JP2023110038A - Methods and compositions for treating cancer or skin lesion using vaccines - Google Patents

Abstract

To provide methods for treating or reducing the incidence of recurrence of cancer, benign tumors or HPV-associated lesions including skin cancer, and particularly squamous cell carcinoma (SCC) and basal-cell carcinoma, by administering one or more doses of HPV recombinant vaccine to a patient.SOLUTION: Provided is a pharmaceutical composition comprising at least one purified viral L1 protein or fragment thereof, a second active pharmaceutical ingredient and pharmaceutically acceptable carrier.SELECTED DRAWING: None

Description

The present invention is directed to treating cancers, including skin cancers, or benign or malignant tumors, and more particularly to treating cancers or tumors, including administration of vaccines, including topical administration of vaccines as therapeutic agents. It relates to methods for treatment or for reducing recurrence rates.

There are three main types of skin cancer: basal cell carcinoma (BCC), squamous cell carcinoma (SCC)
, and melanoma, and is the most common form of cancer worldwide. Of course, for many years there has been ongoing research to find effective ways to treat and possibly cure these types of skin cancer.

Human papillomavirus (HPV) causes certain types of skin cancer, especially squamous cell carcinoma (SCC).
) is generally accepted to be associated with causing HPV is a DNA virus that can infect certain types of tissues in humans. over 30 HP
There are subtypes of V and several of these subtypes, including HPV16 and HPV18, are associated with cervical cancer. HPV is not known to cause or be associated with basal cell carcinoma (BCC) or melanoma.

Vaccines have been developed and shown to prevent cervical cancer in women and other conditions caused by or associated with HPV infection. GARDA
SIL® is a commercially available vaccine with activity against HPV (types 6, 11, 16, and 18).

GARDASIL® 9 is effective against HPV (16, 18, 31, 33, 45, 52,
and 58) is another commercially available vaccine marketed for prevention. GARDASIL® is indicated for use in girls and boys aged 9-26 years, and GARDASIL® 9 is also indicated for use in girls and boys aged 9-26 years.
Indicated for use in boys aged ∼15 years.

Other vaccines have also been produced to treat HPV subtypes, particularly HPV16 and HPV18. GARDASIL® and other known vaccines administered prophylactically to prevent certain HPV infections and related cancers are referred to herein as "prophylactic vaccines." These prophylactic vaccines are generally administered for systemic action, i.e., injected subcutaneously or into a muscle (e.g. deltoid muscle) of the patient away from any specific target such as the cervix. be done. Furthermore, they are generally recognized as effective prior to exposure to HPV and are generally not known to be effective in treatment after exposure or infection with HPV.

Other prophylactic vaccines include, for example, the L1 protein of certain HPV species (GARDAS
IL®) and additional HPV-specific components, Chinese Patent Application No. 101
Included are improved vaccine compositions as described in 890160 (CN'160). Prophylactic vaccines containing HPV type 16 and 18 proteins have also been suggested to provide cross-protection against other HPV types, as described in US Patent Application Publication No. 2005/0287161.

Vaccines used for therapy (referred to herein as "therapeutic vaccines") have been described. However, these therapeutic vaccines require more virus-specific components, such as the HPV L1 protein, including commercially available prophylactic vaccines such as GARDASIL®.

US Patent Application Publication No. 2007/0218074 describes the use of vaccine compositions comprising host cell peptides derived from HPV-infected cells. host cell peptides, such as
The early antigens, E6 or E7, present on the surface of HPV-infected cells, are fragments of host cell proteins. The importance of polypeptide E6 or E7 in vaccines used to treat certain cancer types is described in the "Development of HPV vaccine
nes for HPV-associated head and neck squ
amous cell Carcinoma" Devaraj, et al. , Crit
Rev Oral Biol Med. 2003; 14(5):345-62. Another vaccine containing host cell protein (BAX) is described in US Pat. No. 8,399
, 610.

Yet another vaccine composition comprising other or additional antigens in combination with HPV-16 peptides is the vaccine composition described in US Patent Application Publication No. 2011/0070252 (which further includes Trojan antigens). required).

US 2011/0110979 (US'979) and US 2012/0288538 (US'538) disclose E6 or E7 polypeptides (peptides derived from host cells infected with HPV). Therapeutic use of HPV vaccines including fragments) are disclosed. US'538 describes that E6 and E7 are essential for inducing transformation into HPV-infected cells, and that vaccine compositions lacking E6 or E7 contain E6 or E7. It states that it would not be expected to work on cells that do not have E7, ie cells such as BCC that are not HPV infected. US
The method described in the '979 publication further requires an immunostimulant or adjuvant.

US'979 and US'538 publications describe the use of therapeutic vaccines against skin cancers, such as SCC or epithelial SCC, but these show that BCC and melanoma are caused by HPV.
It does not describe the use of vaccines against other skin cancers such as BCC or melanoma, presumably based on the proviso that they are not associated with infection.

The limitations and drawbacks of the above-described uses of vaccines can be overcome through the use of methods according to the subject invention. There is a need in the medical and health field for safe and effective cancer treatments (including skin cancers or cancers generally unrelated to HPV infection) that are convenient for patients and medical personnel.

