U.S. patent application number 10/859802 was filed with the patent office on 2004-11-04 for synergistic tumorcidal response induced by histamine.
Invention is credited to Gehlsen, Kurt R., Hellstrand, Kristoffer, Hermodsson, Svante.
Application Number | 20040219153 10/859802 |
Document ID | / |
Family ID | 22848072 |
Filed Date | 2004-11-04 |
United States Patent
Application |
20040219153 |
Kind Code |
A1 |
Gehlsen, Kurt R. ; et
al. |
November 4, 2004 |
Synergistic tumorcidal response induced by histamine
Abstract
The present invention relates to methods of treating cancer in
which histamine is administered in conjunction with other cancer
therapies. The cancer therapy includes surgery, radiation,
immunotherapy, the administration of an agent which enhances the
humoral immune response of the patient or any combination
thereof.
Inventors: |
Gehlsen, Kurt R.;
(Encinitas, CA) ; Hellstrand, Kristoffer;
(Goteborg, SE) ; Hermodsson, Svante; (Molndal,
SE) |
Correspondence
Address: |
KNOBBE MARTENS OLSON & BEAR LLP
2040 MAIN STREET
FOURTEENTH FLOOR
IRVINE
CA
92614
US
|
Family ID: |
22848072 |
Appl. No.: |
10/859802 |
Filed: |
June 2, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10859802 |
Jun 2, 2004 |
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10217254 |
Aug 9, 2002 |
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10217254 |
Aug 9, 2002 |
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09226226 |
Jan 6, 1999 |
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6498181 |
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Current U.S.
Class: |
424/155.1 ;
424/1.49; 424/93.2 |
Current CPC
Class: |
A61K 31/417 20130101;
A61K 41/0038 20130101; A61P 35/02 20180101; A61P 35/00 20180101;
A61K 39/395 20130101; A61K 39/395 20130101; A61K 31/415 20130101;
A61K 39/395 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
424/155.1 ;
424/093.2; 424/001.49 |
International
Class: |
A61K 051/00; A61K
048/00; A61K 039/395 |
Claims
1. An improved cancer therapy, wherein the cancer therapy is
selected from the group consisting of surgery, radiation,
immunotherapy, and administration of an agent that enhances the
humoral response of a subject, the improvement comprising
administering to a subject an amount of a pharmaceutically
acceptable form of histamine sufficient to synergistically inhibit
a cancer, wherein said cancer is sensitive to the combination of
said at least one cancer therapy and histamine synergistically.
2. The improved cancer therapy of claim 1, wherein the cancer
therapy is a radiation therapy selected from the group consisting
of external beam radiation, radionucleotides, radioactive implants,
radioactive antibodies, radioactive lipids, radioactive proteins,
radioactive glycolipids, and radioactive glycoproteins.
3. The improved cancer therapy of claim 1, wherein the cancer
therapy is an agent selected from the group consisting of a viral
antigen, a cancer cell antigen, and an inactivated cancer cell.
4. The improved cancer therapy of claim 1, wherein the cancer
therapy is a surgery.
5. The improved cancer therapy of claim 1, wherein the cancer
therapy is an immunotherapy.
6. The improved cancer therapy of claim 5, wherein the
immunotherapy is an antibody.
7. The improved cancer therapy of claim 6, wherein the antibody is
a monoclonal antibody.
8. The improved cancer therapy of claim 1, wherein the cancer is a
stomach cancer.
9. The improved cancer therapy of claim 1, wherein the cancer is a
pancreatic cancer.
10. The improved cancer therapy of claim 1, wherein the cancer is
an ovarian cancer.
11. The improved cancer therapy of claim 1, wherein the cancer is a
prostate cancer.
12. The improved cancer therapy of claim 1, wherein the cancer is a
neuroblastoma.
13. The improved cancer therapy of claim 1, wherein the cancer is a
melanoma.
14. The improved cancer therapy of claim 1, wherein the cancer is a
breast cancer.
15. The improved cancer therapy of claim 1, wherein the cancer is
an acute myleogenous leukemia.
16. The improved cancer therapy of claim 1, wherein the cancer is a
chronic lymphatic leukemia.
17. The improved cancer therapy of claim 1, wherein the cancer is a
multiple myeloma.
18. The improved cancer therapy of claim 1, wherein the cancer is a
Waldenstrom's macroglobinemia.
19. The improved cancer therapy of claim 1, wherein the cancer is a
hairy cell leukemia.
20. The improved cancer therapy of claim 1, wherein the cancer
therapy is a radiation therapy.
21. The improved cancer therapy of claim 1, wherein said cancer is
a solid tumor disease.
Description
RELATED APPLICATION
[0001] This application is a Continuation of U.S. application Ser.
No. 10/217,254, filed Aug. 9, 2002 which is a Continuation of U.S.
application Ser. No. 09/226,226, filed Jan. 6, 1999, now U.S. Pat.
No. 6,498,181, each of which is hereby expressly incorporated by
reference in its entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to methods of treating cancer
in which histamine is administered in conjunction with other cancer
therapies. The cancer therapy includes surgery, radiation,
immunotherapy, the administration of an agent which enhances the
humoral immune response of the patient or any combination
thereof.
