METHOD OF DELIVERING A THERAPEUTIC AGENT TO A SOLID TUMOR FOR TREATMENT

Abstract

A method for delivering a therapeutic agent to a tumor through a target vessel includes delivering the therapeutic agent through a lumen of a catheter which has been coated or otherwise structured to reduce the wall shear stress during delivery of the immunotherapy and by generating turbulent flow during the delivery of the therapeutic agent.

Claims

1. A method of delivering a therapeutic agent through a target vessel in communication with a tumor, the method comprising: a) providing a delivery device including a flexible catheter having a proximal end and a distal end, an expandable fluid pressure modulating structure fixed adjacent the distal end of the catheter, an agent delivery lumen extending through the catheter and opening to an orifice at a distal tip of the catheter, the lumen provided with a coating or structure that is hydrophilic; b) providing the therapeutic agent; c) inserting said device into the target vessel; and d) infusing the therapeutic agent through the lumen and out of the orifice of the catheter into the target vessel under conditions of turbulent flow within the vessel.

2. The method of claim 1, wherein the therapeutic agent comprises immunotherapy cells.

3. The method of claim 1, further comprising: while infusing, preventing reflux of the therapeutic agent into non-target vessels.

4. The method of claim 1, wherein inserting the device includes centering the orifice of the delivery lumen in the target vessel.

5. The method of claim 1, further comprising: preventing reflux of the infused therapeutic agent proximal of the expandable fluid pressure modulating structure.

6. The method of claim 1, wherein the expandable fluid pressure modulating structure is a microvalve responsive to fluid pressure conditions within the target vessel.

7. A method of delivering a therapeutic agent through a target vessel in communication with a tumor, the method comprising: a) providing a delivery device including a flexible catheter having a proximal end and a distal end, an expandable fluid pressure modulating structure fixed adjacent the distal end of the catheter, an agent delivery lumen extending through the catheter and opening to an orifice at a distal tip of the catheter, the lumen provided with a coating or structure that is hydrophobic; b) providing the therapeutic agent; c) inserting said device into the target vessel; and d) infusing the therapeutic agent through the lumen and out of the orifice of the catheter into the target vessel under conditions of turbulent flow within the vessel.

8. The method of claim 7, wherein the therapeutic agent comprises an immunomodulator.

9. The method of claim 7, further comprising: while infusing, preventing reflux of the therapeutic agent into non-target vessels.

10. The method of claim 7, wherein inserting the device includes centering the orifice of the delivery lumen in the target vessel.

11. The method of claim 7, further comprising: preventing reflux of the infused therapeutic agent proximal of the expandable fluid pressure modulating structure.

12. The method of claim 7, wherein the expandable fluid pressure modulating structure is a microvalve responsive to fluid pressure conditions within the target vessel.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0019] FIGS. 1A-1C are schematic diagrams of one exemplary embodiment of an apparatus of the invention respectively in an undeployed state, a deployed partially open state with blood passing in the distal direction, and a deployed fully open state where the blood flow is static.

[0020] FIGS. 2A-2B are schematic diagrams of an exemplary embodiment of a valve having a braid component that is covered by a filter component in respectively an undeployed state and a deployed state.

[0021] FIGS. 3A-3C are schematic diagrams of another exemplary embodiment of an apparatus of the invention respectively in an undeployed state, a deployed partially open state with blood passing in the distal direction, and a deployed fully open state where the blood flow is static.

[0022] FIG. 4 is a graph showing the performance of the apparatus of FIGS. 1A-1C compared to the performance of a prior art end-hole catheter in delivering immunotherapy agent under pressure to target tissue.

[0023] FIG. 5 is a schematic cross-sectional view across an embodiment of the anti-reflux catheter including oleophobic and/or a hydrophobic surface geometry (shown not to scale).

[0024] FIG. 6 is a schematic cross-sectional view across an embodiment of the anti-reflux catheter including a surface geometry that minimizes wall shear (shown not to scale).

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0025] With reference to the human body and components of the devices and systems described herein which are intended to be hand-operated by a user, the terms “proximal” and “distal” are defined in reference to the user's hand, with the term “proximal” being closer to the user's hand, and the term “distal” being further from the user's hand, unless alternate definitions are specifically provided.

