U.S. patent application number 14/498605 was filed with the patent office on 2015-08-20 for method and compositions for treatment of cancers.
The applicant listed for this patent is M. Rigdon Lentz. Invention is credited to M. Rigdon Lentz.
Application Number | 20150231178 14/498605 |
Document ID | / |
Family ID | 22177487 |
Filed Date | 2015-08-20 |
United States Patent
Application |
20150231178 |
Kind Code |
A1 |
Lentz; M. Rigdon |
August 20, 2015 |
METHOD AND COMPOSITIONS FOR TREATMENT OF CANCERS
Abstract
A method to treat cancer uses ultrapheresis, refined to remove
compounds of less than 120,000 daltons molecular weight, followed
by administration of replacement fluid, to stimulate the patient's
immune system to attack solid tumors. In the preferred embodiment,
the patient is ultrapheresed using a capillary tube ultrafilter
having a pore size of 0.02 to 0.05 microns, with a molecular weight
cutoff of 120,000 daltons, sufficient to filter one blood volume.
The preferred replacement fluid is ultrapheresed normal plasma. The
patient is preferably treated daily for three weeks, diagnostic
tests conducted to verify that there has been shrinkage of the
tumors, then the treatment regime is repeated. The treatment is
preferably combined with an alternative therapy, for example,
treatment with an anti-angiogenic compound, one or more cytokines
such as TNF, gamma interferon, or IL-2, or a procoagulant compound.
The treatment increases endogenous, local levels of cytokines, such
as TNF. This provides a basis for an improved effect when combined
with any treatment that enhances cytokine activity against the
tumors, for example, treatments using alkylating agents,
doxyrubicin, carboplatinum, cisplatinum, and taxol. Alternatively,
the ultrapheresis treatment can be combined with local
chemotherapy, systemic chemotherapy, and/or radiation.
Inventors: |
Lentz; M. Rigdon; (Prien am
Chiemsee, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Lentz; M. Rigdon |
Prien am Chiemsee |
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DE |
|
|
Family ID: |
22177487 |
Appl. No.: |
14/498605 |
Filed: |
September 26, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13570876 |
Aug 9, 2012 |
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14498605 |
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12685307 |
Jan 11, 2010 |
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13570876 |
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09699003 |
Oct 26, 2000 |
7854717 |
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12685307 |
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09316226 |
May 21, 1999 |
6231536 |
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09699003 |
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09083307 |
May 22, 1998 |
6620382 |
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09316226 |
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Current U.S.
Class: |
424/85.1 ;
210/196; 210/767; 424/278.1; 600/1 |
Current CPC
Class: |
A61K 38/196 20130101;
A61K 31/555 20130101; A61K 35/14 20130101; A61K 38/18 20130101;
A61K 38/193 20130101; A61K 31/704 20130101; A61M 1/3603 20140204;
A61K 38/196 20130101; A61M 1/3486 20140204; A61N 5/1028 20130101;
B01D 37/00 20130101; A61M 1/3482 20140204; A61K 38/193 20130101;
A61M 2205/75 20130101; A61K 31/337 20130101; A61K 38/1816 20130101;
A61K 41/17 20200101; A61K 31/454 20130101; A61P 37/04 20180101;
A61M 1/34 20130101; A61K 31/00 20130101; A61M 1/3681 20130101; A61M
1/3441 20130101; A61K 38/1816 20130101; A61K 41/00 20130101; A61M
2202/0417 20130101; A61N 5/10 20130101; A61P 33/00 20180101; A61P
37/00 20180101; B01D 29/50 20130101; A61K 38/18 20130101; A61M
1/3472 20130101; A61K 2300/00 20130101; A61K 2300/00 20130101; A61K
2300/00 20130101; A61K 35/16 20130101; A61K 2300/00 20130101; B01D
15/00 20130101; A61M 2205/50 20130101; B01D 61/02 20130101; A61P
35/00 20180101; A61M 1/342 20130101 |
International
Class: |
A61K 35/14 20060101
A61K035/14; A61N 5/10 20060101 A61N005/10; A61M 1/36 20060101
A61M001/36; A61K 35/16 20060101 A61K035/16; A61K 31/454 20060101
A61K031/454 |
Claims
1. A system for inducing an immune response against transformed,
infected, or diseased tissue comprising a device for removing only
components present in blood or plasma having a molecular weight of
120,000 daltons or less, having an inlet and outlet for connection
to a pump and tubing to recirculate the blood or plasma of a
patient through the device.