BACKGROUND OF THE INVENTION
[0003] Despite tremendous advances over the past several years,
current cancer therapies fail to cure many forms of cancer. The
problems faced by investigators and clinicians are numerous. Some
tumors are not resectable or do not respond to radiation or
chemotherapy or combinations of these procedures. Furthermore, the
severe morbidity often associated with these treatments has led
many to look for entirely new approaches to tumor therapy that are
more specifically lethal for cancer cells and less toxic for normal
cells. Attempts to promote an immune response to the tumor by
immunizing the cancer patient with killed cancer cells or antigens
specific for cancer cells have been largely unsuccessful and the
use of monoclonal antibodies (mAbs) as the "magic bullet" to
specifically destroy cancer cells without harming normal cells
remains clinically limited. Methods that enhance the effectivity of
known cancer therapies are desperately needed.
[0004] Surgery is touted by many to be the only potentially
curative therapy for patients suffering from stomach, pancreatic,
carcinoid and ovarian tumors. (Norton, Digestion 55(suppl 3):98-103
(1994)). Although surgery is often the indicated treatment for
malignant disease, this form of cancer therapy has two major
shortcomings. First, many tumors are not resectable because they
are located in or have spread into vital structures. (Dvorak et
al., Cancer Cells 3: 77-85 (1991)). While debulking of tumors in
vital areas has been presented as an alternative, such procedures
are felt by many to inadequately treat the disease and only improve
the quality of life of the patient. (Norton, Digestion 55(suppl
3):98-103 (1994)). Second, by the time of diagnosis and removal of
the primary tumor, many tumors have already metastasized. (Dvorak
et al., Cancer Cells 3: 77-85 (1991)) and (Norton, Digestion
55(suppl 3):98-103 (1994)). Metastases, which tend to be multiple
and wide spread, do not easily lend themselves to surgical excision
and, consequently, many patients undergo major surgical procedures
only to have rapid disease progression found soon after surgery.
(Dvorak et al., Cancer Cells 3: 77-85 (1991)). While surgery
remains a good first line of defense against cancer, oncologists
are now also combining other treatment methods including radiation,
chemotherapy and immunotherapy to obtain better patient survival.
(Hacker and van der Burg, Annals of Oncology 4 (suppl. 4): S17-S22
(1993)).
[0005] External beam radiation has replaced surgery for the
long-term control of many tumors of the head and neck, cervix,
bladder, prostate and skin, in which it often achieves a reasonable
probability of tumor control with good cosmetic result. (Basic
Clinical Radiobiology 2nd edition. Steel ed., Arnold Publishers,
pp. 1-13 (1997)). External beam radiation is generally helpful for
the treatment of localized tumors but this approach is also
problematic because it causes considerable damage to surrounding
cells and compromises the patient's immune system. The use of
radioactive "seed implants" has provided more focus on tumor cells
and less damage to surrounding tissue but a more specific means to
deliver radiation to the tumor is needed. While radiation therapy
is a good alternative to surgery, it is unable to treat a large
percentage of cancers that are radiation-insensitive and, because
of the high morbidity associated with high doses of external beam
radiation, the use of radiation to treat metastastic disease is not
desirable. (Dvorak et al., Cancer Cells 3: 77-85 (1991)).
[0006] Many forms of antibody therapy to treat cancer have also
been reported. Early antibody therapy treatments relied almost
entirely on complement fixation to kill tumor cells. (Cellular and
Molecular Immunology, Eds. Abul K. Abbas, Andrew H. Lichtman, and
Jordan S. Pober, W. B. Saunders Co., Philadelphia (1991)).
Recently, greater success has been achieved using antibodies which
block cancer cell growth factor receptors. (Wong, Genetic
Engineering News pp.23 and 49 (July 1998) and Ashley et al., J. of
Neuro-Oncology 35:259-273 (1997)). The use of antibody conjugates
which bind tumor cells with cytotoxic substances such as toxic
molecules or radioisotopes has also seen promising results. (Larson
et al., ACTA Oncologica 32:709-715 (1993); Quack and van Dongen,
Eur Arch Otorhinolaryngol 251:1-5 (1994); Frankel et al., Cancer
Biology 6:307-317 (1995); Mach et al., Curr Op in Immunol.
3:685-693 (1991) and Recent Results in Cancer Research vol
141:Systemic Radiotherapy with Monoclonal Antibodies, edited by M.
L. Sautter-Bihl and M. Wannenmacher, Springer-Verlag publishers,
(1996)). Another innovative antibody treatment for cancer uses
antibody heteroconjugates--dual purpose antibodies which direct
bound cancer cells to phagocytic cells of the immune system. (Wong,
Genetic Engineering News pp.23 and 49 (July 1998)). Preliminary
clinical trials with mAb heteroconjugates have shown promise in the
treatment of renal and prostate cancer. (Id.).
