies, and pressure-mediated delivery which allows the viruses to transit the cellular boundary of delivery ducts and vessels to become trapped in spongy fluid conduits characterizing, in some cases, the affected tissue. In one embodiment, the virus is applied in a delivery solution having increased viscosity in order to increase the pressure of delivery and to minimize washout of the viruses from the targeted site in the vessel or duct in which the balloon catheter is installed for delivery of the viruses to that site.

[0059] Procedures disclosed herein are particularly directed to the requirements of the clinical practice of interventional medicine, and thus follow the principle that only those approaches that are both (a) relatively easy to perform, with little or no risk but of potentially significant benefit to the patient, and (b) highly cost effective, are likely to be routinely applied in everyday medicine. The approach provided is based on an appreciation by the applicant that biological agents such as viruses are preferably delivered in local concentration to the targeted site, and that such agents need a certain amount of contact time to adhere and migrate from a vascular or ductal bed into the target site.

[0060] In preclinical studies, adhesion of the injected viruses and their migration past the endothelial bather of the vessel or duct by which they are to be intraluminally delivered, and into the defective cells responsible for or attributable to the disease or disorder under treatment, may be confirmed by observation after several hours/days of frozen sections using light microscopy and, if desired, by electron microscopy. In addition, a green fluorescence protein (GFP) or other marker may be used to aid the observation by introduction of the GFP gene into the viral genome with detection of expressed protein by fluorescence microscopy. Alternatively or in addition, the viruses can be grown in radioactive medium to label their RNA or DNA with radioactive tags that may enable a gross estimate of the concentration delivered to the specific targeted tissue. Further methods that are more sensitive include detection of viral DNA/RNA by molecular methods including RT-PCR.

[0061] The disclosed approach is suitable for delivery of any virus that naturally or by engineering is able to preferentially infect and kill or allay (i.e., subdue or reduce the intensity or severity of) the deleterious effect of defective cells, whether cancerous or containing defective genes attributable to or responsible for other disease or disorder. To date oncolytic viruses have been identified or developed in members of both DNA and RNA virus families including herpesviridae (i.e. HSV, CMV and pseudorabies), poxviridae, adenoviridae, parvoviridae, rhabdoviridae (i.e. vesicular stomatitis virus), togaviridae (Sindbis) and picornaviridae (i.e. coxsackie virus and poliovirus).

[0062] In one embodiment of the invention for treating cancers, the oncolytic virus is a parvovirus including wild-type autonomous or modified replication competent derivatives thereof as well as related viruses or vectors based on such viruses or derivatives. Parvoviruses are small (25-30 nanometer (nm)) non-enveloped particles containing a 5.1 kb single-stranded DNA genome from which two nonstructural (NS1, NS2) and two capsid (VP1, VP2) proteins are expressed (see, e.g., Cotmore S F and Tattersall P. “The autonomously replicating parvoviruses of vertebrates” Adv Virus Res 33 (1987) 91-174). Some autonomous parvoviruses belong to the category of oncolytic viruses (see, e.g., Rommelaere J, Cornelis J. “Antineoplastic activity of parvoviruses” J Virol Methods 33 (1991) 233-51). Several members of the parvovirus genus (H-1PV, MVM, LuIII), whose natural hosts are rodents, are presently under consideration for cancer gene therapy applications due to their failure to transform host cells, capacity for asymptomatic infection of humans, and ability to preferentially propagate in (oncotropism) and kill (oncolysis) neoplastically transformed cells (see, e.g., Haag A, et al. “Highly efficient transduction and expression of cytokine genes in human tumor cells by means of autonomous parvovirus vectors; generation of antitumor responses in recipient mice” Hum Gene Ther 11 (2000) 597-609).

[0063] Parvovirus H-1PV has the unique advantage of triggering a distinct death process, at least in brain and some other tumors, namely the cytosolic relocation and activation of lysosomal proteases (cathepsins) (see, e.g., Di Piazza M, et al. “Cytosolic activation of cathepsins mediates parvovirus H-1-induced killing of cisplatin and TRAIL-resistant glioma cells” J Virol 81 (2007) 4186-98). As a further advantage, MVMp and H-1PV viruses have been shown to exert oncosuppressive activities in vivo, i.e. they are able to inhibit the formation of spontaneous, chemically or virally induced tumors in laboratory animals. Suitable parvoviruses for purposes of the present invention in cancer treatment include but are not limited to rodent parvovirus species H-1 PV, LuIII virus, various strains of Minute virus of mice (MVM) (recently renamed mice minute virus (MMV)), including MVPi and MVPp, Mouse parvovirus (MPV), Rat minute virus (RMV), Rat parvovirus (RPV) or Kilham Rat virus (RV).