The subject invention is a method for treating patients with skin cancer, benign or malignant tumors (whether related or related to human papillomavirus (HPV) infection), or other skin lesions, administering to a patient having or in need of treatment a tumor, cancer, or other skin lesion, a commercially available HPV vaccine in an effective dose. The vaccine can be administered directly to the cancer or lesion by direct (local) application to the tumor or lesion or by direct injection into the tumor or lesion. Alternatively, the vaccine can be administered for therapeutic use by systemic injection. Methods of treatment according to the subject invention can also include any combination of topical application, direct or systemic injection. A therapeutically effective dose can be the conventional approved dose per its labeling of the vaccine.

In one embodiment, the method comprises:
a) administering a first dose of an HPV vaccine that is free of host cell peptides, polypeptides, or proteins, or degradation products thereof, to a patient that is 27 years of age or older or has not been previously immunized with an HPV vaccine; and;
b) about one month to about three months after the first administration, administering a second dose of the HPV vaccine to the patient;
c) optionally, about 5 months to about 7 months after the first dose, a third dose of the HPV vaccine;
and administering to the patient.

After the first conventional administration of the vaccine according to step a) above, the second or third administration according to steps b) and c) above may be by injection of a composition comprising the vaccine or by topical administration. It may be due to Alternatively, the second or third administration of step b) or c) can include both injection and topical administration.

In one embodiment, the second dose of HPV vaccine is administered about two months after administering the first dose, and the third dose of HPV vaccine is administered about six months after administering the first dose. administered after a month.

HPV vaccines include HPV tetravalent (types 6, 11, 16, and 18) recombinant vaccines containing HPV L1 proteins, and HPV multivalent (16, 1
8, 31, 33, 45, 52, and 58) recombinant vaccines;
Preferably, it is free or substantially free of host cell early antigens such as E6 or E7.

In one preferred embodiment, the method does not comprise or does not administer an additional or other immunostimulatory drug or adjuvant.

In certain preferred embodiments, the method comprises administering additional or other immunomodulatory agents, such as immunostimulants or adjuvants.

By practicing the method, the size of cancer or HPV-related lesions can be substantially reduced or completely eliminated. Furthermore, the recurrence rate of cancer or HPV-related lesions can be reduced. The method is effective for treating squamous cell carcinoma, basal cell carcinoma, melanoma,
It may be effective in treating cancer, benign tumors, or HPV-related lesions, such as warts vulgaris, or condyloma acuminatum, or reducing their recurrence rate.

In one embodiment, the method may comprise a single dose of vaccine. For example, a single dose of vaccine can be administered locally, by injection directly into the tumor, or systemically to reduce or eliminate tumor size. A physician or healthcare professional can administer a second or subsequent dose as required or determined by the physician or healthcare professional.

In one embodiment, a patient in need of treatment may have been previously immunized with a vaccine. In another embodiment, a patient in need of treatment may be a person who has not been previously immunized with a vaccine.

Each dose of HPV vaccine administered in the above method steps is preferably about 0.5 ml, more preferably 0.5 ml.

The method comprises administering a cancer, benign tumor, or HPV vaccine prior to administering the first dose of HPV vaccine.
It can further comprise confirming a positive diagnosis of V infection.

An alternative embodiment of a method according to the subject invention comprises treating a patient with cancer, a benign tumor, or a human papillomavirus-associated (HPV-associated) lesion, wherein the method comprises administering a dose of an HPV vaccine to Including administration directly to a cancer, tumor, or lesion, or to areas immediately surrounding a tumor or lesion.

This alternative embodiment of the method according to the subject invention comprises:
about one to about three months after administering the first dose, administering a second dose of an HPV vaccine directly to the tumor or lesion or to an area immediately surrounding the tumor or lesion;
About 5 to about 7 months after administering the first dose, a third dose of HPV vaccine is optionally administered directly to the tumor or lesion or to an area immediately surrounding the tumor or lesion. Further steps can be included.

These direct second or third administrations of the composition comprising the vaccine may be topical application or by injection into the lesion.

In this alternative embodiment of the subject method, the second dose of HPV vaccine can be administered about two months after the first dose is administered, and the third dose of HPV vaccine is administered after administration of the first dose. can be administered approximately 6 months after administration of the dose of

cancer, tumor, or HPV by practicing an alternative embodiment of the method according to the subject invention
The associated lesion size can be substantially reduced or completely eliminated. Additionally, the recurrence rate of cancer, tumors, or HPV-related lesions can be reduced.

The preferred dose for each subsequent administration of HPV vaccine, if present, is 0.5 ml.

Methods according to any embodiment of the present invention may be used to treat, but are not limited to, benign tumors, squamous cell carcinoma, basal cell carcinoma, melanoma, warts vulgaris, and warts vulgaris, and condyloma acuminatum associated with or not associated with HPV infection. It can be used to treat cancer, benign tumors, or HPV-related lesions, including.

The method comprises administering a cancer, benign tumor, or HPV vaccine prior to administering the first dose of HPV vaccine.
It can further comprise confirming a positive diagnosis of V infection.

In one preferred embodiment, direct or local administration of the vaccine is administered by injection, more preferably the method includes additional or other immunizations with, during or after administration of the vaccine. It does not involve administering stimulants or adjuvants.

Alternatively, the subject method can include administering additional or other immunomodulatory agents, such as immunostimulants or adjuvants, with, during, or after administration of the vaccine.