[0007] Although a variety of tumor cells can be lysed in vitro by
antibody-dependent mechanisms such as complement activation or
antibody-dependent cell-mediated cytotoxicity, few therapies based
on enhancing the humoral response of a subject have been clinically
successful. (Sedlacek, Critical Reviews in Oncogenesis 5(6):555-587
(1994)). In one study, patients suffering from melanoma were
administered a vaccine containing a mixture of three allogenic
melanoma cell lines and showed a 71% 10-year actuarial survival as
opposed to the 40% 10-year actuarial survival demonstrated by
melanomic patients who received a single cell line vaccine.
(Slingluff and Seigler, Ann Plast Surg 28:104-107 (1992)). In
another study, however, leukemic patients immunized with killed
leukemia cells failed to demonstrate any significant improvement.
(Cellular and Molecular Immunology, Eds. Abul K. Abbas, Andrew H.
Lichtman, and Jordan S. Pober, W. B. Saunders Co., Philadelphia
(1991)).
[0008] In an attempt to improve cancer vaccines, researchers have
tried numerous strategies to make the cancer cell vaccines more
antigenic. (Sedlacek, Critical Reviews in Oncogenesis 5(6):555-587
(1994)). Studies on immunization with plasmid DNA encoding defined
tumor antigens or with a complex comprising hydrophobized
polysaccharides attached to an oncogenic receptor protein, for
example, may show greater clinical success. (Tuting et al., J Mol
Med 75:478-491 (1997) and Gu et al. Cancer Research 58:3385-3390
(1998)). At present investigators have had limited success with
treating cancer by administering agents which enhance the humoral
response of the patient and approaches to improve the effectivity
of this form of treatment are needed.
[0009] Despite recent progress in cancer therapy, many problems
persist. Tumors often metastasize, grow in sensitive areas and are
not treatable by surgery or radiation. (Dvorak et al., Cancer Cells
3: 77-85 (1991)). Tumor cells also generally avoid
immunosurveillance in the cancer patient and most current vaccines
poorly trigger a cancer patient's immune system to overcome this
immunotolerant state. (Sedlacek, Critical Reviews in Oncogenesis
5(6):555-587 (1994)). Further, the use of antibody therapies such
as immunotoxins, immunoradionuclides, immunoheteroconjugates, and
receptor specific antibodies has been limited by low-level
expression of the targeted tumor associated antigen, low-affinity
mAbs, inefficient radionuclides, non-specific toxicity of the
antibody conjugate and poor tumor uptake of the therapeutic agent.
(Ashley et al., J. of Neuro-Oncology 35:259-273 (1997); Frankel et
al., Cancer Biology 6:307-317 (1995); Mach et al., Curr Op in
Immunol. 3:685-693 (1991) and Sedlacek, Critical Reviews in
Oncogenesis 5(6):555-587 (1994)). The need for an agent that
enhances current methods of cancer therapy has long been
manifest.
SUMMARY OF THE INVENTION
[0010] The present invention provides novel methods of treating
cancer in which histamine is administered in conjunction with
conventional cancer therapies such as surgery, radiation,
immunotherapy, and agents which enhance the humoral immune response
of the patient. In one embodiment, a method of augmenting a cancer
therapy encompasses administering to a subject a pharmaceutically
acceptable form of histamine over a period of time such that a
blood histamine concentration sufficient to augment the cancer
therapy is achieved and administering to the subject a cancer
therapy such as surgery, radiation, immunotherapy and an agent
which enhances the humoral response of the subject.
[0011] Preferably, a pharmaceutically acceptable form of histamine
is used such as histamine, histamine dihydrochloride, histamine
phosphate, histamine salts, esters, congeners, prodrugs, histamine
receptor agonists and diphenyleneiodonium. The types of radiation
therapy which can be used include external beam radiation,
radionuclides, radioactive implants, radioactive antibodies,
radioactive lipids, radioactive proteins, radioactive glycolipids
and radioactive glycoproteins. The types of immunotherapy which can
be used include the administration of a monoclonal antibody, a
humanized monoclonal antibody, an Fab, an (Fab').sub.2, an Fv, an
antibody conjugate, an Fab conjugate, an (Fab').sub.2 conjugate, an
Fv conjugate and an antibody heteroconjugate. Several types of
agents which enhance the humoral response of the subject can be
used including viral antigens, cancer cell antigens, inactivated
cancer cells, vaccines, and vitamers.
[0012] Histamine is administered in such a manner that a stable
blood histamine concentration is maintained during the
administration of the cancer therapy to the subject. Histamine can
be administered to the subject indirectly by administering a
substance which induces the release of endogenous histamine such as
retinoic acid, a retinoid, IL-3 or an ingestible allergen.
Histamine can be administered prior to administering the cancer
therapy, after administering the cancer therapy, or during
administration of the cancer therapy. Furthermore, histamine is
administered in a dose from 0.1 to 10.0 milligrams per day.