[0064] The oncolytic (or non-oncolytic, for treatments of diseases or disorders other than malignancies) viruses are delivered in an effective dose and combined with a pharmaceutically acceptable carrier. An “effective dose,” as used herein, refers to amounts of the active ingredients that are sufficient to affect the course and the severity of the disease, leading to the reduction or remission of such pathology. An “effective dose” useful for treating and/or preventing diseases or disorders addressed by the present invention may be determined using methods known to those ordinarily skilled in the art. Such methods and background art are disclosed for example by Marchini et al. in U.S. patent application Ser. No. 14/355,691 published Oct. 16, 2014. The terminology “pharmaceutically acceptable” is used herein to encompass any carrier that does not interfere with the effectiveness of the biological activity of the active ingredients and that is not toxic to the patient to whom it is administered. Examples of pharmaceutically acceptable carriers suitable for selection under those premises are well known in the art and include phosphate buffered saline solutions, water, emulsions, such as oil/water emulsions, various types of wetting agents, sterile solutions, etc. Such carriers are or can be formulated by conventional methods and administered to the subject with an effective dose of oncolytic virus(es) contained therein.

[0065] As used herein, “effective extravasation pressure” means a pressure sufficient to exceed the normal fluid pressure of a given lumen and cause fluids to be forced between cells forming the lumen walls and thereby overcome the endothelial barrier consisting of endothelial cells and the basal membranes of the vessel or duct, and sufficient to penetrate and enter the targeted cells themselves. Because of the abnormal vasculature of tumor tissue, tumor tissue is particularly susceptible to pressure-mediated delivery. In one embodiment, the oncolytic virus formulation includes a marker such as a dye or radiomarker that can be visualized during administration with adjustment of extravasation pressure to assure effective perfusion of the administered agent into the tumor and immediately surrounding tissue. In one embodiment, the marker is a nuclear tracer such as Tc-99 or a MRI sensitive agent such as Gadolinium or derivatives thereof, and small superparamagnetic particles such as iron oxide nanoparticles. Typically, a change in pressure of 20 mm Hg is sufficient to overcome the endothelial pressure in normal tissue. Visualization of the delivery process permits adjustment of delivery pressure to achieve desired perfusion of the tumor tissue.

[0066] The essence of the present invention pertains to methods of delivery of the therapeutic substances, and not only to methods of delivery of oncolytic or non-oncolytic viruses, but also to delivery of other agents selected to enhance the effectiveness of treatment utilizing those very same methods of the delivery. Non-limiting examples of those other agents include substances such as natural or engineered exosomes, microvessicels, cytotoxic and cytostatic agents such as interferons or chemical compounds inducing cytotoxic/static effects or substances modifying the immune tolerance such as negative co-stimulators or check point inhibitors. For these therapy-enhancing agents, the same principle applies, that is, of overcoming without harming the endothelial barrier lining a blood vessel or fluid duct in fluid communication with defective cells of tissue affected by the manifestation of the disease or disorder to be treated, and thence, penetration of the cells of the affected tissue by controlled application of an extravasation pressure effective within a compartment or chamber of the vessel or duct blocked against perfusion therethrough and in which a target site of the affected tissue is present to selectively enhance delivery and concentration so as to force the therapy-enhancing agents and selected virus(es) from the compartment in dosages effective to alleviate the defect in the penetrated cells.

[0067] These therapy-enhancing agents may be delivered either together with the virus or delivered completely independently thereof. Transluminal or intraluminal delivery of the infecting viruses with or without therapy-enhancing agents through a blood vessel may be performed through an arterial or venous vessel in cardiovascular communication with the designated target site of affected tissue. Non-oncolytic viruses are typically selected for delivery by virtue of their capacity to infect the defective cells, and their having been engineered (or in some instances, natural propensity) to supply or remove or overexpress or suppress certain cellular genes and connected protein expression, thereby altering the function of the cells.

[0068] A balloon catheter is employed for the intraluminal application of infecting viruses for reasons noted earlier herein and especially reasons of simplicity, effectiveness, and widespread use in a number of diagnostic and therapeutic procedures, and is therefore in keeping with the clinical practice of interventional medicine. In a preferred embodiment of the method and system of the present invention, the catheter is of a two-balloon type, wherein the two balloons are spaced-apart from or near the vicinity of the catheter's distal end. Occlusion of the blood vessel or duct to prevent or to stem perfusion of the fluid normally carried therethrough is performed by inflating the catheter's balloons simultaneously for a time interval prescribed to increase the pressure, concentration and effectiveness of oncolytic agents (in the case of cancer treatment, or of selected non-oncolytic viruses in the case of treatment of other diseases and disorders) delivered to the targeted body tissue to be treated.

[0069] Use of the two-balloon catheter allows the desired delivery of therapeutic viruses, agents and substances to be achieved by effective extravasation pressure as defined above. Typically, bolus injection will result in pressure in excess of the normal range of fluid pressure within the respective artery, vein or duct into which the balloon catheter has been advanced for purposes of treatment of the disease or disorder of interest. The effective extravasation pressure is achieved by controlling the volume of virus and its fluid carrier infused into the aforementioned compartment or chamber created by inflating both balloons when positioned with the target site therebetween, and may be expected to force fluid including the virus into the intercellular space between cells lining the blood vessel or duct.