In another preferred embodiment, the vaccine is formulated for topical administration and includes topical solutions or suspensions such as liquids or sprays, gels, creams, salves, ointments (
ointments), foams, or mousses, which can be applied directly to the lesion.

Specifically, the subject invention is a method for treating a tumor, comprising:
A method comprising administering at least one dose of a commercially available HPV vaccine can be concerned. Advantageously, the subject methods have been found to be effective in treating tumors in glandular tissue such as the breast, pituitary (eg, invasive pituitary adenoma), prostate, or pancreas. This embodiment can involve administering at least one dose of the vaccine directly to the tumor itself.

The subject invention provides at least one dose of the vaccine systemically, e.g., by intramuscular (IM) injection, alone or in combination (simultaneously, immediately before, or after) administration of the vaccine directly to the tumor. administering.

Alternatively, in certain cases, e.g., when a tumor resides on or near the surface of the body,
This method includes at least one dose of H, either alone or in combination with direct injection into the tumor, in combination with systemic injection, or in combination with both direct and systemic injection.
Topical administration of PV vaccines can further be included.

Compositions comprising vaccines are also included as part of the invention. For example, an HPV vaccine can be formulated with one or more additional active pharmaceutical ingredients for administration to a patient. Additional active pharmaceutical ingredients may include one or more immunomodulators to modulate the efficacy of the vaccine, or one or more local anesthetics to reduce patient discomfort during injection, such as lidocaine (epinephrine). with or without).

An example of a composition of the invention is 0.5 ml of commercially available HPV vaccine and 0.5 ml of commercially available HPV vaccine.
5 ml of commercially available lidocaine solution (e.g. 0.5% (w/v), 1% (
w/v), or a mixture with 2% (w/v)) in a 1:1 (v/v) ratio. The composition can be mixed thoroughly and injected into the patient for treatment. As will be understood in the art, ratios ranging from 1:10 (v/v) vaccine:anesthetic to 10:1 (v/v) vaccine:anesthetic can be used.

HPV vaccines can also be formulated with one or more excipients or diluents for administration to a patient. Excipients and diluents are one or more useful in formulating topical preparations, including but not limited to bases for preparing creams, emollients, gels, lotions, salves, and the like. can contain conventional pharmaceutically acceptable ingredients of
Penetration enhancers, preservatives, controlled release agents, solubilizers, stabilizers, thickeners or thinners may optionally be included.

Solutions for injection may also contain one or more buffers, emollients, diluents, pH adjusting agents, preservatives, solubilizers, stabilizers, and the like.

These compositions can be prepared as articles of manufacture that can be shipped, stored and used at any time, including at a later point in time, or can be stored away at the point of care or for immediate as-needed treatment. You can also synthesize at a certain place.

Compositions of the present invention can contain one or more additional active pharmaceutical ingredients without excipients or diluents, or can contain one or more active pharmaceutical ingredients and one or more excipients. Agents or diluents may also be included.

The compositions of the present invention can contain one or more excipients or diluents without additional active pharmaceutical ingredients, or one or more excipients or diluents and one or more It can also contain an active pharmaceutical ingredient.

previously unimmunized patients or 27 to eliminate or reduce the recurrence rate of skin cancer, benign or malignant tumors, or other skin lesions not associated with HPV, to the best of the inventor's knowledge. The administration of HPV vaccines containing only HPV antigens (no host cell peptides) to adult patients aged 12 years and older has not been previously described. Direct or local injection of vaccines by local application or by direct injection to lesions or tumors to clear lesions and reduce the incidence of their recurrence has also not been previously described.

The present invention is directed to methods of treating cancers, benign tumors, skin cancers such as squamous cell carcinoma (SCC), or skin lesions related or unrelated to human papillomavirus (HPV) infection, breast, pituitary , prostate, or treating tumors derived from glandular tissue such as pancreatic tissue. One embodiment of a method according to the subject invention comprises administering a commercially available HPV vaccine, such as a HPV tetravalent (types 6, 11, 16, and 18) recombinant vaccine, to a patient with cancer or tumor. .

In certain preferred embodiments, the subject method comprises administering at least one dose of an HPV vaccine to a patient not previously immunized with an HPV vaccine or to an adult patient aged 27 years or older. For the purposes of the subject invention, a patient who has not been previously immunized with an HPV vaccine is referred to as an "unimmunized patient," regardless of whether the patient may have other immunizations against other conditions or diseases. Called.

Dosage regimens can be single doses by direct injection, systemic injection, or topical application, or any combination of these routes of administration. Alternatively, the subject method includes repeated (two or more) administrations, or repeated (
simultaneous) administration.

A subject method can also include administering according to a routinely accepted dosing regimen for vaccines. For example, HPV vaccines are generally administered at a first dose, about two doses of the first dose.
administered using a dosing regimen that includes a second dose about six months after the first dose, and a third dose about six months after the first dose. These second, third, or subsequent administrations may be systemic injections, such as conventional intramuscular injections, or direct administration to the lesion by intralesional injection or by local administration.

Surprisingly, method embodiments of the present invention treat the development, recurrence, and/or progression of cancerous lesions or benign tumors unrelated to HPV infection, such as basal cell carcinoma (BBC) or melanoma. It has been found to yield beneficial results in minimizing.