[0013] In another embodiment, the invention provides a method of
screening cancer treatments in which a non-human mammal, having
been grafted with human tumor cells, is administered histamine and
a cancer therapy, such as a radioactive substance, an antibody, an
agent that enhances the humoral immune response of the non-human
mammal, radiation, or surgery. After administering the cancer
therapy, the tumorcidal response of the non-human mammal is then
determined at various time points. According to this method,
monoclonal antibodies, monoclonal antibodies conjugated to a
compounds such as a toxin, a radioactive substance, a radionuclide,
an antibody fragment or a second antibody, a vaccine (including
killed cancer cells), a radioactive seed implant or external beam
radiation can be used.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0014] Histamine is a biogenic amine, i.e., an amino acid that
possesses biological activity mediated by pharmacological receptors
after decarboxylation. The role of histamine in immediate-type
hypersensitivity is well-established. (Plaut, M. and Lichtenstein,
L. M., 1982, Histamine and Immune Responses in Pharmacology of
Histamine Receptors, Ganellin, C. R. and M. E. Parsons, eds. John
Wright & Sons, Bristol, pp. 392-435). Histamine also mediates
arteriole dilation which causes a rise in capillary and venule
pressure. (Majno et al., J Cell Bio 42:647-672 (1969)).
Furthermore, histamine induces contraction of endothelial cells
resulting in the formation of intercellular gaps and extravasation
of blood vessels. (Id.).
[0015] The present invention is based on the unexpected discovery
that histamine produces a synergistic tumorcidal response when it
is administered in conjunction with surgery, radiation, antibody
therapy or agents which enhance the humoral response of a cancer
patient.
[0016] By "histamine" is meant histamine, its dihydrochloride salt
(histamine dihydrocholride), histamine phosphate, other histamine
salts, esters, or prodrugs, and histamine receptor (H.sub.1,
H.sub.2, H.sub.3) agonists. Seratonin, bradykinin,
diphenyleneiodonium and 5HT agonists are also contemplated. Other
analogs of histamine or histamine receptor agonists that are
suitable for use in the present invention are disclosed in U.S.
Pat. No. 5,728,378 and are known to those of skill in the art. The
administration of compounds which induce the release of endogenous
histamine from the patient's own tissues are also included within
the scope of the present invention; thus, the term "histamine" as
used herein incorporates these compounds as well.
[0017] By "cancer therapy" is meant surgery, radiation,
chemotherapy, antibody therapy and agents which enhance the humoral
immune response of a patient suffering from cancer. "Cancer
therapy" may also include combinations of the treatments mentioned
above. It will be appreciated by those skilled in the art that
several combinations of the above cancer therapy methods produce
synergistic effects on malignancies. Optimization of such
combination treatment protocols in conjunction with histamine
treatment, as detailed below, would be routine.
[0018] By "surgery" is meant surgical procedures to remove cancer
cells from a patient including but not limited to tumor resection
and/or debulking of a tumor. Established methods of surgical
oncology vary according to the type of tumor and the patient's
particular situation. Examples of surgical techniques are found in
Surgical Oncology, edited by Raphael E. Pollock, Kluwer Academic
Publishers, 1997.
[0019] By "radiation therapy" is meant the application of external
beam radiation or the administration of radioactive substances to a
cancer patient including but not limited to radionuclides,
radioactive implants, radioactive antibodies or radioactive
proteins. Many approaches to radiation therapy are known in the art
and examples can be found in Basic Clinical Radiobiology (second
edition), edited by G. Gordon Steel, Arnold publishers, 1997.
[0020] By "antibody therapy" is meant the administration of an
antibody, an antibody conjugate or an antibody heteroconjugate to a
cancer patient for the purpose of treating or preventing cancer.
Many forms of antibody therapy are known in the art including, but
not limited to, the administration of monoclonal or humanized
monoclonal antibodies, the administration of toxin or radionuclide
conjugated antibodies and the administration of monoclonal antibody
heteroconjugates having one domain that binds to a cancer antigen
and another domain that binds to the Fc region of IgG. Further, the
term antibody therapy is meant to include the administration of
(Fab').sub.2 or Fab fragments with or without conjugated toxins or
radionuclides. Several examples of antibody therapy are found in
Recent Results in Cancer Research vol 141:Systemic Radiotherapy
with Monoclonal Antibodies, edited by M. L. Sautter-Bihl and M.
Wannenmacher, Springer-Verlag publishers, 1996.
[0021] By "agents which enhance the humoral immune response" is
meant substances which are administered to a cancer patient for the
purpose of enhancing their humoral immune response. Many methods of
enhancing the humoral immune response of a patient suffering with
cancer are known, including but not limited to, the administration
of viral antigens, cancer cell antigens, inactivated cancer cells,
vaccines and vitamers including ascorbic acid, tocopherol and
betacarotene.
[0022] The administration of histamine can follow several treatment
regimens and the following protocols are meant to exemplify some of
the ways to use the present invention but they are not intended to
limit the scope of the present discovery. The present invention
includes the delivery of a beneficial amount of histamine to the
cancer patient before, during or after the administration of an
established form of cancer therapy such as surgery, radiation,
antibody therapy or an agent which enhances the humoral immune
response of the patient.
[0023] Beneficial levels of circulating blood histamine are
obtained by administering histamine at a dosage of around 0.1 to
10.0 mg/day, preferably around 0.5 to 8.0 mg/day and more
preferably around 1.0 to 5.0 mg/day. In a further embodiment, the
histamine is administered over a period of 1-4 weeks. In a highly
preferred embodiment, the histamine is administered for a period of
1-2 weeks. In one embodiment of the invention, a beneficial stable
level of circulating blood histamine concentration (i.e a stable
level of circulating blood histamine concentration of at least
about 0.2 .mu.M) is maintained.