2. A system according to claim 1, where said device has immobilized
therein absorbents to remove specific cytokine or cellular
inhibitors selectively from the blood, wherein said cytokine or
cellular inhibitors are selected from the group consisting of
soluble tumor necrosis factor receptor-1 (sTNFR-1), soluble tumor
necrosis factor recepts-2 (sTNFR-2), soluble interluekin-2 receptor
(sIL-2R), soluble interleukin-1 receptor (sIL-1R), soluble
interleukin-6 receptor (sIL-6R), and soluble interferon-gamma
receptor (sIFN-gammaR).
3. The system of claim 1 wherein the device comprises: a capillary
membrane filter with a pore size of between about 0.02 and 0.05
microns; a parallel plate filter with a pore size of between about
0.04 and 0.08 microns; filters with different pore sizes or
geometries to provide for staggered removal of materials from the
blood; or an absorbent column selectively removing specific
cytokine or cellular inhibitors from the blood or plasma.
4. (canceled)
5. (canceled)
6. (canceled)
7. The system of claim 3 wherein the cytokine or cellular
inhibitors are selected from the group consisting of sTNFR-1,
sTNFR-2, sIL-2R, sIL-1R, sIL-6R, and sIFN-gammaR.
8. The system of claim 3 wherein the absorbent column further
comprises cytokines or antibody or antibody fragments which are
immunoreactive with the cytokine or cellular inhibitors, and
wherein the patient's blood or plasma is circulated through the
absorbent column prior to being returned to the patient.
9. (canceled)
10. The system of claim 1 further comprising a radiation source
operable to treat the patient.
11. (canceled)
12. A method of inducing an immune response against transformed,
infected, or diseased tissue comprising administering to a patient
blood, plasma, or a blood fraction from which only components
having a molecular weight of 120,000 daltons or less have been
removed by the system of claim 1, whereby administration of said
blood, plasma, or blood induces an immune response against
transformed, infected, or diseased tissue in the patient until the
transformed, infected, or diseased tissue is reduced in amount.
13. The method of claim 12 wherein the tissue is a solid tumor.
14. The method of claim 12 wherein the components are removed from
one volume of blood or plasma, or wherein the components are
removed in multiple treatments.
15. (canceled)
16. The method of claim 12 wherein the tissue is to be treated
further with an agent selected from the group consisting of
anti-angiogenic compounds, procoagulant compounds, cytokines,
chemotherapeutic agents, and radiation, wherein when the agent is a
cytokine, the cytokine is selected from the group consisting of
GM-CSF, erythropoietin, thrombopoetin, G-CSF, M-CSF, and SCF.
17. (canceled)
18. The method of claim 12 wherein the removal of the components
comprises selectively removing soluble cytokine receptor molecules
by binding the molecules to a filter, wherein the soluble cytokine
receptor molecules are selected from the group consisting of
sTNFR-1 and sTNFR-2.
19. (canceled)
20. (canceled)
21. The method of claim 16 wherein the agent is thalidomide.
22. The method of clam 12 wherein the patient is to be vaccinated
with a vaccine against the transformed, infected or diseased
tissue.
23. A method for preparing blood, plasma, or a blood fraction ex
vivo for inducing an immune response against transformed, infected,
or diseased tissue until the transformed, infected, or diseased
tissue is reduced in amount, the method comprising removing from
provided blood or plasma ex vivo only components having a molecular
weight of 120,000 daltons or less.
24. (canceled)
25. (canceled)
26. A kit for treatment of a patient to induce an immune response
against transformed, infected or diseased tissue comprising: a
device for removing only components present in blood or plasma
having a molecular weight of 120,000 daltons or less and an agent
selected from the group consisting of anti-angiogenic compounds,
procoagulant compounds, cytokines, chemotherapeutic agents, and a
radiation source, in a dosage formulation for treatment of the
patient.
27. The kit of claim 26 wherein the agent is an anti-angiogenic
compound, or wherein the agent is a procoagulant compound.
28. (canceled)
29. The kit of claim 26 wherein the agent is a cytokine selected
from the group consisting of GM-CSF, erythropoietin, thrombopoetin,
G-CSF, M-CSF, and SCF.
30. (canceled)
31. The kit of claim 26 wherein the agent is a chemo-therapeutic
agent selected from the group consisting of alkylating agents,
doxorubicin, carboplatin, cisplatin, and taxol.