Without being limited to any particular theory, it is believed that the subject methods increase the patient's immune response to
boosting (which can be clinically manifested as enhanced immune surveillance in skin cells) the development and progression of abnormal skin cells that give rise to skin cancer, particularly but not exclusively SCC. It is proposed that the properties can be reduced.

Alternatively, the methods of the invention can interfere with the intrinsic functional activity of viral and virus-like proteins by other mechanisms. This disturbance can be caused by exogenous factors such as ultraviolet light and/or
or complete or partial functional inactivation of viral and virus-like proteins that are altered or activated by environmental factors.

As used herein, the terms "HPV" and "human papillomavirus" refer to non-enveloped, double-stranded DNA viruses of the papillomavirus family. Its genome is circular and approximately 8 kilobase pairs in size. Most HPV have 6 "early stages"
It encodes eight major proteins, located in the region (E1-E2) and two in the 'late' regions (L1 (major capsid protein) and L2 (minor capsid protein)). Over 120 HPV types have been identified and these are designated by numbers (
For example, HPV-16, HPV-18, etc.).

In one embodiment, the HPV vaccine of the subject invention is 1, 2, 3, 4, 5, 6, 7, 8, 9
, 10, or more proteins from different HPV types (eg, recombinant L1 proteins). Methods of expressing HPV L1 proteins and methods of making HPV vaccines are known in the art, e.g., US Pat. No. 5,820,870, which is hereby incorporated by reference in its entirety for all purposes. Specification and 6th,
251,678.

In one embodiment, the HPV vaccine used in the subject method is HPV tetravalent (6,1
Types 1, 16, and 18) commercially available GARDASI which is a recombinant vaccine
L®, or GARDASIL® 9, HPV multivalent (16,
Types 18, 31, 33, 45, 52, and 58) contain purified, inactive viral and virus-like proteins, such as recombinant vaccines. In another embodiment, the HPV vaccine is the commercially available CERVARIX®, an HPV bivalent (16 and 18) recombinant vaccine. Vaccines useful according to this embodiment of the subject method are preferably early antigens that are fragments of host cell peptides present on the surface of host cells and/or non-L1 HPV peptides, polypeptides, or proteins, such as HPV-infected cells. , E6 or E7, etc.

The vaccine may be used in cancerous or benign tumors, including cancerous lesions unrelated to HPV infection, cancers (tumors or lesions) associated with HPV infection, benign tumors unrelated to HPV infection, or non-immune tumors in unimmunized patients. It can be administered to treat cancerous HPV-related lesions.

Alternatively, the vaccine can be administered to reduce the recurrence rate of cancer, benign tumors, or HPV-related lesions in unimmunized patients. In another embodiment, the vaccine treats cancer, benign tumors, or HPV-related lesions in adult patients 27 years of age or older.
Or it can be administered to reduce their recurrence rate.

More specifically, one preferred embodiment of the present invention is a method for the treatment of cancer, benign tumors, or HPV-related lesions in unimmunized patients or adult patients aged 27 years or older, comprising:
i. A first dose of HPV without host cell peptides, polypeptides, or proteins
administering a recombinant vaccine to a patient;
ii. from about one month to about three months after the first dose, administering to the patient a second dose of an HPV recombinant vaccine that is free of host cell peptides, polypeptides, or proteins; and iii. optionally about 5 to about 7 months after administering the first dose, administering to the patient a third dose of an HPV vaccine that does not contain host cell peptides, polypeptides, or proteins. including.

The second or third or subsequent administration of vaccine doses may be systemic, eg, by intramuscular injection, or by direct administration to the lesion. Administration of the vaccine composition directly to the lesion may be by intralesional injection or may be applied locally to the lesion. In further embodiments, the second, third, or subsequent administration is both systemic and by direct application of the vaccine to the lesion. Such direct administration to a lesion may be by intralesional injection or by topical application of a vaccine composition formulated for local administration.

It will be understood by medical personnel that references to the timing of subsequent administrations of vaccines are broad and may vary from day to week or week to week. This variability is measured by the patient's adherence or non-adherence to the dosing schedule, clinically determined by the treating physician, who may decide to advance (for more aggressive treatment) or delay subsequent dosing for medical reasons. It may be due to knowledge. Generally, however, effective results are obtained by following a dosing schedule in which the second dose is administered about two months after the first dose and the third dose is administered about six months after the first dose. can be obtained. Additional (fourth or fifth) doses may also be administered if the physician believes that subsequent administrations may provide benefit to the patient.

A typical total dose for each administration according to the methods of the subject invention is about 0.5 ml of vaccine, preferably 0.5 ml of commercially available HPV vaccine.