[0024] It will be appreciated by those of skill in the art that the
patient's circulating blood histamine level can also be monitored
during the course of treatment and boosted whenever the level drops
below the beneficial level or approaches the lower limits of the
beneficial level. For example, in this embodiment, histamine can be
administered whenever the subject's histamine levels drop below 0.2
.mu.M. Alternatively, it will be appreciated that histamine can be
administered at periodic intervals at dosages sufficient to
establish and maintain beneficial levels.
[0025] Routes and carrier compositions for administering histamine
have been disclosed in U.S. Pat. Nos. 5,348,739 and 5,728,378,
which are incorporated herein by reference. Controlled release
vehicles are also well-known to those of skill in the
pharmaceutical sciences. The technology and products in this art
are variably referred to as controlled release, sustained release,
prolonged action, depro, repository, delayed action, retarded
release and time release; the words "controlled release" as used
herein is intended to incorporate each of the foregoing
technologies. U.S. patent application Ser. No. 08/767,338 also
discloses numerous controlled release vehicles as well as infusion
devices for use in the administration of histamine.
[0026] Preferably, the histamine is injected, infused or released
into the patient at a rate of from about 0.5 to 0.2 mg per minute.
A rate of about 0.1 mg per minute is preferred. The histamine is
preferably administered over a period of time ranging from about 1,
3 or 5 minutes to about 30 minutes, with an upper limit of about 20
minutes being preferred, such that the total daily adult dose of
histamine ranges from between about 0.1 to about 10.0 mg, with
about 1.0 to about 5.0 mg being preferred. Histamine administered
over longer periods of time (i.e., longer than about 30 minutes)
has been found to result in a decrease or lack of efficacy, while
rapid administration over less than 1 to 3 minutes can cause more
pronounced and serious sides effects, which include anaphalaxis,
heart failure, broncospasm, pronounced flushing, discomfort,
increased heart rate and respiratory rate, hypertension, and severe
headache.
[0027] Administration of each dose of histamine can occur from once
a day to up to about four times a day, with twice a day being
preferred. Administration can be subcutaneous, intravenous,
intramuscular, intraoccular, oral, transmucosal, or transdermal,
and can utilize direct hypodermic or other injection or infusion
means, or can be mediated by a controlled release mechanism of the
type disclosed above. Any controlled release vehicle or infusion
device capable of administering a therapeutically effective amount
of histamine over a period of time ranging from about 1 to about 30
minutes can be used.
[0028] In addition to histamine, histamine dihydrochloride,
histamine phosphate, or other histamine salts, esters, congeners,
prodrugs and histamine receptor agonists, the use of seratonin, 5HT
agonists, and compounds which induce the release of histamine from
the patient's own tissues is also included within the scope of the
present invention. Retinoic acid, other retinoids such as
9-cis-retinoic acid and all-trans-retinoic acid, IL-3 and
ingestable allergens are compounds which are known to induce the
release of endogenous histamine. These compounds can be
administered to the patient by oral, intravenous, intramuscular,
subcutaneous or other approved routes. However, the administration
of the compound which induces the release of histamine from the
patient's own tissue should result in a release of endogenous
histamine in the range of from about 0.1 to 10.0 mg/day, preferably
around 0.5 to 8.0 mg/day and more preferably around 1.0 to 5.0
mg/day.
[0029] Administration of each dose of a compound which induces
histamine release can occur from once per day to up to about 4
times per day, with twice per day being preferred. Administration
can be subcutaneous, intravenous, intramuscular, intraoccular,
oral, transmucosal, or transdermal, and can incorporate a
controlled released mechanism of the type disclosed above. Any
controlled release vehicle capable of administering a
therapeutically effective amount of a compound which induces
histamine release over a period of time ranging from about 1 to
about 30 minutes can be used.
[0030] Malignancies against which the treatment may be directed
include, but are not limited to, primary and metastic malignant
solid tumor disease, and hematological malignancies such as acute
and chronic myelogenous leukemia, acute and chronic lymphatic
leukemia, multiple myeloma, Waldenstrom's macroglobulinemia, hairy
cell leukemia, myelodisplastic syndrome, polycytaemia vera, and
essential thrombocytosis.
[0031] The present invention can be better understood by way of the
following examples which are representative of the preferred
embodiments but which are not to be construed as limiting the scope
of the invention.
Blood Histamine Levels can be Raised and Maintained at a Beneficial
Level Following Histamine Administration
[0032] To practice the present invention, beneficial levels of
histamine must be raised in a subject suffering from a malignant
disease. The following example provides one approach to establish
stable beneficial levels of circulating blood histamine in a cancer
patient.
EXAMPLE 1
[0033] Five patients suffering from acute myleogenous leukemia
(AML) in remission received treatment with histamine
dihydrochloride diluted in sterile sodium chloride. Histamine was
administered morning and night at separate subcutaneous injection
sites over a period of 21 consecutive days. The histamine was given
as subcutaneous injections using 1 ml syringes containing 0.1 mg of
histamine per ml. The histamine treatment was given twice daily
(morning and night) at a dosage of 0.4 to 0.7 mg histamine per
injection (i.e., a daily total dose of histamine of 0.8 to 1.4 mg
per day).