32. (canceled)
33. The kit of claim 26 further comprising an anticoagulant to
treat the device prior to use.
34. The kit of claim 27 wherein the agent is thalidomide.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 12/685,307, filed Jan. 11, 2010, which is a continuation of
U.S. application Ser. No. 09/699,003, now U.S. Pat. No. 7,854,717,
filed Oct. 26, 2000, which is a continuation of U.S. application
Ser. No. 09/316,226, now U.S. Pat. No. 6,231,536, filed May 21,
1999, which is a continuation-in-part-of U.S. application Ser. No.
09/083,307, now U.S. Pat. No. 6,620,382, filed May 22, 1998, each
of which is hereby incorporated by reference.
BACKGROUND OF THE INVENTION
[0002] The present invention is generally in the field of enhancing
an immune response, and particularly relates to the removal of
inhibitors of immune mediators, in combination with anti-angiogenic
compounds, cytokines, compounds inducing a procoagulant state,
chemotherapeutics and/or radiation.
[0003] Conventional cancer therapy is based on the use of drugs
and/or radiation which kills replicating cells, hopefully faster
than the agents kill the patient's normal cells. Surgery is used to
reduce tumor bulk, but has little impact once the cancer has
metastasized. Radiation is effective only in a localized area.
[0004] The treatments can in themselves kill the patient, in the
absence of maintenance therapy. For example, for some types of
cancer, bone marrow transplants have been used to maintain the
patient following treatment with otherwise fatal amounts of
chemotherapy. Efficacy has not been proven for treatment of solid
tumors, however, "Cocktails" of different chemotherapeutic agents
and combinations of very high doses of chemotherapy with
restorative agents, for example, granulocyte macrophage colony
stimulating factor ("GM-CSF"), erythropoietin, thrombopoetin,
granulocyte stimulating factor, ("G-CSF"), macrophage colony
stimulating factor ("M-CSF) and stem cell factor ("SCF") to restore
platelet and white cell levels, have been used to treat aggressive
cancers. Even with the supportive or restrictive therapy, side
effects are severe.
[0005] Other treatments have been tried in an attempt to improve
mortality and morbidity. Vaccines to stimulate the patient's immune
system have been attempted, but not with great success. Various
cytokines, alone or in combinations, such as tumor necrosis factor,
interferon gamma, and interleukin-2 ("IL-2") have been used to kill
cancers, but have not produced cures. More recently,
anti-angiogenic compounds such as thalidomide have been tried in
compassionate use cases and shown to cause tumor remission. In
animal studies, compounds inducing a procoagulant state, such as an
inhibitor of protein C, have been used to cause tumor remission.
New studies have shown that inhibitors of cytokine receptors, such
as tumor necrosis factor receptors ("TNF-Rs") which are released in
a soluble form from tumor cells, in high concentrations relative to
normal cells, may restore the immune system's attack on the tumor
cells (Jablonska and Peitruska, Arch. Immunol. Ther. Exp. (Warsz)
1997, 45(5-6), 449-453, Chen, et al., J. Neuropathol. Exp. Neurol.
1997, 56(5), 541-550).
[0006] U.S. Pat. No. 4,708,713 to Lentz describes an alternative
method for treating cancer, involving ultrapheresis to remove
compounds based on molecular weight, which promotes an immune
attack on the tumors by the patient's own white cells.
[0007] Despite all of these efforts, many patients die from cancer;
others are terribly mutilated. It is unlikely that any one therapy
will be effective to cure all types of cancer.
[0008] It is therefore an object of the present invention to
provide a method and compositions for treatment of solid
tumors.
[0009] It is a further object of the present invention to provide a
method and compositions that does not involve non-selective,
extremely toxic, systemic chemotherapy.