The terms "cancer,""cancerous," or "malignant" refer to or describe the physiological condition in mammals that is typically characterized by uncontrolled cell growth. Examples of cancers include, but are not limited to, heart: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; lung: bronchial primary lung cancer (squamous cell, undifferentiated small cell,
large undifferentiated cells, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; ), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (pancreatic ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, VIP-producing tumor), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, angiomas) tumor, lipoma, neurofibroma, fibroma), colon (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma) colorectal; urogenital: kidney (adenocarcinoma, Wilms tumor (nephroblastoma), lymphoma , leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma),
prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonic carcinoma, teratocarcinoma, choriocarcinoma, sarcoma,
stromal cell tumor, fibroma, fibroadenoma, adenomatous tumor, lipoma); liver: hepatoma (hepatocellular carcinoma)
, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; omentosarcoma),
Multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondral exostosis), benign chondroma, chondroblastoma, chondomyxoid fibroma, osteoid, and giant cell tumor; nervous system: cranial (osteoma, hemangioma, granuloma, xanthoma, osteitis osteoarthritis), meninges (meningioma, meningiosarcoma, glioma), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pineophylloma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal cord (neurofibroma, meningioma, glioma, sarcoma); gynecology: uterus (endometrial cancer), cervix (cervical cancer, pre-tumor
r) cervical dysplasia), ovarian (ovarian cancer [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassifiable carcinoma]
, granulosa follocytoma, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma)
, vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, sarcoma grape (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma), breast blood system: blood (myelogenous leukemia (acute and chronic), acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); ); skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles, dysplastic nevus,
Lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal: neuroblastoma. In another embodiment, the cancer is carcinoma, lymphoma, leukemia, blastoma, and sarcoma. More specific examples of such cancers include squamous cell carcinoma, myeloma, small cell lung cancer, non-small cell lung cancer, glioma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, acute myelogenous leukemia (AML), multiple myeloma. , gastrointestinal cancer, renal cancer, ovarian cancer, liver cancer, lymphoblastic leukemia, lymphocytic leukemia, colorectal cancer,
Endometrial cancer, kidney cancer, prostate cancer, thyroid cancer, melanoma, chondrosarcoma, neuroblastoma, pancreatic cancer, glioblastoma multiforme, cervical cancer, brain cancer, gastric cancer, bladder cancer, hepatoma, breast cancer, colon cancer , and head and neck cancer. In certain exemplary embodiments, the cancer is a cancer associated with HPV.

Specific examples of cancer include skin cancer, such as basal cell carcinoma and/or skin cancer, among other known skin cancers.
Or squamous cell carcinoma. Another example of cancer includes breast cancer. Yet another example of cancer includes prostate cancer. Yet another example includes penile cancer. Further examples of cancer include ovarian, cervical, vaginal, and/or vulvar cancer. Yet another example of cancer includes bladder cancer. Yet another example of cancer includes colorectal and/or anal cancer. Yet another example of cancer includes oropharyngeal cancer (eg, cancer of the pharynx, soft palate, tongue base, pharyngeal tonsil, and/or tonsil). Yet another example of cancer includes kidney cancer. Yet another example of cancer includes liver cancer.

In certain exemplary embodiments, the cancer is characterized by Bcl-2 binding X protein (BAX) and/or
or associated with decreased expression of Bcl-2 homologous antagonist/killer (BAK1). In another exemplary embodiment, the cancer is associated with one or more abnormal mitochondrial activities. In certain exemplary embodiments, the HPV vaccines of the invention target BAX and/or B
Increase AK1 expression and/or promote tumor cell apoptosis. In another aspect, the combination of vitamin D and the HPV vaccines of the invention reduces BAX in tumor cells.
and/or increase BAK1 expression and/or promote apoptosis of tumor cells. In another embodiment, the HPV vaccines of the invention modulate one or more mitochondrial activities in tumor cells.

The above embodiments of the therapeutic methods of the present invention can be effective in treating skin cancer, and in particular squamous cell carcinoma, in a patient, wherein skin cancer lesions are reduced in size to Decrease or disappear.

Treatment methods according to the subject invention can also reduce the recurrence rate of benign or cancerous tumors or lesions (including skin cancer) in patients.

In particular, methods of treatment according to the subject invention are directed to eliminating or reducing the size or recurrence rate of cancerous tumors of the breast, eliminating or reducing the size or rate of recurrence of cancerous tumors of the prostate, cancer of the pancreas. eliminating or reducing the size or rate of recurrence of cancerous tumors of the pituitary gland, or eliminating or reducing the size or rate of recurrence of cancerous tumors of the pituitary gland, such as invasive pituitary adenomas.

can benefit from treatment using an HPV vaccine according to the methods of the subject invention;
Other specific types of cancers or tumors include, but are not limited to, cervical cancer, anal cancer, oropharyngeal cancer (pharynx, soft palate, base of tongue, or tonsils), vaginal cancer, vulvar cancer, penile cancer, colorectal cancer. cancer, bladder cancer, lung cancer,
Kidney cancer, liver cancer, ovarian cancer, pancreatic mucinous cystic tumor, gastric or stomach
) including cancer.

The methods of the invention are also useful for reducing the size or eliminating non-cancerous lesions associated with HPV, such as warts, including genital warts, such as common warts or warts acuminata. can be valid.

HPV tetravalent (types 6, 11, 16 and 18) recombinant vaccine (wherein the vaccine contains host cell peptides, polypeptides, It is a further unexpected result of the present invention to provide a method of reducing the recurrence rate of skin cancer, and in particular squamous cell carcinoma, following administration of one or more injections of squamous cell carcinoma or squamous cell carcinoma. .
A further unanticipated consequence of the subject treatment modalities is that basal cell carcinoma or melanoma, such as
Including reducing the size, disappearing, or reducing the recurrence rate of skin lesions unrelated to HPV infection.

