U.S. patent application number 15/064158 was filed with the patent office on 2016-10-06 for apparatus and method for infusing an immunotherapy agent to a solid tumor for treatment.
This patent application is currently assigned to Surefire Medical, Inc.. The applicant listed for this patent is Surefire Medical, Inc.. Invention is credited to James E. Chomas, David Benjamin Jaroch.
Application Number | 20160287839 15/064158 |
Document ID | / |
Family ID | 57004599 |
Filed Date | 2016-10-06 |
United States Patent
Application |
20160287839 |
Kind Code |
A1 |
Jaroch; David Benjamin ; et
al. |
October 6, 2016 |
Apparatus and Method for Infusing an Immunotherapy Agent to a Solid
Tumor for Treatment
Abstract
An immunotherapy delivery device is provided including a
catheter and a pressure modulating device fixed adjacent the distal
end of the catheter. In accord with aspects of the device, the
lumen of the catheter is coated to facilitate delivery of a healthy
immunotherapy agent. A method for delivering an immunotherapy agent
to a tumor includes advancing the delivery device into a vessel of
a patient, and infusing the agent under pressure into the vessel to
penetrate the tumor. The delivery device prevents reflux of the
agent toward non-treatment sites.
Inventors: |
Jaroch; David Benjamin;
(Arvada, CO) ; Chomas; James E.; (Denver,
CO) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Surefire Medical, Inc. |
Westminster |
CO |
US |
|
|
Assignee: |
Surefire Medical, Inc.
Westminster
CO
|
Family ID: |
57004599 |
Appl. No.: |
15/064158 |
Filed: |
March 8, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
62140651 |
Mar 31, 2015 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61F 2/013 20130101;
A61L 2420/08 20130101; A61L 29/085 20130101; A61M 2025/0042
20130101; A61M 2025/1052 20130101; A61L 29/08 20130101; A61M
25/0029 20130101; A61M 2202/0007 20130101; A61M 2025/0004 20130101;
A61M 2025/0047 20130101; A61L 29/06 20130101; A61M 2025/105
20130101; A61L 2300/426 20130101; A61L 29/16 20130101; A61L
2300/608 20130101; A61L 2420/02 20130101; A61L 29/041 20130101;
A61L 2400/10 20130101; A61M 25/04 20130101; A61M 25/10 20130101;
A61L 29/145 20130101 |
International
Class: |
A61M 25/00 20060101
A61M025/00; A61M 25/04 20060101 A61M025/04; A61L 29/04 20060101
A61L029/04; A61L 29/14 20060101 A61L029/14; A61L 29/08 20060101
A61L029/08; A61L 29/06 20060101 A61L029/06; A61M 25/10 20060101
A61M025/10; A61L 29/16 20060101 A61L029/16 |
Claims
1. An apparatus for infusion of an immunotherapy agent into a
patient, comprising: a) a flexible catheter having a proximal end
and a distal end, an agent delivery lumen extending through the
catheter and opening to a distal orifice, the agent delivery lumen
including at least one of a coating or structure that is
hydrophilic, oleophobic, hydrophobic, or at least reduces flow
along the lumen of the catheter; and b) an expandable fluid
pressure modulating structure fixed adjacent the distal end of the
catheter.
2. The apparatus according to claim 1, wherein the lumen includes
both of a structure and a coating that are at least one of
hydrophilic, hydrophobic, or at least reduces flow along the lumen
of the catheter.
3. The apparatus according to claim 1, wherein the structure is an
oleophobic and/or a hydrophobic surface geometry.
4. The apparatus according to claim 1, wherein the catheter carries
a negative charge during use.
5. The apparatus according to claim 4, wherein the catheter carries
a zero current or a negligible current during use.
6. The apparatus according to claim 1, further comprising the
immunotherapy agent, wherein at least one of the lumen and the
agent are provided with a surfactant.
7. The apparatus according to claim 1, where the coating includes a
hydrogel that acts (i) to inhibit T-cell attachment, (ii) to
inhibit T-cell activation, or (iii) as a protectants against
fluid-mechanical T-cell damage.
8. An apparatus for infusion of an immunotherapy agent into a
patient, comprising: a) a flexible outer catheter having a proximal
end and a distal end; b) a flexible inner catheter having a
proximal end and a distal end, a lumen extending through the inner
catheter and opening to a distal orifice, the inner catheter
extending through and longitudinally displaceable relative to the
outer catheter, the lumen coated with at least one of, i) a first
coating including cytokines, and ii) a second coating including at
least one of a hydrophilic coating, a hydrophobic coating, and a
coating layer that at least reduces flow along the lumen of the
catheter; and c) a filter valve having a proximal end and distal
end, the proximal end of the filter valve coupled to the distal end
of the inner catheter such that the orifice of the inner catheters
opens into the proximal end of the filter valve, wherein
longitudinal displacement of the inner catheter relative to the
outer catheter moves the filter valve from a non-deployed
configuration to a deployed configuration, the filter valve having
a proximal portion comprising a braided filamentary structure that
is adapted to dynamically open and close based on the relatively
proximal and distal fluid pressure conditions to which the filter
is subject, and at least a portion of the braided filamentary
structure including a polymeric filter thereon deposited by
electrospinning or electrostatic deposition to bond with the
braided filamentary structure, the filter having a pore size not
exceeding 500 .mu.m.