[0070] Whether employed for treatment of malignant tumors or of other diseases or disorders, the delivery method applies pressure-mediated viral delivery of either oncolytic viruses that selectively infect, replicate in and destroy tissue (in the case of tumors), or non-oncolytic viruses that selectively infect and destroy or allay the effects of defective cells (in the case of other diseases or disorders), through a blood vessel or duct or a tree thereof in the subject's body, and into defective cells of targeted tissue of the tumor or other disease or disorder navigable therethrough in such a way as to assure that regional high concentrations in effective dosage of the selected virus(es) are able to penetrate the endothelial barrier of the vessel or duct lining without injury or compromise thereof.

[0071] Emerging clusters of tumor cells, for example, which may include millions of cells, are too small to be individually perceived and targeted by intra-tumoral injection, and thus, such injection of oncolytic viruses is very likely to be ineffective to permit exposure of the viruses to all of the foci of tumor cells in a targeted organ or region of body tissue. It is important to recognize that the selected oncolytic (or non-oncolytic, as the case may be) virus in its pharmaceutically acceptable carrier can be applied broadly in the affected region of the body while localizing the viruses in the area of the affected tissue and cells for an interval of time (as in the aforementioned compartment or chamber created by the inflated balloons at the target site) sufficient to achieve an effective extravasation pressure and thereby, attachment of and infection by an effective dose of the viruses. Tumor vasculature and the endothelial lining of vascular and ductal structures in a tumor are abnormal, but these abnormalities can be overcome to advantage by techniques known to those of skill in the art.

[0072] In various methods of deployment of the system for practicing the methods of the invention, a guide wire is first introduced through the blood vessel or duct to the target site of the body tissue to be treated, and thereafter the balloon catheter is advanced either manually or mechanically driven over the guide wire until the distal end of the catheter reaches a selected point in the vicinity of the affected body tissue that places a target site for treatment between the two balloons (when inflated) for delivering the virus and its carrier thereto.

[0073] Reference will now be made to the accompanying figures in describing exemplary methods and systems for viral delivery. The description of the figures may refer in some instances to virus delivery for destroying a tumor, and in other instances to virus delivery for altering or allaying the effective of defective cells in affected body tissue of another disease or disorder, but it is to be understood that the basic method of virus delivery is the same or substantially the same in either case. That is, the only significant differences may be the type of virus employed in the treatment, and that virus' effect on the affected tissue or cells thereof.

[0074] In practice, a preferred method of the present invention utilizes a two-balloon catheter of length and diameter to accommodate its threading through the vasculature or ductwork necessary to reach the body tissue designated for treatment, and the catheter having multiple lumens therein to accommodate delivering multiple materials therethrough. For example, a two-balloon catheter having diameter size of about four French (equivalent to about 1.3 millimeters, mm), and a balloon diameter of about 2.54 centimeters (cm) when inflated (i.e., the same for each balloon) might be selected, for a snug fit and suitable blockage of perfusion in the vessel. Balloon catheters are available or readily produced with up to 3 or 4 channels (lumens), including a proximal lumen at or near the diametric center of the catheter and extending through the entire length of the catheter to accommodate its being advanced over a guide wire initially inserted into the vessel or duct. Another channel to be provided in the instant embodiment is an inflation lumen for selective inflation or deflation of both balloons simultaneously, and yet another channel as an injection or infusion (delivery) lumen for the virus and its carrier fluid to be discharged from a port or ports between the two spaced-apart balloons when positioned with the target site therebetween, one balloon located at or very near the catheter's distal end (i.e., referred to from time to time herein as the more distal balloon) and the other situated proximally thereto (i.e., referred to from time to time herein as the more proximal balloon), spaced about 1 to 2 inches apart, for example.

[0075] An alternative, but less preferred method utilizes a single balloon catheter, to be advanced through the vessel or duct path leading to the target site of the affected tissue to be treated, over the initially inserted guide wire, as in the case of the two-balloon catheter. In this alternative method, however, the single balloon is situated as was the more proximal balloon of the two-balloon catheter. One or more discharge ports of the injection lumen from which the virus and carrier fluid are to be discharged is disposed distally of the single balloon and proximally of the distal end of the catheter so that when the catheter is fully advanced (for delivery of the treatment) in the vessel or duct, the target site is located between the balloon and the distal end of the catheter substantially opposite the discharge port(s). Blockage of normal perfusion through the vessel or duct using this single balloon embodiment is established in the manner described below. The catheter is provided with three lumens, including the previously-mentioned injection or infusion lumen, and as well, an inflation/deflation lumen for the single balloon, and a central lumen extending the entire length of the catheter.