The present invention relates to the use of the agents mentioned above for the therapeutic treatment of cancer. Accordingly, the HPV vaccine compositions of the invention are incorporated into pharmaceutical compositions suitable for administration. Such compositions typically comprise HPV viral or virus-like proteins and a pharmaceutically acceptable carrier. As used herein, the term "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents that are compatible with pharmaceutical administration. etc. shall be included. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions is contemplated. Additional active compounds can also be incorporated into the compositions.

A pharmaceutical composition of the invention is formulated to be compatible with its intended route of administration.
Examples of routes of administration include parenteral, e.g., intravenous (IV), intradermal, subcutaneous (SC or SQ
), intraperitoneal, intramuscular, oral (eg, inhalation), transdermal (topical), and transmucosal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can contain the following components: sterile diluents such as water for injection, saline, fixed oils, polyethylene. glycol, glycerin, propylene glycol, or other synthetic solvents; antibacterial agents;
antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetate, citric acid, or phosphate; and adjustment of osmotic pressure. for example sodium chloride or dextrose. pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. A parenteral preparation can be enclosed in ampoules, disposable syringes, or multiple dose vials made of glass or plastic.

Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions,
and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include saline, bacteriostatic water, Cremophor E
™ (BASF, Parsippany, N.J.), or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringability exists. The composition comprises
It must be stable under the conditions of manufacture and storage, and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyols such as glycerol, propylene glycol, and liquid polyethylene glycols, and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, or in the case of dispersion, by maintenance of the required particle size, or by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, sodium chloride in the composition. Prolonged absorption of an injectable composition can be brought about by including in the composition agents which delay absorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions, optionally with one or a combination of ingredients enumerated above,
They may be prepared by incorporating the active compound in the required amount in the appropriate solvent, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze drying, which yield a powder of the active ingredient plus any additional desired ingredients from a previously sterile-filtered solution thereof. is.

Oral compositions generally include an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier to be swallowed or ingested as a solution or suspension, or for use as a mouthwash. Here, the compound in a fluid carrier is applied orally, circulated in the mouth, expelled or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. Tablets, pills, capsules, troches and the like may contain any of the following ingredients, or compounds of similar nature: binders such as microcrystalline cellulose, gum tragacanth or gelatin; excipients such as starch. or lactose, disintegrants such as alginic acid, Primogel
glidants, such as colloidal silicon dioxide; sweeteners, such as sucrose or saccharin; or flavoring agents, such as peppermint, methyl salicylate, or orange flavor.

For administration by inhalation, the compounds are delivered in the form of an aerosol spray from a pressurized container or dispenser, or a nebulizer, containing a suitable propellant, for example a gas such as carbon dioxide.

Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, for example, for transmucosal administration, surfactants,
Bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams commonly known in the art.

The compounds can be prepared in the form of suppositories (eg, with conventional suppository bases such as cocoa butter and other glycerides) or retention enemas for rectal delivery.

In one embodiment, the HPV viral or virus-like proteins are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. . Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. These materials are also available from Alza Corporation and Nova Pharmaceuticals, Inc.; can be obtained as a commercial product from Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies against viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in US Pat. No. 4,522,811.

It is especially advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form, as used herein, refers to physically discrete units adapted as unitary dosages for the subjects to be treated; each unit containing a required pharmaceutical carrier. calculated to provide the desired therapeutic effect with
It contains a predetermined amount of active compound. Details regarding the dosage unit forms of the present invention will include the unique properties of the active compounds and the particular therapeutic effects to be achieved, as well as those inherent in the art in formulating such active compounds for individual therapy. Determined by and directly dependent on limits.

Toxicity and therapeutic efficacy of such compounds are evaluated, for example, to determine the _LD50 (dose lethal to 50% of the population) and _ED50 (dose therapeutically effective in 50% of the population). , can be determined by standard pharmaceutical procedures in cell cultures or experimental animals. The dose ratio between toxic and therapeutic effects is the therapeutic index, which is the ratio _LD50 /
It can be expressed as _ED50 . Compounds that exhibit large therapeutic indices are preferred. Although compounds that exhibit toxic side effects can also be used, targeted delivery of such compounds to the site of the affected tissue minimizes the potential for damage to uninfected cells, thereby reducing side effects. Care should be taken to design the system.

The data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage of such compounds is preferably
It lies within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage may vary within this range depending on the dosage form employed and the route of administration utilized.
For any compound used in the method of the invention, the therapeutically effective dose can be estimated initially from cell culture assays. Dose is EC determined in cell culture
A range of circulating plasma concentrations inclusive of 50 (ie, the concentration of the test compound that achieves half-maximal response) can be formulated in animal models. Such information can be used to more accurately determine useful doses in humans. Levels in plasma may be measured, for example, by high performance liquid chromatography.

The pharmaceutical compositions can be included in a container, pack, or dispenser together with any instructions for administration.

The route of delivery may depend on the patient's disability. In certain exemplary embodiments, subjects diagnosed with skin cancer can be administered the HPV vaccine compositions of the invention by topical administration. Patients may receive a second therapy, eg, palliative therapy and/or disease-specific therapy, in addition to the HPV vaccine compositions of the invention. The second therapy can be, for example, symptomatic (e.g., to alleviate symptoms), prophylactic (e.g., to slow or halt disease progression), or restorative (e.g., to reverse the disease process). can be used). For cancer treatment, for example, symptomatic treatment can further include another chemotherapeutic agent used as combination therapy as further described herein.