[0034] Peripheral blood venous samples were drawn in 10 ml
heparinized test tubes before the onset of treatment and weekly
thereafter. The samples were drawn at least 8 hours after the last
injections of histamine. The concentration of histamine in the
whole blood samples was analyzed by the use of a double antibody
radioimmunoassay kit obtained from Bionerica, Inc., Newport Beach,
Calif. 92663 (catalog number 1051). The manufacturer's instructions
provided with the kit, dated June, 1989, were followed. Blood
histamine levels were measured at the indicated times.
[0035] The patients exhibited blood histamine levels of less than
0.2 .mu.M at the start of the experiment. Following histamine
administration, circulating blood histamine levels rose to
beneficial levels (i.e a stable level of circulating blood
histamine concentration of at least about 0.2 .mu.M). Surprisingly,
the circulating blood histamine levels remained elevated for
sustained periods of time, even after histamine administration was
discontinued. The results of this experiment demonstrated that
blood histamine levels can be raised and maintained at a beneficial
level following histamine administration.
[0036] This ability to raise circulating blood histamine levels in
a patient suffering from a malignancy disease, and maintains the
histamine concentration at a beneficial level, can be combined with
methods of cancer therapy as detailed in EXAMPLES 2, 3, 4, and 5
below.
Cancer Therapy Employing a Combination of Histamine and Surgery
[0037] As contemplated by the present inventors, histamine is
administered in conjunction with surgical resection of the tumor so
as to achieve a synergistic tumorcidal response in the patient. By
one approach, histamine is administered before surgery for a
sufficent time to raise the stable concentration of histamine in
the patient's blood to at least about 0.2 .mu.M. Surgical removal
of the tumor is then performed according to standard techniques.
(See for example, Surgical Oncology, edited by Raphael E. Pollock,
Kluwer Academic Publishers, 1997). After the tumor burden has been
removed, histamine therapy is continued for a time sufficient to
conclude that a complete response to the tumor has been achieved.
Depending on the type of malignancy, several methods of determining
the persistance of cancer cells are available including the
detection of shed cancer cell-specific antigens by ELISA or in situ
detection of cancer cells using radiolabeled antibodies and imaging
techniques. (Quak and van Dongen, Eur. Arch. Otorhinolaryngol
251:1-5(1994)).
EXAMPLE 2
[0038] A synergistic tumorcidal response is obtained by
administering histamine before, during and after surgical removal
of a prostate tumor. Accordingly, a pharmaceutically acceptable
form of histamine in a sterile carrier solution is injected
subcutaneously into a patient suffering from prostate cancer for
one week (0.5-2.0 mg per day) prior to surgery. After this period
of treatment and when circulating blood histamine levels have
increased to at least 0.2 .mu.M, surgical resection of the tumor
burden is performed.
[0039] Once the tumor is removed, circulating levels of blood
histamine are maintained at at least about 0.2 .mu.M until a
complete response is observed. The tumorcidal response is evaluated
by determining the level of PSA antigen in the patient over time
according to conventional methods. By employing the method
disclosed in this example, a synergistic tumorcidal response is
observed and prostate cancer is effectively treated.
Cancer Therapy Employing a Combination of Histamine and Radiation
Treatment
[0040] In another embodiment, histamine is administered in
conjunction with radiation therapy so as to achieve a synergistic
tumorcidal response in the patient. By one approach, histamine is
administered before radiation therapy for a sufficent time to raise
the stable concentration of histamine in the patient's blood to at
least about 0.2 .mu.M. The tumor is then subjected to external beam
radiation according to standard techniques. (See for example, Basic
Clinical Radiobiology (second edition), edited by G. Gordon Steel,
Arnold publishers, 1997). Histamine therapy is continued until a
complete response is observed, as determined above. Further
treatment of radiation can also be administered in conjunction with
histamine therapy if tumor regression is not readily apparent.
EXAMPLE 3
[0041] A synergistic tumorcidal response is obtained by
administering histamine before, during and after radiation
treatment of a prostate tumor. Accordingly, a pharmaceutically
acceptable form of histamine in a sterile carrier solution is
injected subcutaneously into a patient suffering from prostate
cancer for one week (0.5-2.0 mg per day) prior to radiation
therapy. After this period of treatment and when circulating blood
histamine levels have increased to at least 0.2 .mu.M, the tumor
burden is subjected to external beam radiation (60-70 Gy).
[0042] Once the tumor has been irradiated, circulating levels of
blood histamine are maintained at least 0.2 .mu.M until a complete
response is observed. The tumorcidal response is evaluated by
determining the level of PSA antigen in the patient over time
according to conventional methods. By employing the method
disclosed in this example, a synergistic tumorcidal response is
observed and prostate cancer is effectively treated.