[0076] The central lumen of this alternative embodiment provides two purposes, viz., (1) it allows the catheter to be advanced over the guide wire, after which the guide wire is removed through the proximal outlet of the central lumen, and (2) the now-open central lumen is utilized to inject under pressure a multiplicity of relatively fast-dissolving beads such as of gelatin or collagen composition therethrough for ejection from the central lumen's open port at the distal end of the catheter. The beads are formed or selected to be of an initial size large enough (in a range of, for example, 10 to 12 microns (μm) and not plastically compressible) to form a wall as they are ejected from the distal end of the catheter so as to temporarily block perfusion through that portion of the vessel or duct between the inflated balloon and the bead-formed temporary wall. The beads should be delivered through the central lumen for at least a period of time before and over which the virus is forced under pressure through the infusion lumen and discharged therefrom through the discharge port, to maintain the integrity of the formed wall and avoid virus escape therethrough during that period. The volume of the beads ejected into the blood vessel or duct should be sufficient (e.g., a very few milliliters) to not only block perfusion therethrough but also to prevent the virus from escaping through that route from the chamber bounded by the inflated balloon, the bead wall and the outer surfaces of the catheter and the lining of the vessel or duct wall. As always, when perfusion of blood is being blocked intentionally, appropriate attention must be given to a compromise between (i) penetration of the delivered virus through the lining endothelium and into the infected cells of the affected tissue and (ii) allowance of the capillary flow to resume before damage to or cell death of healthy tissue.

[0077] Referring now to FIG. 1A, a partial cut away cross-sectional view of a positioned-in-place preferred catheter 11 for performing the virus delivery method of the invention has two balloons spaced-apart along its length, one of which is the more distal balloon 3 and the other of which is the more proximal balloon 4. In this Figure, the catheter is depicted after having been advanced at its distal end to a designated location 6 in a blood vessel or duct 16 (only the vessel wall 17 being shown in a lengthwise cross-section through its central axis, for the sake of clarity and simplicity), and the two balloons inflated for a snug fit and perfusion blockage in the vessel. Simultaneous inflation of the two balloons is effected by infusing a suitable biocompatible fluid through an inflation lumen 19 having an outlet port 20 into each balloon. The catheter also has a central lumen 21 open at each of its proximal and distal ends for passage over a guide wire (not shown) that was initially inserted into the vessel 16 to at least the designated end point 6, and after the catheter has been advanced to the appropriate position, as viewed by applicable means such as fluoroscopy, the guide wire is removed.

[0078] The positioning of the catheter 11 in the vessel or duct is intended to place a designated target site 22 of the affected tissue attributable to or responsible for the tumor 23 or other disease or defect, between the two balloons 3, 4 within a space forming a chamber 24 bounded by the opposing surfaces of the two balloons, and the surface of the catheter and the inner surface of the vessel wall between the balloons. After the proper positioning has been achieved, the balloons are deployed by inflation thereof to block perfusion through the chamber. Then, an appropriate volume of the selected infecting virus constituting an effective dose within its pharmaceutically acceptable carrier, is proximally infused through the catheter's infusion lumen 25. The infused virus and carrier may be in the form of a stream or a bolus, and the infusion is performed under pressure for ejection from a discharge port (or ports) 26 of lumen 25 into the chamber 24. The pressure of the virus and carrier within the chamber is controlled by the volume and concentration of the virus/fluid delivered therein, as well as the time interval over which those elements are maintained within the chamber. This control is maintained so as to force the effective dose of the virus under an effective extravasation pressure through the natural endothelial barrier at the lining 28 of the vessel or duct wall 17 and into the infected cells of the affected tissue. It is noteworthy that penetration of the endothelium of the vessel's lining is achieved without damage, denuding or other compromise to or of that barrier or to the vessel lining itself This assures that the desired “cure,” remission or revision will not bring about an equally or other deleterious outcome as the original disease or disorder sought to be treated.

[0079] Referring now to the also partial cutaway and cross-sectional view of FIG. 1B, an alternative, but less preferred embodiment than that of catheter 11 of FIG. 1A, is utilized for performing the method of the present invention with a single balloon version designated 11A. Catheter 11A is shown in a portion of a vessel or duct 16 of the subject's body selected for viral delivery. The single balloon 4A of this catheter is situated as was the more proximal balloon of the two-balloon catheter. A second more distal balloon 3, not present in this embodiment, would have been located on the catheter as shown by dotted lines. As with catheter 11, the catheter 11A has three lumens, designated here as 19A, 21A and 25A, but unlike the embodiment of FIG. 1A, inflation lumen 19A extends only as deeply as and into balloon 4A for inflation thereof, and central lumen 21A is used for two purposes.

[0080] First, the central lumen accommodates removal of a guide wire (not shown) that had been inserted initially into duct 16 to a point 6A beyond that of point 6 to which the distal end of two-balloon catheter 11 was advanced, for a reason that will become clear presently. After the catheter 11A is advanced over the guide wire to position its distal end short of point 6A, the guide wire is withdrawn from the proximal outlet of the central lumen 21A, leaving that lumen open as an outlet at its distal end. The infusion lumen 25A extends into catheter 11A only sufficiently deeply to situate its discharge port 26A (more than one of which may be spaced circumferentially on the catheter at that depth so as to allow greater infusion but not so many as would sacrifice the integrity of the catheter thereat) approximately midway between balloon 4A and the catheter's distal end. And the positioning of the catheter 11A within duct 16 for deployment and inflation of balloon 4A is made to place the discharge port(s) 26A substantially directly opposite a target site 22 of the affected tissue to be treated.