9. An apparatus for infusion of an immunotherapy agent into a
patient, comprising: a) a flexible catheter having a proximal end
and a distal end, a first lumen, and an agent delivery second lumen
extending through the catheter and opening to a distal orifice, the
second lumen coated with at least one of, i) a first coating
including cytokines, and ii) a second coating including at least
one of a hydrophilic coating, a hydrophobic coating, and a coating
layer that at least reduces flow along the lumen of the catheter;
and b) a fluid expandable balloon coupled adjacent the distal end
of the catheter and in fluid communication with the first
lumen.
10. A method of delivering an immunotherapy agent to a tumor,
comprising: a) providing an immunotherapy delivery device
including, i) a flexible catheter having a proximal end and a
distal end, an agent delivery lumen extending through the catheter
and opening to a distal orifice, the agent delivery lumen coated
with at least one of, A) a first coating including cytokines, and
B) a second coating including at least one of a hydrophilic
coating, a hydrophobic coating, and a coating layer that at least
reduces flow along the lumen of the catheter, and ii) an expandable
fluid pressure modulating structure fixed adjacent the distal end
of the catheter; b) inserting said device into a vessel; and c)
infusing the immunotherapy agent through the lumen of the catheter,
into the vessel and into the tumor.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application claims priority under 35 U.S.C.
.sctn.119(e) to U.S. provisional application Ser. No. 62/140,651,
filed Mar. 31, 2015, the entire contents of which are hereby
incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates devices and methods for
administering immunotherapy to a patient, particularly for the
treatment of patients with solid tumors.
[0004] 2. State of the Art
[0005] For many years the basic treatment for cancer has consisted
of surgery, chemotherapy and radiation therapy. More recently,
drugs that target cancer cells, such as imatinib (Gleevac.RTM.) and
trastuzumab (Herceptin.RTM.) by guiding themselves to specific
molecular changes seen in the cancer cells have also become
standard treatments for a number of cancers.
[0006] Now, therapies that take advantage of a patient's immune
system to fight their cancers are in clinical use or in development
and gaining interest. There are four basic versions of
immunotherapy products today, which can be used alone or in
combination. These immunotherapy products include immunomodulators,
vaccines, modified cells and check-point inhibitors.
[0007] Immunomodulators include IL-2, IL-7, IL-12, Interferons,
G-CSF, Imiquimod, CCL3, CCL26, CXCL7, cytosine phosphate-guanosine,
oligodeoxynucleotides, and glucans, and all operate to systemically
increase the patient's immune response. Vaccines comprise an
infusion of antigen directly or antigen-activated dendritic cells,
which activate the patients white blood cells. Modified cells are
blood-derived immune cells from the patient which are engineered
and incubated to grow to a large number of modified cells that
specifically target a region of tumor. This approach, referred to
as adoptive cell transfer (ACT) has generated remarkable responses
in the small clinical trials in which it has been investigated.
Check-point inhibitors include anti-PD-1, which block the patient's
natural suppression of T-cells, thereby effectively increasing the
time and number of T-cells that can fight the cancer.
[0008] Immunotherapy practice has had success in "liquid" tumors,
such as leukemia, where the therapy is easily delivered to the site
of the cancer via intravenous injection or infusion. Further,
immunotherapy has promise for solid tumors. However, delivery of
the therapy with sufficient penetration into the tumors to allow
the therapy to interact with the cancer cells remains a
challenge.
[0009] In current practice, the immunotherapy agents are delivered
by oral dosage, venous delivery, or catheter-based delivery to an
organ of interest with a traditional microcatheter.
[0010] In venous delivery, the agent is generally infused into the
patient through a peripherally inserted central catheter (PICC) or
a port implanted in the patient. PICCs and ports can remain in
place for several weeks or months and are used to reduce the number
of times that a patient is subject to needle sticks and to reduce
risk of tissue and muscle damage that can occur with a standard IV.
While a PICC or port may be suitable for infusion of a chemotherapy
treatment agent, which is generally circulated throughout the
patient's circulation system, or for a "liquid" tumor, it may not
be suitable for delivery of the immunotherapy agent to a solid
tumor.
[0011] Microcatheters can be delivered to localize delivery of the
agent to the vascular system adjacent the organ of interest.
However, various issues prevent desirable agent uptake at the
tumor.