[0026] Methods are provided herein for infusing an immunotherapy agent to a tumor site for treatment of cancer. The method includes use of an infusion catheter device. In accord with the method, the infusion catheter device is an infusion microcatheter with valve and filter, or filter valve, (hereinafter “microvalve catheter”) or an infusion microcatheter with a distal balloon (hereinafter “balloon catheter”), with both such devices collectively referred to herein as “anti-reflux infusion catheters”. Whereas the balloon catheter is manually operable between expanded (open) and collapsed (closed) configurations, the microvalve catheter is a dynamic device, automatically moving between open and closed configurations based on local fluid pressure conditions to which the proximal and distal surfaces of the valve and filter are subject.

[0027] By way of example, referring to FIGS. 1A through 1C, an embodiment of an anti-reflux catheter 202 includes a flexible microcatheter 204 having a proximal end (not shown) and a distal end 206. A lumen 208 extends through the microcatheter and has a distal orifice 210, preferably coaxial with the axis of the catheter. A filter valve 212 is attached to the distal end 206 of the microcatheter, such that the orifice 210 opens into the proximal end 214 of the filter valve 212. The filter valve 212 comprises a braided polymeric filamentary structure 216 that is adapted to dynamically open and close based on the relatively proximal and distal pressure conditions of the fluid to which the filter valve is subject within a vessel 224. At least a portion of the braided filamentary structure 216 includes a polymeric filter 218 thereon, preferably deposited by electrospinning or electrostatic deposition to bond with the braided filamentary structure (FIGS. 1A and 2B). The filter 218 has a pore size not exceeding 500 μm. With such pore size, the filter 218 construct is semi-porous and allows elevated pressure differentials (greater distal pressure) to dissipate. The microcatheter 204 is adapted for use with an outer delivery catheter 220, with the inner microcatheter 204 extending through the outer delivery catheter 220. Longitudinal displacement of the outer catheter relative to the inner catheter (in the direction of arrow 221) allows the filter valve 212 to move from a non-deployed configuration (FIG. 1A) to a deployed configuration (FIG. 1B). Once deployed, the filter valve 212 is adapted to dynamically move between open and closed configurations (FIG. 1B to FIG. 1C and back) based upon fluid pressure forces 222, 226 applied to the proximal and distal sides of the filter valve when the device 202 is deployed within a vessel 224 (FIG. 1C). Such a microvalve catheter is disclosed in detail in incorporated U.S. Pat. Nos. 8,500,775 and 8,696,698 and in U.S. Pat. No. 9,968,740. In addition, microvalve catheters structurally and functionally similar to that described are sold by Surefire Medical, Inc., Westminster, Colo., as part of the Surefire Infusion System.

[0028] Turning now to FIGS. 3A through 3C, as another example, another microvalve catheter 302 includes a catheter 304 having a first lumen 306 for infusing the embolizing agent out of a distal orifice 308, and a second inflation lumen (not shown). An elastic membrane 310 is provided about a distal portion 312 of the catheter 304 and has a lower surface in communication with the inflation lumen to define a fluid inflatable balloon 314. FIG. 3A shows the balloon 314 in a collapsed configuration, FIG. 3B shows the balloon 314 in a partially expanded configuration (i.e., expanded insufficiently to reach across the vessel walls 224), and FIG. 3C shows the balloon 314 in a fully expanded configuration (i.e., expanded fully to the vessel walls 224). It is preferred that the balloon 314 be proximally offset from the distal tip 316 of the catheter 304 and particularly the orifice 308 of the first lumen. The balloon catheter device 302 may additionally include multiple balloons, optionally of different sizes, and either radially or longitudinally offset. The balloon is preferably provided for use with an outer delivery catheter 330, as discussed below.

[0029] In accord with one preferred aspect of the anti-reflux infusion catheter used in the method, the anti-reflux infusion catheter is adapted to self-center within a vessel 224. This can be accomplished with the expandable balloon 314 being centered about the balloon catheter, or the expandable valve 212 (FIGS. 1B and 1C) expanding radially symmetrically about the catheter. The self-centering of the anti-reflux infusion catheter is effected to promote homogeneous distribution of immunotherapy in a downstream branching network of vessels. That is, in distinction from a single streamline of delivery from a prior art end-hole catheter, a centrally-positioned anti-reflux infusion catheter creates turbulent flow in a vessel to mix the infused immunotherapy evenly across the cross-sectional area of a vessel.