SUMMARY OF THE INVENTION
[0010] A method to treat cancer uses ultrapheresis, refused to
remove compounds of less than 120,000 daltons molecular weight,
followed by administration of replacement fluid, to stimulate the
patient's immune system to attack solid tumors. In the preferred
embodiment, the patient is ultrapheresed using a capillary tube
ultrafilter or parallel plate filter having a molecular weight
cutoff or 120,000 daltons, sufficient to filter at least one blood
volume. The preferred replacement fluid is ultrapheresed normal
plasma. Alternatively, the patient is pheresed to selectively
remove soluble receptor/inhibitors to soluble tissue necrosis
factor receptor-1 ("sTNFR-1"), soluble tissue necrosis factor
receptor-2 ("sTNFR-2"), soluble interleukin-2 receptor ("sIL-2R"),
soluble interleukin-1 receptor ("sIL-1R"), soluble interleukin-6
receptor ("sIL-6R"), or soluble interferon-gamma receptor
("sIFN-gammaR"). These can be removed by binding to the cytokine,
an epitope thereof, or an antibody to the receptor. These can be
immobilized in the filter, in a column, or using other standard
techniques for binding reactions to remove proteins from the blood
or plasma of a patient. The patient is preferably treated daily for
three weeks, diagnostic tests conducted to verify that there has
been shrinkage of the tumors, then the treatment regime is
repeated.
[0011] The treatment is preferably combined with an alternative
therapy, for example, treatment with an anti-angiogenic compound,
one or more cytokines such as TNF, gamma interferon, other
interferons, or IL-2, or a procoagulant compound. The treatment
increases the inflammation against tumors by allowing cytokines,
such as TNF, to work effectively. This provides a basis for an
improved effect when combined with any treatment that enhances
cytokine activity against the tumors, for example, treatments using
alkylating agents, doxyrubicin, carboplatinum, cisplatinum, and
taxol, and other drugs which may be synergistic in effect with
"unblocked" cytokines. Alternatively, the ultapheresis treatment
can be combined with local chemotherapy, systemic chemotherapy,
and/or radiation.
BRIEF DESCRIPTION OF THE DRAWINGS
[0012] FIGS. 1 and 2 are schematics of the system for
ultrapheresis.
DETAILED DESCRIPTION OF THE INVENTION
[0013] The methods and devices disclosed herein are useful for
treatment of patients with cancer, immune-mediated disorders,
chronic parasitism, some viral diseases, and other disorders
characterized by elevated levels of TNF receptors or inhibitors to
IL-2, IL-6, gamma interferon, or other pro-inflammatory signals as
well as white cell activation. Examples demonstrate efficacy in
treating cancer patients.
I. Ultrapheresis
A. Ultrapheresis System
[0014] 1. Filters
[0015] The filter must be biocompatible, and suitable for contact
with blood, without causing excessive activation of platelets or
clotting. Devices will typically be either parallel plate filters
or capillary membrane filters. These can be adapted from devices
currently in use for kidney dialysis. The capillary membrane
filters will typically have a surface area of between about 0.25
and 1 m.sup.2 for use with children and between about 1 and 3
m.sup.2 for use with adults. The parallel plate filters will
typically have a surface area in the range from 0.1 and 2
cm.sup.2/ml of blood to be filtered.
[0016] The filter membranes will typically be a biocompatible or
inert thermoplastic such as polycarbonate, polytetrafluorethylene
("Teflon"), polypropylene, ethylene polyvinyl alcohol or
polysulfone, having a pore size typically of between 0.02 and 0.05
microns in a capillary membrane filter and of between 0.04 and 0.08
microns in a parallel plate filter. The actual pore size that
yields the desired cutoff of approximately 120,000 daltons is
determined based on the fluid flow geometry, shear forces, flow
rates, and surface area. The effective cutoff for a capillary
membrane filter with a pore size of 0.03 microns is 120,000
daltons, with a sieving coefficient of between 10 and 30%. This
results in only a trivial amount of IgG being removed from the
patient's blood. The filter membrane should be less than about 25
microns, preferably less than about 10 microns, thick. The
permeable membrane should not cause blood clotting or otherwise
react with the blood.
[0017] A preferred membrane is one in which the pores are made by
electron beams directed perpendicularly to the surface because the
size and density of the pores can be accurately controlled in this
manner. The pores are essentially circular in cross section so the
effective pore size is the actual pore size. The effective pore
size of ultrafiltered media having pores with non-circular cross
sections shall be the diameter of a circular pore which will pass
molecular or other components of an equivalent size to the
molecules or other components which pass through the filter medium
in question.
[0018] Suitable devices can be obtained from Asahi Chemical
Company, Japan, and Kuraray Co., Ltd, 1-12-39, Umeda, ite-ku, Osaka
530, Japan.