Cancer Therapy Employing a Combination of Histamine and Antibody
Therapy
[0043] In another embodiment of the present invention, histamine is
administered in conjunction with an antibody therapy. According to
one aspect of this embodiment, a radioactive monoclonal antibody is
administered in conjunction with histamine. Preferably, histamine
is administered for 1-2 weeks before the antibody therapy to raise
the stable concentration of histamine in the patient's blood to at
least about 0.2 .mu.M. After a stable level of blood histamine of
at least bout 0.2 .mu.M has been achieved, a radiolabeled mAb
directed to a cancer cell antigen is administered in conjunction
with histamine treatment to the patient. (See for example, Recent
Results in Cancer Research vol 141:Systemic Radiotherapy with
Monoclonal Antibodies, edited by M. L. Sautter-Bihl and M.
Wannenmacher, Springer-Verlag publishers, 1996). Histamine
treatment may be continued until a complete response is observed,
as determined above.
[0044] Radiolabelled mAbs specific for a tumor antigen are prepared
by labeling the antibody with an isotope or combinations of
isotopes, such as .sup.131I, .sup.90Y, .sup.67CU, .sup.186Re,
.sup.188Re, .sup.212Bi or .sup.211At. Preferable radiolabeled mAbs
are able to deliver more than 6000 rads to the tumor and have
sufficient affinity so that the patient's bone marrow is not
exposed to more than 300 rads. .sup.131I labeled anti-B1 (Bexxar)
mAb, raised to the CD-20 antigens that are expressed on the surface
of mature B-cells, is one example of a radiolabeled mAb that has
seen successful in treating follicular non-Hodgkins lymphoma in
recent clinical trials. (Wong, Genetic Engineering News pp.23 and
49 (July 1998)). Use of .sup.131I labeled anti-B1 (Bexxar) mAb, as
well as other radiolabeled mAbs, in conjunction with histamine
treatment is within the scope of this embodiment.
[0045] In another aspect, heteroconjugate mAbs which direct the
bound cancer cell to the phagocytic cells of the immune system are
used in conjunction with the histamine treatment protocol detailed
above. For example, the mAb MDX-210 (Medarex) which comprises one
domain that binds the proto-oncogene HER-2/neu (C-erbB2), the
cell-surface growth factor p185.sup.HER-2 receptor with partial
homology to the epidermal growth factor (EGF) receptor, and a
second domain which recognizes the Fc receptor for high affinity
IgG that activates and guides natural killer cells (NK) of the
immune system to the disease site has been shown to be an effective
treatment for renal and prostate cancer. (Wong, Genetic Engineering
News pp.23 and 49 (July 1998)). The present inventors contemplate
the use of this and similarly designed heteroconjugate antibodies
in conjunction with the administration of histamine to obtain a
synergistic tumorcidal response.
[0046] Another use included in this embodiment of the present
invention involves the administration of humanized mAbs raised
against cancer cell-specific receptors. The p185.sup.HER-2 receptor
(Genetech), for instance, has been shown to block binding of
epidermal growth factor to the receptor and, thus, shut-off the
subsequent transducing signal for cell proliferation. (Wong,
Genetic Engineering News pp.23 and 49 (July 1998)). In clinical
trials with the p185.sup.HER-2 antibody, breast cancer patients
have exhibited significant improvement in overall tumor response.
The use of humanized mAbs raised against the p185.sup.HER-2
receptor (Genetech) and other mAbs directed to cancer cell-specific
receptors in conjunction with histamine treatment are also
contemplated by the present inventors.
EXAMPLE 4
[0047] A synergistic tumorcidal response is obtained by
administering histamine before, during and after antibody treatment
of a patient suffering with breast cancer. Accordingly, a
pharmaceutically acceptable form of histamine in a sterile carrier
solution is injected subcutaneously into the patient for one week
(0.5-1.0 mg per injection 1-2 times per day) prior to antibody
therapy. After this period of histamine treatment, the patient is
administered humanized .sup.131I labeled p185.sup.HER-2 antibody
(Genetech) and histamine therapy is continued.
[0048] Once the tumor has been treated with the antibody,
circulating levels of blood histamine are maintained at least 0.2
.mu.M until a complete response is observed. The tumorcidal
response is evaluated by determining the level of p185 .sup.HER-2
receptor in the patient over time according to conventional
methods. (Quak and van Dongen, Eur. Arch. Otorhinolaryngol
251:1-5(1994)). By employing the method disclosed in this example,
a synergistic tumorcidal response is observed and breast cancer is
effectively treated.
Cancer Therapy Employing a Combination of Histamine and Approaches
to Enhance a Humoral Immune Response in a Cancer Patient
[0049] A further embodiment of the present invention involves the
administration of an agent which enhances the humoral immune
response of a patient in conjunction with histamine therapy. By one
approach, histamine is administered before the agent is provided to
the patient so that a stable concentration of at least about 0.2
.mu.M histamine in the patient's blood is initially established. An
humoral immune response enhancing agent such as a viral antigen, a
cancer cell antigen, an inactivated cancer cell, a vaccine or a
vitamer is then administered to the patient. Histamine therapy is
continued until a complete response is observed, as determined
above. Further, the present inventors contemplate treatments with
the agent which enhances the humoral immune response of the patient
in conjunction with histamine therapy and the administration of
cytokines known to enhance the cellular immune response.