[0030] In accord with another preferred aspect of the anti-reflux infusion catheter, such catheter blocks retrograde flow of immunotherapy into proximal non-target vessels proximal to the catheter tip, or a balloon or a valve on the catheter. In accord with yet another aspect of the anti-reflux infusion catheter, the valve and filter or a partially deployed balloon permit forward flow at a reduced pressure when not infusing the immunotherapy to target regions of low vascular resistance (tumor) and high capacitance (tumor).

[0031] In accord with yet another aspect of the anti-reflux infusion catheter, the valve and filter or a fully deployed balloon allows the infusion pressure to be increased during infusion, with the pressure being modulatable by the physician. By increasing the pressure, an increase in delivery and penetration of the immunotherapy into regions of the tumor that are naturally subject to high pressure conditions is effected. Referring to FIG. 4, it is seen that a microvalve anti-reflux catheter of the type available from Surefire Medical, Inc. allows infusion to generate substantially elevated distal pressures relative to a prior art end-hole catheter (with no anti-reflux structure or function). The pressure applied by the Surefire device dissipated after infusion, as fluid was able to diffuse back through the semi-porous membrane of the valve and filter. The end-hole catheter was unable to generate pressure gradients distal to the tip during infusion as fluid was able to reflux, equalizing fluid pressure in the system.

[0032] In accord with another aspect of the anti-reflux catheter (with reference to device 202, but equally applicable to device 302), an inner lining of the lumen 208 of the catheter 204 is tailored to minimize surface energy and interaction with T-cells. The inner lining of the lumen 208 is coated with one or more polymers 230 (FIG. 2A) such as silicones and silicone oils, polypropylene, polyethylene and fluoropolymers such as polytetrafluoroethylene, polyvinylidene fluoride, fluorinated ethylene-propylene, and perfluorinated elastomers.

[0033] In accord with another aspect of the anti-reflux catheter, as an addition to or alternative to the coating described above, an inner lining surface 232a of the lumen 208a of the catheter 204a is structurally patterned to create an oleophobic and/or a hydrophobic surface geometry (FIGS. 2A and 5). In accord with such aspect, the inner lining surface 232a can be patterned to include micro and/or nano scale ridges, pillars, or other features that generate a rough hydrophobic surface. Such features may be further chemically modified with fluoropolymers 230a (such as perfluoropolyether), silicones, or other chemical entities to enhance the hydrophobic effect and/or to provide oleophobic functionality to the surface features.

[0034] In accord with another aspect of the anti-reflux catheter, as an addition to or alternative to the coatings and structure described above, the inner lining surface of the lumen can be modified with hydrogels that can act to inhibit T-cell attachment and/or activation or can be used as protectants against fluid-mechanical cell damage. Such polymers are typically hydrophilic and electrically neutral and hydrogen bond acceptors rather than hydrogen bond donors. Examples include but are not limited to polyvinyl alcohol (PVA) and chemically modified PEO-(X) hybrid gels, poly(ethylene) glycol (PEG) and chemically modified PEG-(X) hybrid gels (PEGylated polymers), polyethylene oxide (PEO) and chemically modified PEO-(X) hybrid gels, Poly(acrylic acid), 2-hydroxyethyl methacrylate (HEMA)-based polymers and zwitterionic hydrogels such as phosphobetaine, sulfobetaine, and carboxybetaine which can display variable surface activity based on environmental pH. Furthermore, natural or artificial protein layers can be provided to the lumen surface or the hydrogel network and can have specific cellular stabilizing activities. Such a protein layer can include cytokines. Such polymers and proteins can be attached in cross-linked networks or in “brushy” layers of polymer strands. Methodology includes self-assembled monolayers of short chain hydrogels or peptides attached to the inner surface of the lumen of the catheter using a variety of covalent or ionic bonding chemistry and layer-by-layer self-assembly of tailored functionality nano-composite gels.