[0019] Staged filters can also be used, which have different pore
sizes and/or geometries or surfaces areas, to provide for a
"staggered" removal of materials from the blood, Alternatively,
although not at this time preferred, one can use differential
centrifugation, to provide for an appropriate separation of blood
components. Specific absorbing columns can also be employed to
selectively remove specific cytokine and cellular inhibitors from
the filtered plasma so that the ultrafiltrate (treated plasma) can
be returned to the patient.
[0020] 2. Process Controls and Fluid Handling
[0021] The patient will typically be connected to the blood
processing device using standard intravenous tubing, with
connections similar to those used for plateletpheresis, so that
blood can be removed from the patient at one site and returned at
another. The tubing is connected to a pomp that controls the flow
rate so that in the preferred embodiment one blood volume (based on
approximately 7% of the total body weight) is processed over a
period of approximately 21/2 hours. The filtrate is then returned
from the filtration device to the patient at the second site.
Standard microprocessor controls can be used to regulate the blood
flow, for example, by monitoring the volume of the blood products
being removed, in combination with flow rate monitors and pump
speed.
[0022] The entire system should first be flushed with saline and
then treated with an anticoagulant or anticlotting agent, such as
sodium heparin, to be sure that there are no locations within the
system where blood clotting can occur. Moreover, small amounts of
anticoagulants should be continually introduced into the blood
stream directed to the ultrafilter to ensure than no clotting
occurs during the filtration process. All of the surfaces of the
system which come in contact with the blood and fluids which are
infused into the patient must be sterilized prior to commencing
treatment.
[0023] FIG. 1 illustrates a system for ultrapheresis. Blood is
removed from a patient by means of a venous catheter 10 with the
distal lead 11 thereof disposed in the superior vena cava 12
leading to the patient's heart 13. The blood passes through conduit
14 to a drip chamber 15 and then into pump 16 which controls the
pressure of the blood to the separation unit 17, preferably an
ultrafilter as shown, through conduit 18. A pressure gauge 19 is
provided on conduit 14 to continually monitor arterial pressure. A
syringe pomp 20 feeds an anti-clotting drug such as sodium heparin
to conduit 18 to prevent the clotting of blood in the ultrafilter
17. In the ultrafilter 17 the blood stream passes over the
ultrafilter medium or membrane 21 under pressure. The blood
fraction including the low molecular weight components passes
through the membrane 21 and is discharged as permeate through
conduit 22. The retentate or treated blood containing the high
molecular weight components, which include whole blood cells and
platelets, is discharged into conduit 23 which ultimately leads
back to the patient. Volumetric pump 27 passes a controlled amount
of permeate to a container 28 for containment and for measuring.
Volumetric pump 30, which is preferably the same type and capacity
as pump 27, pumps replacement fluid from a container 31 to conduit
32, which directs the fluid to conduit 23 where it mixes with the
retentate or treated blood. The treated blood and other components
are returned to the patient through venous catheter 34, the distal
or discharge end of which is disposed in the brachiocephalic vein.
The volumetric pumps 27 and 30 are preferably set either to pump
the same total amount of fluid or to pump at the same rate, so that
the same volume of fluid which is removed from the patient's blood
stream as permeate is returned as replacement fluid. The blood
stream in conduit 23 is passed through filter 36 to remove clots or
other debris from the blood stream. A drip chamber 37 ensures that
no significant quantities of air enter the patient's blood stream.
A pressure gauge 38 is provided to continually monitor venous blood
pressure.
[0024] FIG. 2 illustrates another embodiment wherein blood removed
from a patient is first passed through conduit 30 to a first
ultrafilter 31 to selectively separate a blood fraction with
components having molecular weights less than about 1,000,000
Daltons. The retentate from this ultrafiltration which contains the
high molecular weight components is returned through conduit 32 to
the patient. The permeate from the first ultrafilter, 31 is passed
through conduit 33 to a second ultrafilter 34 where a blood
fraction having a molecular weight below 30,000 is removed from the
permeate stream from the first ultrafilter 31. The permeate front
the second ultrafilter 34, which contains the very low molecular
weight components such as salts and nutrients may be returned to
the patient through conduit 35. The retentate from the second
ultrafilter which contains blocking factors, IgG immunoglobulins
and other components is discharged through conduit 36.
[0025] Blood should be pumped through the ultrafilter unit at
sufficient pressure to cause the blood components having the
immunosuppressive effects to pass through the filter but at a
velocity which will not excessively shear or otherwise damage the
blood cells passing over the membrane. Generally it has been found
that the ratio of the area of the membrane to the amount of blood
treated per hour should be within about 0.1 to 2 cm/mL.