[0081] After such positioning of the catheter and deployment of its balloon, a multiplicity of relatively fast-dissolving beads 30 such as composed of gelatin, mannitol, dextrose, sorbose, sucrose, or collagen (see, for example, U.S. Pat. No. 4,827,940) are injected under low pressure through now-open central lumen 19A from its proximal inlet to its distal outlet for ejection therefrom. As the beads, which are selected to have an initial size in a range of, for example, 10 to 50 μm and of low compressible consistency, emerge in large numbers from the distal outlet and stick together in an outward flow large enough to form a temporary wall 36 slightly beyond the distal end of the catheter 11A at the capillary level. After a time interval sufficient to allow wall 36 to be established to block perfusion through the duct and form chamber 24, but before the wall begins to disintegrate as the result of dissolution of beads by which it was formed, i.e., an interval of about one to a few minutes, a predetermined volume of the pharmaceutically acceptable fluid carrier containing an effective dose of the selected infecting virus (and therapy-enhancing agent, if desired) is driven under increasing pressure through infusion lumen 25A and from discharge port(s) 26A. The discharge is monitored and largely maintained by controlling its volume and pressure within chamber 24 until it builds to the desired effective extravasation pressure sufficient for the virus to penetrate the endothelial barrier presented by the lining 28 in the vessel or duct wall 17, without damage thereto, and into the defective cells of the affected tissue at and around the target site 22.

[0082] A sufficient volume of beads 30 (e.g., typically consisting of only a few milliliters, such as 2 to 5 ml) is selected for ejection into the blood vessel or duct to form the temporary wall 36 and thereby block perfusion therethrough, as well as to avoid escape of the virus/carrier fluid from the chamber 24 except for penetration of vessel wall 17 without denuding its lining, and into the affected tissue and its cells thereunder. Chamber 24 occupies the same space as described above for FIG. 1A, except that one “surface” is formed by the ejected beads, in the absence of and substitution for that of the more distal balloon 3 (depicted in phantom) of FIG. 1A. Blood perfusion should not be blocked for a time interval exceeding that absolutely necessary to achieve such penetration, and in all events the interval of blockage should be capped at a limit that comfortably assures avoidance of damage to or ischemia of cells that may cause death of otherwise healthy tissue, resulting from the shortage of oxygen needed to meet the demand for cellular metabolism.

[0083] Referring now to FIG. 2, in one embodiment of a method for treating a tumor, oncolytic viruses within fluid carrier may be applied to the subject (patient) by initially introducing two-balloon catheter 11 into the vascular system, e.g., at the patient's groin using an introducer, and through a short guiding catheter 5 over a guide wire 18. The guide wire is inserted into the vascular system to a depth sufficient to accommodate advancement of the balloon catheter 11 over the guide wire via central lumen 12 of the catheter and into a blood vessel (an artery 8, in this example) or duct (as the case may be). The distal end of catheter 11 is advanced in proximity to the target site of the cancerous tissue (tumor 2) to receive the therapy to be provided by a method of the present invention. After such advancement of the catheter, guide wire 18 is then removed from the proximal end of the catheter via central lumen 12.

[0084] In the depicted example of FIG. 2, the tumor 2 is supplied with blood through artery 8 and its distal branches 9 and 10, etc., of the arterial tree. After the catheter is properly positioned as described above in the discussion of FIG. 1A, with at least a portion of tumor 2 situated between the more distal and more proximal balloons 14, respectively, the balloons are deployed by simultaneous inflation through an inflation lumen (not shown) to maintain the catheter's position within the artery. A combination of the effective dose of selected infecting oncolytic virus and pharmaceutically acceptable fluid carrier may then be injected under increasing pressure through an entry port at the proximal end of an infusion lumen 13 of the catheter 11 by hand injection or by means of a motor driven constant speed injection syringe (not shown). The virus and its fluid carrier are thereby discharged under pressure from one or more discharge port(s) of infusion lumen 13 located between the inflated balloons 14 bounding the target site of tumor 2 to receive treatment from the effective dose of virus delivered thereto.

[0085] The oncolytic virus particles 15 are thus delivered into the space occupied by the chamber formed at the target site by the confronting surfaces of the two balloons 14, the surface of catheter 11 and inner surface of vessel 8 therebetween. As the controlled pressure and volume of the virus particles and containment fluid in that space builds to a designated effective extravasation pressure, typically within a period of from 10 seconds to a few minutes, for example, the effective dose of infecting oncolytic virus particles of some 30 to 250 nm size is forced through the endothelial barrier at the inner lining of artery 8 bounding the target site and into the typically 10 μm entry holes of the defective cells of the tumor to destroy them or to allay their effect (e.g., place them in remission).