Generally, the HPV vaccine compositions of the invention can be administered by any suitable method. As used herein, topical delivery refers to the direct application of an HPV vaccine composition to any surface of the body, including surfaces of the eye, mucous membranes, body cavities, or to any internal surface. be able to. Formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, sprays, and liquids. Conventional pharmaceutical carriers, aqueous, powdered or oily bases, thickening agents and the like may be necessary or desirable. Topical administration can also be used as a means to selectively deliver HPV vaccine compositions to the epidermis or dermis of a subject, or to specific layers thereof, or to underlying tissues.

Formulations for parenteral administration may include sterile aqueous solutions which may also contain buffers, diluents and other suitable additives. Intraventricular injection can be facilitated by, for example, a ventricular catheter fitted with a reservoir. For intravenous use, the total concentration of solutes should be controlled to give isotonicity to the preparation.

The HPV vaccine compositions of the invention can be administered to a subject by pulmonary delivery. A pulmonary delivery composition is such that the composition within the dispersion can reach the lungs, where it can be immediately absorbed through the alveolar region and directly into the blood circulation. It can be delivered by inhalation of the dispersion. Pulmonary delivery can be effective for both systemic and localized delivery to treat diseases of the lung.

Pulmonary delivery can be accomplished by a variety of techniques including the use of nebulized, aerosolized, micellar, and dry powder-based formulations. Delivery is liquid nebulizer,
It can be accomplished with aerosol-based inhalers and dry powder dispersion devices. A metered dose inhaler is preferred. One advantage of using an atomizer or inhaler is that the device is self-contained, thus minimizing the potential for contamination. Dry powder dispersion devices, for example, deliver drugs that can be readily formulated as dry powders. The HPV vaccine composition, by itself or in combination with a suitable powder carrier,
It can be stably stored as a lyophilized or spray-dried powder.
Delivery of a composition for inhalation can be mediated by a dosing timing element. The dosing timing component, when incorporated into the device, provides for the patient during administration of the aerosol pharmaceutical product
A timer, dose counter, timing device, or time indicator may be included to allow dose tracking, compliance monitoring, and/or dosing initiation.

Types of pharmaceutical excipients that are useful as carriers include stabilizers such as human serum albumin (HSA), bulking agents such as carbohydrates, amino acids and polypeptides; pH adjusters or buffers; salts such as sodium chloride; is mentioned. These carriers may be in crystalline or amorphous form, or a mixture of the two.

Bulking agents of particular value include compatible carbohydrates, polypeptides, amino acids, or combinations thereof. Suitable carbohydrates include monosaccharides such as galactose, D-mannose, sorbose and the like; disaccharides such as lactose, trehalose and the like; cyclodextrins such as 2-hydroxypropyl-β-cyclodextrin; and polysaccharides such as raffinose, maltodextrin, dextran and the like; alditols such as mannitol, xylitol and the like. A preferred group of carbohydrates includes lactose, trehalose, raffinose, maltodextrin, and mannitol. Suitable polypeptides include aspartame. Amino acids include alanine and glycine, with glycine being preferred.

Suitable pH adjusters or buffers include organic salts prepared from organic acids and bases, such as sodium citrate, sodium ascorbate, and the like; sodium citrate is preferred.

One or more HPV viral or virus-like proteins (ie, HPV vaccines) of the invention can be administered by oral or nasal delivery. For example, drugs administered through these membranes have a rapid onset of action, provide therapeutic plasma concentrations,
It avoids the first-pass effect of hepatic metabolism and avoids exposure of the drug to the harsh gastrointestinal (GI) environment. Additional advantages include easy access to membrane sites such that drugs can be easily applied, localized and removed.

Another embodiment according to the subject invention includes administering the HPV vaccine administered to the patient by direct or topical administration, eg, injection, to the skin lesion or areas surrounding the skin lesion. This direct administration method may be useful in patients with cancer, especially skin cancer. This embodiment of the method is also useful for treating non-cancerous (benign) tumors, or non-cancerous lesions associated with HPV, such as warts, such as warts vulgaris or warts acuminata. can be

In one embodiment involving direct perilesional injection into a lesion, the dosing regimen may comprise single or multiple doses. For example, a dosing series of third doses can be continued as described above. Alternatively, the physician can administer subsequent doses as needed (prn) after the first dose directly at or around the lesion. A split dose of vaccine for any particular single time point is considered a single dose.

This direct administration embodiment of the present invention is useful for treating cancers such as basal cell carcinoma (BBC) or melanoma.
development of cancerous lesions or tumors unrelated to HPV infection, or non-cancerous (benign) tumors;
Beneficial results in treating or minimizing recurrence and/or progression can result.

In one embodiment of the subject invention, the method is practiced without the administration of additional or other immunostimulants or adjuvants concurrently with, during, or after the method of treatment of the invention. be done.