Differential pressure across the membrane should range from about 2
to 20 mM Hg.
[0026] 3. Replacement Fluids
[0027] The patient must receive replacement fluids following
filtration. The preferred replacement fluid is ultrapheresis normal
plasma, for example, expired plasma obtained from the Red Cross,
which has been filtered using the same filter as used to treat the
patient. Alternatively, the patient can be administered normal
albumin, or fresh frozen plasma diluted with saline.
II. Treatment with Adjuvant Therapies
[0028] Standard ultrapheresis is conducted over a period of time
until a positive indication is observed. This is typically based on
diagnostic tests which show that there has been some reduction in
tumor size or which suggests tumor inflammation. The patient is
preferably treated daily for three weeks, diagnostic tests
conducted to verify that there has been shrinkage of the tumors
and/or inflammation, then the treatment regime is repeated.
[0029] Surgical (or vacuum) removal of necrotic material may be
required prior to or during treatment to avoid toxicity associated
with high tumor burden.
[0030] This procedure has been demonstrated to cause a significant
response (greater than 50% reduction in size of tumors) in a
variety of solid tumors in approximately 50% of patients who have
failed all other treatment modalities. A tumor specific
inflammatory response provoked by ultrapheresis has been documented
in approximately 75% of patients in metastatic melanoma clinical
trials. This inflammation is characterized by redness, swelling,
warmth, and tenderness and is confined to tumors only. There has
been no associated injury to non-cancerous tissue. This tumor
specific inflammatory response has led to a 50% or greater
reduction in the size of tumors in 50% of patients studied so far.
Clinical trials have also demonstrated a 44% major reduction of
tumor metastases in human breast cancer and prostate cancer.
[0031] Tumor specific inflammation has been observed in patients
with metastatic colon cancer, ovarian cancer, lung cancer, head and
neck cancer, cervical and endometrial cancers. In some cases, this
inflammation has been followed by significant tumor regressions in
each tumor type. The significance of response in such diverse tumor
types strongly suggests that ultrapheresis modifies the patient's
response to the tumor in favor of successful immunologic control of
the tumor. Types of tumors that are particularly sensitive to the
ultrapheresis include epithelial tumors, sarcomas, melanomas and
glioblastomas.
[0032] It would clearly be advantageous to cause complete
remissions. Based on the presumed mechanism that the process is
removing immune inhibitors produced by the tumors, especially
inhibitors of cytokines and other immune mediators, it is possible
to treat the patients with adjuvant or combination therapies, that
enhance the results achieved with the ultrapheresis. TNF-alpha and
beta receptors are thought to be particularly important immune
inhibitors. Therefore, compounds which enhance TNF activity are
particularly preferred. These include anti-angiogenic compounds,
such as thalidomide, procoagulant compounds, cytokines and other
immunostimulants. Standard chemotherapeutic agents and/or radiation
can also be used with the ultrapheresis.
A. Anti-Angiogenic Compounds
[0033] Any anti-angiogenic compound can be used. Exemplary
anti-angiogenic compounds include O-substituted fumagillol and
derivatives thereof, such as TNP-470, described in U.S. Pat. No.
5,135,919, 5,698,586, and 5,290,807 to Kishimoto, et al.;
angiostatin and endostatin, described in U.S. Pat. No. 5,290,807,
5,639,725 god 5,733,876 to O'Reilly, thalidomide, as described in
U.S. Pat. Nos. 5,629,327 and 5,712,291 to D'Amato; and other
compounds, such as the anti-invasive factor, retinoic acid, and
paclitaxel, described in U.S. Pat. No. 5,716,981 to Hunter, et al.,
and the metalloproteinase inhibitors described in U.S. Pat. No.
5,713,491 to Murphy, et al. Thalidomide is administered once daily,
200 mg orally.