SUMMARY
[0012] In accord with the invention, systems and methods are
provided for delivery of immunotherapy agents to a solid tumor.
[0013] Solid tumors undergo angiogenesis, which creates unique
vascular characteristics compared to healthy tissue. Solid tumors
often have regions of high vascular density, a reduced resistance
to flow, and a high capacitance for therapy. As a result of the
unregulated tumor angiogenic process, a dense branching network of
vessels is formed in the tumor. The formed dense network has a
different vessel structure than health vessels. A healthy vessel is
encased in endothelium, which maintains vascular tone and provides
resistance to flow. Tumor vessels have a deteriorated endothelium
and lack tone; this results in lower resistance to flow. Also, the
dense network of vessels creates a relatively large vascular volume
for the relative volume of the tissue, permitting a significantly
higher volume of therapy to be deposited in the tumor compared to
healthy tissue. Further, solid tumors can exhibit regions of low
pressure within their vessels where there is robust flow, and they
can have regions of high pressure where the vessels have become
leaky and there is poor to no endogenous arterial flow. For these
reasons, it is important to have an infusion system that does not
rely solely on endogenous arterial flow to control delivery.
[0014] In view of these identified factors, it is believed by the
inventors that immunotherapy systems and procedures should achieve
several goals. Highly targeted delivery to the organ of interest
should be obtained without the chance of back-flow into non-target
regions. There should be the ability to increase pressure during
infusion to overcome regions of high pressure in the tumor. More
therapy should be deposited in the tumor than in the healthy
tissue. The immunotherapy dose should deliver a maximum amount of
intact cells or antibodies (a maximum percentage of healthy
immunotherapy dose), and a minimum amount of damaged, destroyed
cells, or activated cells during infusion. In addition, it is
desirable to have a catheter deliver a homogenous immunotherapy
dose across a vessel, including across a vessel branching
network.
[0015] In accord with these goals, an immunotherapy treatment is
delivered through a fully or partially deployed intravascular
pressure modulating anti-reflux catheter, such as a catheter with
microvalve and filter or a balloon catheter.
[0016] Further, the anti-reflux catheter may have one or more
additional attributes that are advantageous in the delivery of
cancer treatments. By way of example, these attributes can include
the following. The catheter has self-centering capability that
provides homogeneous distribution of therapy in a downstream
branching network of vessels. The catheter includes an anti-reflux
capability that blocks the retrograde flow of therapy into proximal
non-target vessels proximal to the catheter tip. The system allows
forward flow at a reduced pressure when not infusing therapy to
target regions of low vascular resistance (tumor) and high
capacitance (tumor). The valve and filter or a fully deployed
balloon allows the pressure to be increased during infusion, with
the pressure being modulated by the physician. An increased
pressure allows increased delivery to and penetration into regions
of the tumor that are naturally subject to high pressure
conditions. According to another aspect of the device, a coating
can be provided to the hub and inner lumen of the catheter to
inhibit T-cell activation. According to yet another aspect of the
device, a coating or construct can be provided to the hub and inner
lumen of the catheter that optimize the wall shear during delivery
of the therapy. By optimizing the wall shear gradient, the T-cells
are subject to reduced trauma and maintain integrity during
delivery while preventing clumping of the cells.
[0017] In accord with the method described herein, the treatment
catheter is used in a method of delivering an immunotherapy agent.
The treatment includes infusion of immunotherapy cells,
anti-bodies, and/or other biologics into the target organ,
including a selected location within the target organ, while
maintaining a high integrity of the cells of the immunotherapy
dose.
[0018] A modified Seldinger technique is used to introduce the
catheter into the patient. More particularly, the catheter is
introduced into the femoral artery, and then advanced up the aorta
to the celiac axis. The catheter is then advanced into the left
gastric artery. From the left gastric artery, the distal end of the
catheter is advanced to the target artery that feeds the target
organ. The catheter is then deployed for organ targeting.
[0019] Then, the immunotherapy agent, including immunotherapy
T-cells, is infused under pressure through the catheter and 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.
[0020] 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.
BRIEF DESCRIPTION OF THE DRAWINGS
[0021] 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.
[0022] 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.
[0023] 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.
[0024] 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.
[0025] 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).
[0026] 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
[0027] 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.
[0028] 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.
[0029] 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 .mu.m. 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 previously incorporated U.S. Pat. Nos. 8,500,775 and
8,696,698 and pending U.S. Ser. No. 14/330,456. 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.
[0030] 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.
[0031] 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.
[0032] 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).
[0033] 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.
[0034] 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.
[0035] 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.
[0036] 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.
[0037] 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 .mu.m thick. The coating in the lumen
can mimic such biological structure.
[0038] 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.
[0039] 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.
[0040] 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.
[0041] 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.
[0042] 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.
[0043] 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.
[0044] 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.
[0045] 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.
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