EXAMPLE 5
[0050] A synergistic tumorcidal response is obtained by
administering histamine before, during and after treatment of a
patient suffering from melanoma with an agent that enhances the
immune response. Accordingly, a pharmaceutically acceptable form of
histamine in a sterile carrier solution is injected subcutaneously
into the patient for one week (0.5-1.0 mg per injection 1-2 times
per day) prior to administration of the agent that enhances the
humoral immune response. After this period of histamine treatment
and when circulating blood histamine levels have increased to at
least 0.2 .mu.M, the patient is administered a vaccine comprising a
killed mixture of three melanomic cell lines according to standard
techniques. (Slingluff et al., Ann. Plast. Surg. 28:104-107
(1992)).
[0051] Once the tumor has been treated with the vaccine,
circulating levels of blood histamine are maintained at least 0.2
.mu.M until a complete response is observed. The tumorcidal
response is evaluated by determining the presence of melanoma in
the patient over time according to conventional methods. (Quak and
van Dongen, Eur. Arch. Otorhinolaryngol 251:1-5(1994)). By
employing the method disclosed in this example, a synergistic
tumorcidal response is observed and the melanoma is effectively
treated.
[0052] While the methods of EXAMPLES 2-5 detail several protocols
which would produce a synergistic tumorcidal response by virtue of
the administration of histamine in conjunction with established
cancer treatments, many more cancer therapy protocols which take
advantage of histamine induced synergism can be developed by using
the screening method, or variation thereof, described in EXAMPLE
6.
Screening of Therapeutics for a Synergistic Tumorcidal Response
when the Agent is Administered in Conjunction with Histamine
[0053] Methods to screen therapeutics for their ability to produce
a synergistic tumorcidal response when they are administered with
histamine is another embodiment of the present invention.
Generally, a model system for the cancer is first established, then
histamine and the therapeutic agent are administered to the subject
and the tumorcidal response is determined.
EXAMPLE 6
[0054] Preparation of a model system and a radiolabelled mAb is as
follows. By example, human neuroblastoma xenografts are established
by subcutaneous injection of about 10.sup.6 tumor cells of the
human SK-N-SH neuroblastoma cell line (purchased from the American
Type Culture Collection, Rockville Md.) into the right flank of
nude mice. The cancer is allowed to proliferate until the tumor
measures approximately 1 cm in diameter. The mAb BW575/9
(Behringwerke, Marburg, Germany) is a murine IgG1 isotype directed
against the neural cell adhesion molecule (NCAM) and expressed by
neurobalstomas, melanomas and other cancers. (Bosslet et al.
European Pat. Pub. No. EP 0443 599 A2). BW575/9 has been reported
to bind specifically to the neuroblastoma cell line SK-N-SH.
(Recent Results in Cancer Research vol 141:Systemic Radiotherapy
with Monoclonal Antibodies, edited by Sautter-Bihl and
Wannenmacher, Springer-Verlag publishers, Bihl and Bihl,
Experimental Data in a Mouse Neuroblastoma Xenograft System pp.
124-135 (1996)). As a control, the anti-idiotypic mAb B40
(purchased from the German Cancer Research Center, Heidelberg,
Germany) is used. The mAbs are labeled with .sup.131I by the
Iodogen method to a specific activity of 1 .mu.Ci/.mu.g according
to esatblished methods. (Id.).
[0055] To assess the synergistic tumoricidal response obtained by
histamine therapy administered in conjunction with
radioimmunotherapy, an experiment is conducted. A pharmaceutically
acceptable form of histamine in a sterile carrier solution is
injected into the tail vein of nude mice having a malignancy for
one week (0.5 mg per day) prior to antibody treatment. One control
group is not administered histamine so that the synergistic
tumorcidal response of histamine therapy can be determined. After
this period of histamine treatment and when circulating blood
histamine levels have increased to at least 0.2 .mu.M, the mice are
administered 10 .mu.Ci of .sup.131I labeled mAbs by injection into
the tail vein, according to standard techniques.
[0056] Mice are killed by cervical dislocation on 1, 4, 12, 24, 36
and 48 days after administration of the antibody therapy and the
tumor, spleen, kidney, liver, muscle and bone are harvested,
measured and analyzed in a multichannel gamma counter for
.sup.131I. Daily histamine treatment, as above, is continued during
the course of the experiment and a second administration of the
antibody is provided on day 24. The results of this experiment show
that a greater tumorcidal response is obtained when the BW575/9 mAb
is administered in conjunction with histamine than when the BW575/9
is administered by itself.
[0057] Using variations of the model system presented above, newly
developed therapeutic agents and treatment protocols can be rapidly
screened for their ability to produce synergistic tumorcidal
response when they are administered or performed in conjunction
with histamine treatment. Indeed, the appraoch used in EXAMPLE 6
can be used or readily adapted to screen other antibodies, antibody
conjugates, antibody heteroconjugates, agents which enhance the
humoral immune response of the subject, radiation therapies and
surgical techniques.
[0058] Although the invention has been described with reference to
embodiments and examples, it should be understood that various
modifications can be made without departing from the spirit of the
invention. Accordingly, the invention is limited only by the
following claims. All references cited herein are hereby expressly
incorporated by reference.
* * * * *