B. Procoagulant Compounds
[0034] Protein C is a vitamin K-dependent plasma protein zymogen to
a serine protease. Upon activation it becomes a potent
anticoagulant. Activated protein C acts through the specific
proteolysis of the procoagulant cofactors, factor VIIIa and factor
Va. This activity requires the presence of another vitamin
K-dependent protein, protein S, calcium and a phospholipid
(presumably cellular) surface. As described in Hemostasis and
Thrombosis: Basic Principles and Clinical Practice 2nd Ed., Colman,
R. W., et al., p. 263 (J. B. Lippincott, Philadelphia, Pa. 1987),
protein C circulates in a two-chain form, with the larger, heavy
chain bound to the smaller light chain through a single disulfide
link. Protein C is activated to activated protein C (APC). Thrombin
is capable of activating protein C by the specific cleavage of the
Arg.sup.12-Leu.sup.13 bond in the heavy chain. In vivo, in the
presence of physiological concentrations of calcium, the rate of
this activation is enhanced dramatically when thrombin is bound to
the endothelial cell cofactor, thrombomodulin. Matschiner, et al.,
Current Advances in Vitamin K Research, pp. 135-140, John W.
Suttie, ed. (Elsevier Science Publishing Co., Inc. 1988) have
further reviewed the role of the Vitamin K dependent proteins in
coagulation.
[0035] Blockage of the natural anticoagulant pathways, in
particular the protein C pathway, uses the natural procoagulant
properties of the tumor to target the tumor capillaries for
microvascular thrombosis, leading to hemorrhagic necrosis of the
tumor, as described in U.S. Pat. No. 5,147,638 to Esmon, et al.
Examples of such compounds include anti-protein C and anti-protein
S.
C. Cytokines
[0036] The biologic activity and clinical effectiveness of
pro-inflammatory cytokines is augmented by ultrapheresis in the
patient with cancer and other states of acquired immune tolerance.
Specifically, both TNF alpha and TNF beta, in doses of between
approximately 100 to 500 micrograms per meter squared body surface
area (M2BSA), can enhance the immune reaction in aggressive tumors.
Monocyte and lymphocyte activation is augmented by INF-alpha,
INF-beta and gamma. The IL-1 and IL-2 receptor antagonists are
removed by ultrapheresis and thereby upregulate the in vivo
activity of these cytokines. An 80 kD glycoprotein, which is
responsible for inhibiting blastoid transformation in advanced
malignancy, chronic infectious disease and pregnancy, has recently
been found, and appears to be responsible for the loss of delayed
hypersensitivity reactions in these diseases, which is removed by
this process. This is significant because in removing this type of
suppression, vaccines of all types will work better. Dosage regimes
for IFN-alpha and beta are 3 M units subcutaneous three times a
week up to 20 M units/M2 BSA daily. Interferon-gamma is
administered in a dosage of between 100 to 1000 micgms per day.
D. Anti-cytokine Receptor Molecules.
[0037] It is well established that TNF receptor 1 and TNF receptor
2 molecules are shed by tumor cells, and that these molecules
appear to inhibit immune mediated attack by the host on the tumor
cells. The ultrapheresis is believed to remove the majority of
these soluble receptors. Additional, and/or selective, removal of
these soluble receptor/inhibitors to soluble tissue necrosis factor
receptor-1 ("sTNFR-1"), soluble tissue necrosis factor receptor-2
("sTNFR-2"), soluble interleukin-2 receptor ("sIL-2R"), soluble
interleukin-1 receptor ("sIL-1R"), soluble interleukin-6 receptor
("sIL-6R"), or soluble interferon-gamma receptor ("sIFN-gammaR")
can be used to supplement or instead of the ultrapheresis. The
advantage of selective removal is that the same beneficial effect
is obtained in treatment of the disorder but the treatment is much
less expensive and safer since exogenous plasma or albumin does not
have to be administered to the patient when there is selective
removal. These can be removed by binding to the cytokine, an
epitope thereof, or an antibody to the receptor. These can be
immobilized in the filter, in a column, or using other standard
techniques for binding reactions to remove proteins from the blood
or plasma of a patient. As used herein, antibody refers to
antibody, or antibody fragments (single chain, recombinant, or
humanized), immunoreactive against the receptor molecules. In the
preferred embodiment, these antibodies are immobilized on the
ultrapheresis membrane filters, using standard antibody coupling
techniques. In the most preferred embodiment, the antibody is
reactive with the carboxy-terminus of the shed receptor molecules,
thereby avoid concerns with signal transduction by the receptor is
still present on the ceil surface.
E. Chemotherapeutic Agents
[0038] Preferred chemotherapeutic agents are those which are
synergistic with TNF, for example, alkylating agents, doxyrubicin,
carboplatinum, cisplatinum, and tomoxifen. Tamoxifen plays a role
not only in blocking of estrogen receptors but also certain growth
factor receptors such as epidermal derived growth factor ("EDGF"),
fibroblast derived growth factor ("FDGF"), tumor derived growth
factor ("TDGF"), TDGF-.beta. and platelet derived growth factor
("PDGF") and therefore may be complementary to inflammation against
cancers provoked by ultrapheresis.