[0086] The disclosed delivery method overcomes several problems with prior vascular or ductal delivery schemes. During transit through the vascular system by a typical prior technique in which viruses are blood-borne, the viruses are susceptible to binding by antibodies that normally participate in deactivating viruses and removing them via the reticulo-endothelial system. Furthermore, any particles transiting a blood vessel or duct, including viruses, are normally separated from the parenchymatous organ or the tissue outside the vessel by the continuous cells lining the vascular or ductal conduit. Intravenously delivered oncolytic agents would be separated from the cancer tissue to be treated by the endothelial lining and other tissue layers of blood vessels that lead to the cancerous tissue. However, under circumstances produced by the methods of the present invention, virus delivery is through a catheter, and this endothelial barrier is overcome, to enable the virus to attach to the inner surface of the vessel, migrate and proliferate through the endothelial layer into the adjacent tissue. Here, an increase in pressure with increasing injection volume of the virus following balloon inflation defining the distribution zone (at the target site) can overcome the endothelial layer and effect extravasation from the vascular system and into the defective cancer cells to reduce or destroy the tumor or allay its effect as by remission.

[0087] The methods disclosed herein further provide for optimum numbers of the viral particles to contact and enter cells of the malignant tissue without dilution. Use of the two-balloon catheter 11 (or other mechanism such as the single balloon 4 of catheter 11A aided by the oppositely disposed bead wall 30 of FIG. 1B) allows for selective blockage of the antegrade blood flow and loss of the agent into the systemic circulation. Balloon catheters are preferred for use in methods of the present invention for reasons previously enumerated herein, and also because such catheters are well known, often used and reliable devices for introduction to a predetermined site in a vessel such as an artery or vein, or a duct. In the methods of the invention, the balloons 14 of catheter 11 are simultaneously inflated with biocompatible fluid through a separate inflation lumen of catheter 11 to occlude artery 8 and its distal branches 9, 10, etc. of its arterial tree, thereby causing perfusion through the vessel to cease. Inflation of the balloons may be commenced immediately before or at the time of injection of the oncolytic virus through the infusion lumen 13 of the catheter, and is maintained throughout the period of injection. This enables adhesion of a desired large number of infectious oncolytic viral agents to the target tissue.

[0088] Absence of blood flow at the delivery site has several advantageous effects. It prevents what would otherwise result in a retrograde loss of injected agents as well as antegrade dilution with blood flow, while providing a capability on the part of the physician or control instrumentation performing the method to increase the pressure at the injection site to an effective extravasation pressure to overcome the endothelial barrier and force the viruses into the sub-endothelial cells of the affected tissues.

[0089] Depending on location of the balloon(s), the type of vessel or duct, the type of organ to be treated, and the multiplicity of viral agents delivered, the blockage is maintained for a relatively short period of time, preferably on the order of one to fifteen minutes, and in any event sufficient to allow a high concentration and considerable number of viral attachments to defective cells of the cancer tissue (or other tissue of a disease or disorder) at the designated target site. In the case of a slow infusion of the oncolytic (or non-oncolytic) agents, the period of blockage is maintained longer by steady inflation of the balloon over the infusion period, for example up to about 30 minutes, for enhancement of contact and adherence to the endothelium. In the example of two-balloon catheter usage, both balloons are deflated simultaneously, and in any case, the balloon catheter is removed from the patient after the treatment procedure is completed.

[0090] The concepts of the present invention include using the natural distribution tree of the arterioles and the capillaries or the ductal distribution tree to cover the complete inner, medial and outer layers of the cancer tissue with oncolytic agents, or of affected tissue of other disease or disorder with non-oncolytic agents penetrating defective cells thereof.

[0091] The methods of the invention are not limited to treatment of a particular cancer, but rather, of various different types of cancer. For example, the method of treatment may be applied to brain cancer, e.g., glioma, in which case the infusion catheter is advanced to the site of the cancer tissue through an appropriate arterial path into the applicable region of the patient's brain, as described more fully below. Blockage of blood flow in this case would add a period (e.g., minutes) of limited blood supply but would enable the oncolytic agents to overcome the endothelial barrier.

[0092] Other possible cancers to be treated by the process disclosed herein include cancer of the pancreas, the liver, and the kidneys. The pancreas has a duct (the ductus Wirsungii) through which pancreatic enzymes are delivered into the intestines, and which can be accessed in a retrograde manner by endoscopic retrograde choledocho-pancreaticography (ERCP). By means of the visual guidance, such as through a small fiber optic instrument, a small balloon catheter may be introduced into this duct, and the balloon inflated to occlude the duct during delivery of oncolytic agents through the catheter's inner lumen to the site of the cancer tissue, so as to prevent the injected agents from being washed out into the intestines and thereby enhancing adhesion and penetration by a relatively large number of the administered agents. An analogous procedure may be used for treatment of cancerous tissue of the liver, through the bile duct system. Here also, it is important to overcome the barrier of the normal bile duct with pressure that can be generated only if the balloon is inflated while the agents are slowly injected. The pressure distal to the injection site increases as more and more volume is injected. Treatment of cancerous tissue in the kidney(s) may be conducted by an analogous procedure.