[0035] In accord with another aspect of the anti-reflux infusion catheter, an alternative or additional coating or structure can be provided to the hub and/or inner lining of the lumen of the catheter that will reduce the wall shear stress during delivery of the immunotherapy. Such a coating or structure can include a hydrophilic coating, a hydrophobic coating, or a small ‘brushy’ fibrous layer that acts to create a region of low flow or no flow along the wall of the catheter. By way of example, the coating can include glycocalyx or a glycocalyx-mimicking layer. Glycocalyx is a glycoprotein-polysaccharide, including several carbohydrate moieties of membrane glycolipids and glycoproteins. In the vascular endothelial tissue, the glycocalyx is a small, irregularly shaped layer extending approximately 50-100 nm into the lumen of a blood vessel, but can be up to 11 μm thick. The coating in the lumen can mimic such biological structure.

[0036] In accord with another aspect of the anti-reflux infusion catheter, wall shear stress along the lumen can be modified by incorporating a surfactant coating 230b into the lining of the lumen of the catheter. By way of another example, the wall shear stress can be modified by extruding the lumen 208b of the catheter 204b with features, including elongate channels 234b formed along length and open to the central lumen 208b (FIG. 6). Such channels 234b are either smaller or bigger than the diameter of a T-cell (e.g., less than 7 microns across or greater than 20 microns across) so as to prevent the channels from engaging and filling with captured T-cells. Thus, the channels will fill with fluid, but no T cells, and the peripheral channel-fluid will guide passage and minimize wall shear stress of the T cells through the lumen.

[0037] By way of another example, the catheter is negatively charged. In one manner, this can be effected by providing wires or even a braid about the lumen and applying a negative voltage to the wires (with no/negligible current during use); in another manner, the catheter is constructed with a negatively charged polymer. The immunotherapy agent is naturally negatively charge (as T-cells have negative surface charge). Then, the T-cells in the immunotherapy agent are repelled from the lumen surface to thereby reduce the shear stress upon infusion of the immunotherapy agent.

[0038] In accord with another manner of reducing wall shear stress, the wall shear stress can be minimized by incorporating a surfactant into the immunotherapy fluid containing the T cells. The surfactant can be premixed with the immunotherapy agent or mixed at the time of infusion.

[0039] In accord with a preferred procedure for delivering immunotherapy, a modified Seldinger technique is utilized. In the Seldinger technique, which is well-known and will not be described in detail herein, access is provided from the thigh to the femoral artery and a guidewire is advanced to the aorta. The delivery catheter is advanced over the guidewire. Once the delivery catheter is at its intended position, and in accord with the method herein, an anti-reflux infusion catheter is advanced through the delivery catheter and over the guidewire.

[0040] Then the anti-reflux catheter is displaced relative to the delivery catheter to expose the distal end of the anti-reflux catheter. The anti-reflux catheter is deployed.

[0041] Then, the immunotherapy agent, including immunotherapy T-cells, is infused through the catheter and under pressure to the tumor. Infusion is continued until the prescribed dose of immunotherapy is completely infused. This can occur at sub-stasis, at stasis, or beyond stasis. At stasis, the immunotherapy can be infused without any reflux. Further, by either manually inflating the balloon of a balloon catheter to block flow past the balloon in the vessel, or by use of the dynamically adjustable anti-reflux infusion catheter with valve, the immunotherapy can be infused beyond stasis without concern that the immunotherapy will reflux back toward the vessels of non-target tissues and/or organs.

[0042] After the infusion of the immunotherapy agent, the anti-reflux catheter is removed from the patient, and an arterial closure device is used to close the arterial access point for the procedure.

[0043] There have been described and illustrated herein embodiments of apparatus and methods for delivering immunotherapy agents to target tissue. While particular embodiments of the invention have been described, it is not intended that the invention be limited thereto, as it is intended that the invention be as broad in scope as the art will allow and that the specification be read likewise. Particularly, it is intended that various aspects presented with respect to coated and structurally modifying the lining of the lumen described herein can be used either alone, or in combination with one or multiple other aspects. To such extent, it is anticipated that the lumen can include both structural modification and/or multiple coatings to facilitate passage of the immunotherapy with the least negative effect on the T-cells in the therapy. It will therefore be appreciated by those skilled in the art that yet other modifications could be made to the provided invention without deviating from its spirit and scope as claimed.