F. Radiation
[0039] Radiation therapy is destructive of normal tissue, causing
tumors to die partially by an inflammatory attack. Ultrapheresis
allows the use of lower doses of radiation to kill residual tumor
cells sad spare normal tissue. In a preferred method, ultrapheresis
is used as the initial therapy, followed by radiation at
approximately one-half of the normal dosages. If is well
established that TNF kills tumor cells by generating free oxygen
radicals, hydroxyl radicals and halide ions, and that radiation
therapy generates carbonium ions in tissue. Therefore the
combination of the two is more effective in killing cancer cells
than either alone.
III. EXAMPLES
Example 1
Treatment of A Patient with Metastatic Leiomyoscarcoma with
Ultrapheresis
[0040] Mrs. J. K. is a 43 year old lady with metastatic
leiomyoscarcoma with six (6) lung metastases all of which developed
within one month of surgery on both lungs to remove tumors. These
tumors had also failed methotrexate, adriamycin, ifosphomide, and
dactiaomycin.
[0041] She received 24 ultrapheresis procedures with no side
effects. One month later, CAT scan revealed only four (4) tumors
and these were reduced in size by 50%.
Example 2
Treatment of Patients with Breast Cancer by Ultrapheresis and
Thalidomide
[0042] Mrs. J. R. is a 44 year old lady who had metastatic breast
cancer that had failed radiation therapy and treatment with
chemotherapeutic agents: cytoxan, adriamycin, 5-FU, taxol,
cis-platin, navalbine, tamoxofin and arimedex. Tumor at the time of
ultrapheresis was documented in lungs, bone and skin of the entire
left anterior and lateral chest.
[0043] She was treated with 15 ultrapheresis procedures over a
three week period. She experienced marked inflammation in the
tumors of his skin, increased pain from the tumors in her bones,
and swelling of the tumors in her lungs. She then received the drug
thalidomide 200 mg at night. The redness and swelling in her skin
improved within 2 days and her breathing returned to normal within
one week. Two weeks after completing treatment, all tumor in her
skin had resolved clinically, her bone pains resolved and the
tumors in her lungs resolved on repeat CAT scan. One week later,
she returned to work as a school counselor. She tested disease free
two months after treatment and was being maintained on thalidomide
at the same dose.
Example 3
Treatment of Patient with Metastic Melanoma with Ultrapheresis and
Thalidomide
[0044] Mr. P. G. is a 54 year old engineer with metastatic melanoma
with metastases to lung and to lymph nodes in the mediastinum.
[0045] He received 24 ultrapheresis procedures, resulting in a 25%
reduction of tumors. He was subsequently treated with an additional
12 procedures, resulting in minor tumor reduction despite evidence
of tumor inflammation. The tumors regrew within one month. He was
again retreated with ultrapheresis, again resulting in inflammation
and some minor regression, but was then treated with thalidomide at
the time of tumor inflammation. Two months later, repeat CAT scan
showed complete disappearance of tumors in the lung and
mediastinum. He is being followed closely and shows no evidence of
disease and has no medical complaints six months after completing
treatment.
Example 4
Treatment of a Patient with Metastic Adenocarcinoma with
Ultrapheresis and Thalidomide
[0046] Dr. R. S. is a 59 year old gentlemen with metastatic
adenocarcinoma of the left upper lung with metastases to liver,
brain and bones. His tumors had failed to respond to taxol,
cis-platin and etoposide. His brain tumors had responded to
radiation therapy.
[0047] He received 15 ultrapheresis procedures. Each procedure
caused increased pain in tumors of his spine, pelvis, right hip and
left shoulder. Follow up scans after ultrapheresis treatment
revealed resolution of tumors in pelvis, spine, hip, and ribs.
There was a 50% reduction in the primary tumor in the lung and
liver. Thalidomide was then started at 200 mg each night. One month
later, the scans revealed further reduction in the tumors in lung
and liver. The patient's pains have all been resolved and he is
asymptomatic at this time.
[0048] Modifications and variations of the method and compositions
described herein will be obvious to those skilled in the art. Such
modifications and variations are intended to come within the scope
of the appended claims.
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