[0093] In an embodiment of the invention, effective delivery of the oncolytic viral agent may be visualized concurrently for accuracy of location in the subject's body. In one embodiment of delivery to the bile duct, intraoperative cholangiography is performed to visualize the anatomy of the duct system as well as effective delivery of the viral agent. In another embodiment, the viral agent is formulated with a dye such as a fluorescent dye that can be visualized such as with the same fiber optic guidance system that is used to introduce the balloon catheter into the duct or vessel. In one non-limiting example of a visualization system that may be employed, a dye visible at a wavelength of 750 nm or greater is used together with an exciting light source such as that as disclosed in U.S. Pat. No. 8,050,745, issued Nov. 1, 2011, incorporated herein by reference. Further examples of a visualization systems are disclosed in U.S. patent application Ser. No. 11/868,432, published as US 2008/0249400, and now abandoned, incorporated herein by reference. Other imaging methods include SPECT, CT and MRI together with their respective enhanced visualization agents.

[0094] Brain cancer: FIG. 3A is a transparent front view of a subject illustrating an exemplary procedure for injecting a prescribed quantity of virus contained in body-compatible fluid into the cerebral circulation of a patient, useful to describe an example of a method for delivery of oncolytic agents through a balloon-guided catheter to the anterior cerebral circulation in a patient 31. An introducer sheath 33 of appropriate size, typically 5-7 French, is advanced through the right groin 32. Then a two-balloon guided double lumen catheter 34 is advanced through introducer sheath 33 and over a small guide wire 48 directed to the artery of interest. Guide wire 48 has a diameter in a range of 0.014 to 0.018 inches, and a flexible distal tip to render it bendable so as to direct the guide wire through the vessel to the vicinity or locality of the selected target site. The proximal end of guide wire 48 is left to project from opening 35a of catheter 34. A side branch opening 35b of catheter 34 is operatively coupled through an inflation lumen of the catheter for selective simultaneous inflation and simultaneous deflation of its two balloons 46.

[0095] Initially, after guide wire 48 is advanced to its desired position, catheter 34 is inserted into the subject's vascular system and manoeuvred to the selected site by gliding it over the guide wire through the central lumen of the catheter. The distal end of the catheter may be advanced through iliac artery 37, abdominal and thoracic aorta 38, aortic arch 39, and into the right carotid artery 40 beyond the branching off of the vessels 41 for the right arm. As an alternative, guide wire 48 and catheter 34 may be advanced to a location in the left carotid artery 42. The left carotid artery either originates after the branch-off of the left subclavian artery 43, or directly from the aortic arch 39 where the left subclavian artery originates from a separate orifice in the aortic arch. After advancing catheter 34 through the common carotid artery into the right carotid artery 40 and into the proximal circulation of the circulus willisi 44, the anterior cerebral artery 45 is encountered at its origination. Alternatively, in lieu of access through the femoral artery, vascular access to the carotid may be obtained through the right radial artery, particularly in patients with a strong radial pulse.

[0096] After the catheter 34 has been advanced so that its distal tip 47 and two spaced-apart balloons 46 are positioned in the anterior cerebral artery 45, with tip 47 located such that the target site to which parvoviruses are to be delivered is situated between the two balloons, guide wire 48 is removed. The opening 35a of the same lumen that had been used for the guide wire is now available for injecting oncolytic agents, and that lumen is closed at the distal end of catheter 34 to open one or more discharge ports from the lumen into the space between the two balloons at the cerebral circulation. Toward that end, reference is now made also to FIGS. 3B and 3C, companion simplified views of syringes used in the course of the procedure shown and described with respect to FIG. 3A. The conus 50 of a syringe 49 (FIG. 3B) is connected to port 35a of catheter 34, and the conus 53 of another syringe 52 (FIG. 3C) is connected to the inflation port 35b of catheter 34. Port 35b opens through the inflation lumen for balloons 46 of catheter 34. Syringe 52 is typically of small size and includes a pressure gauge 55 to measure the applied pressure as the fluid 54 within the syringe is expelled into port 35b to inflate balloons 46 simultaneously to a low pressure of 0.5 to 0.8 atm. This pressure is sufficient to tightly seal the vessel (anterior cerebral artery 45) at the locations of the two balloons, and thereby block perfusion of blood between them. To assist in recognizing a possible rupture of either of balloons 46, the fluid 54 in syringe 52 may be a 50/50 mixture of saline and contrast dye. Balloons 46 may be deflated simultaneously at the completion of the procedure or in the event of an emergency by withdrawing the fluid 54 back into syringe 52.

[0097] While anterior cerebral artery 45 is tightly sealed at both its ends, oncolytic viral agents 51 within syringe 49 are slowly ejected from conus 50 into port 35a of the catheter 34. The oncolytic infecting viruses travel through the central lumen of catheter 34 formerly occupied by guide wire 48 and exit that lumen under pressure at the discharge port(s) between the inflated balloons and into the space of the chamber formed thereat, while blood perfusion is blocked in that part of the cerebral circulation. After a period in which the pressure builds as a result of the controlled volume and pressure of virus entering the chamber, an effective dose of the virus is delivered under an effective extravasation pressure for entry into the blocked cerebral circulation at that target site. The very brief period of limited blood supply during blockage of blood flow through the anterior cerebral artery 45 by the inflated balloons 46 and the pressure of the viral agents at that site is sufficient for the virus to overcome the endothelial barrier and enter the cancer cells in the underlying tissue, but not enough to cause injury to the brain. Repetitive injections with the allowance of intermittent blood flood may be employed as one means to increase the total virus delivered to affected tissue at the treatment site.

[0098] Renal cancer: For treating cancer of the kidneys, an oncolytic agent may be introduced in a similar manner through a two-balloon catheter navigated over a guide wire in the patient's right groin into the iliac artery 37, the abdominal aorta 38, the applicable renal artery 57, and the diseased kidney 58.

[0099] Ductal Delivery: FIG. 4 is a transparent front view of a subject illustrating an exemplary procedure for administering a prescribed quantity of selected virus in body-compatible fluid intraluminally through a natural duct of the subject's body via a two-balloon catheter installed in the duct, to infect targeted tissue of the body attributable to or responsible for a disease or disorder under treatment. Referring to that Figure, in this exemplary initial procedure prior to delivery of treatment, an endoscope 64 is advanced through the mouth 62 and esophagus 63 of the patient 61. The endoscope 64 is flexible, and is designed and implemented with a plurality of channels including, in this illustrative embodiment, visualization and fiber optics channel 65, flushing channel 66, side port open channel 67, and working channel 68. The distal tip 75 of endoscope 64 is readily bendable to allow the endoscope to be advanced through a tortuous path. During the procedure the patient may be give a local anaesthetic to prevent gagging. The endoscope 64 is advanced via the esophagus 63 through the diaphragm 70, into and through the stomach 69, and further until its distal tip is located in the duodenum 71.

[0100] Pancreatic cancer: If the pancreas is target organ to be treated, the location of the distal tip should be such that a side port 72 (FIG. 4) of the endoscope adjacent its distal tip is aligned for entry into the ductus Wirsungii 76, which supports the internal structure of the pancreas 73 with all its side branches. Proper alignment may be verified through the visualization and fiber optics channel 65 of endoscope 64. Then, a small two-balloon guided catheter 77 (e.g., 2.7 French outer diameter) is advanced over a guide wire 78 threaded through the side port open channel 67 and out of the side port 72 into the ductus Wirsungii. Oncolytic viral agents are delivered and the balloon is inflated by the use of syringes in a method similar to that described with respect to FIGS. 3B and 3C. The distal tip of the catheter is advanced through channel 67 of the endoscope 64 and out of the side port 72 to the site of the pancreatic tissue to be treated. The catheter's two balloons are then inflated through the inflation lumen of the catheter to occlude the Wirsungii duct while oncolytic viruses in fluid carrier are introduced under pressure into the pancreatic tissue through an infusion lumen and discharge port(s) of the catheter between the spaced-apart inflated balloons. By proper positioning of the discharge port(s) at the site of the cancer tissue, an effective dose of the virus is delivered to the target site under an effective extravasation pressure locally in high concentration. Occlusion of the duct prevents the virus from washing out into the intestines, so as to enhance large scale adhesions and penetration of the virus into the target tissue.

[0101] Liver cancer: Blood enters the liver from both the hepatic artery and the hepatic portal vein. Oxygenated blood is carried via the hepatic artery into the sinusoids of the liver. Deoxygenated blood and nutrients from the digestive system are via the portal vein into the sinusoids of the liver, which are lined by plates of liver (hepatic) cells. Blood leaves the liver first through the sinusoids and into the central vein of each lobule before finally leaving the liver through the hepatic vein. Bile produced by the liver cells lining the sinusoids leaves the liver first through the bile canaliculi and ultimately through the bile duct. Thus, compounds delivered to the liver may be considered to be delivered with the normal direction of flow (antegrade) if delivered through the hepatic artery or the hepatic portal vein, and against the normal direction of flow (retrograde) if delivered through the hepatic vein or through the bile duct. Retrograde delivery through the bile duct can be accomplished endoscopically as is done with contrast dyes in ERCP procedures or percutaneously as in PTCA procedures (Percutaneous Transhepatic Cholangiography).

[0102] As depicted in FIG. 4, for retrograde ductal delivery, the distal tip 75 of endoscope 64 is positioned in the duodenum 71 such that its side port 72 is aligned for entry into the common biliary duct 80, which supports the liver 82 and the gall bladder 81. As an alternative, the side branch of the bile duct may be used. The guide wire and balloon catheter are fed through channel 67 and out of side port 72 of the endoscope, into the duct. The distal tip of the catheter is positioned at the target site of the liver tissue, the guide wire is removed, and the catheter's balloon is inflated to occlude the biliary duct during the introduction of the virus. The oncolytic viruses are injected through the infusion lumen and ejected from its discharge port(s) of the catheter for adhesion to and engraftment within or in proximity to the tumor.

[0103] All publications, patents and patent applications cited herein are hereby incorporated by reference as if set forth in their entirety herein. While this invention has been described with reference to illustrative embodiments, this description is not intended to be construed in a limiting sense. Various modifications and combinations of illustrative embodiments, as well as other embodiments of the invention, will be apparent to persons skilled in the art upon reference to the description. It is therefore intended that the appended claims encompass such modifications and enhancements and that the invention shall be limited only by the appended claims and the rules and principles of applicable law.