Alternatively, the subject method comprises concurrently, during, or after administration of the vaccine,
Administration of additional or other immunomodulatory agents, such as immunostimulants or adjuvants, can be included. Non-limiting examples of immunomodulatory agents useful as part of the subject methods include:
1) Vitamin D and its analogues;
2) sirolimus;
3) interferons and their analogues;
4) Vitamin A and its analogues such as Soriatane (retinoids)
5) imiquimod;
6) ingenol mebutate; and 7) T4 endonuclease 8) antimetabolites such as 5 fluorouracil, methotrexate 9) cyclooxygenase inhibitors such as diclofenac.

These agents can be given locally or systemically in combination with the HPV vaccines as described herein or concurrently with the HPV vaccines as described herein to enhance the efficacy of the treatment. . For example, previously HPV with tumors (skin, lung, etc.)
A combination of interferon and HPV antigen vaccine may be given locally in patients immunized with . Interferon may also be given systemically at the same time or not. This administration can promote local destruction of tumors or other lesions without the systemic side effects associated with interferon.

In another aspect of the invention, the invention provides a method for treating cancer in an individual, comprising H
Methods are provided comprising administering to an individual a combination therapy comprising a PV vaccine and one or more additional chemotherapeutic agents other than an HPV vaccine. Specific dosages and dosing schedules for additional therapeutic agents may also vary, and optimal doses, dosing schedules and routes of administration will be determined based on the specific therapeutic agent used. .

Examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa (
benzodopa), carbocones, meturedopa, and uredopa; ethyleneimine and methylamelamine
elamine) (altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylomelamine)
lomelamine); acetogenins (particularly bratacin and bratacinone); camptothecins (including the synthetic analogue topotecan); bryostatin; callistatin; cryptophycins (especially cryptophycin 1 and cryptophycin 8);
); dolastatin; duocarmycin (synthetic analogs, KW-2189 and CBI-T
MI); erythrobin; pancratistatin; sarcodictine (sarc
spongistatin; nitrogen mustards such as chlorambucil, chlornafadine, cholophosphamide (chol
ophosphamide), estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novenbicin,
phenesterine, prednimustine, trophosphamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics such as enediyne antibiotics (eg calicheamicin,
In particular, calicheamicin γII and calicheamicin φII (e.g. Agnew, Che
m. Intl. Ed. Engl. , 33:183-186 (1994));
dynemicin (including dynemicin A); bisphosphonates such as clodronic acid; esperamicin; and neocardinostatin chromophore and related chromoprotein enediyne antibiotic chromomophore), aclacinomycin, actinomycin, authramycin , azaserine, bleomycin, cactinomycin, carabicin, caminomycin, cardinophylline, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (morpholino -doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, and deoxydoxorubicin), epirubicin,
Ethorubicin, idarubicin, marceromycin, mitomycin, e.g. mitomycin C, mycophenolic acid, nogaramycin, olibomycin, peplomycin, potfiromycin, puromycin, queramycin (qu
elamycin), rodorubicin, streptonigrin,
streptozocin, tubercidin, ubenimex, dinostatin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues,
denopterin, methotrexate, pteropterin, trimetrexate; purine analogues such as fludarabine, 6-mercaptopurine, thiamipurine, thioguanine; pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as carsterone, dromostanolone propionate, epithiostanol, mepitiostane, testolactone; anti-adrena
l), e.g. aminoglutethimide, mitotane, trilostane; folic acid supplements (reple
nisher), such as florinic acid; acegratone;
aldophosphamide glycosides; aminolevulinic acid; eniluracil; amsacrine;
gallium nitrate; hydroxyurea; lentinan; lonidamine; maytansinoids such as maytansine and ansamitocin; podophyllic acid; 2-ethylhydrazide; procarbazine; lazoxan;
sizofuran); spirogermanium; tenuazonic acid; triazicone;
2″-trichlorotriethylamine; trichothecins (especially T-2 toxin, verracurin A, roridin A, and anguidine); urethane; vindesine; dacarbazine; Ara-C");cyclophosphamide;thiotepa; taxoids such as paclitaxel and doxetaxel (do
chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogues such as cisplatin and carboplatin; ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; capecitabine; Included are acceptable salts, acids, or derivatives. Also, anti-hormonal agents that act to modulate or inhibit hormone action on tumors, such as antiestrogens and selective estrogen receptor modulators (SERMs) (e.g., tamoxifen, raloxifene, droloxifene). fen, 4-hydroxytamoxifen, trioxyphene, keoxifene, LY117018, onapristone, and toremifene (Fairstone)); aromatase inhibitors that inhibit the enzyme aromatase that regulates estrogen production in the adrenal glands (e.g., 4 (5 )—imidazole, aminoglutethimide, megestrol acetate, exemestane, formestane, fadrozole, vorozole, letrozole, and anastrozole); and antiandrogens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; Also included are pharmaceutically acceptable salts, acids, or derivatives of any of the foregoing.

Each Therapeutic Agent in the combination therapy of the invention may be a pharmaceutical product (the present (also referred to herein as pharmaceutical compositions).

Each therapeutic agent in the combination therapy of the invention may be administered simultaneously (i.e., in the same pharmaceutical agent), concurrently (i.e., in separate pharmaceutical agents administered one immediately after the other in either order), or They can be administered sequentially in either order. Sequential administration means that the therapeutic agents in the combination therapy are in different dosage forms (one agent is a tablet or capsule and another agent is a sterile liquid) and/or are administered on different dosing schedules ( For example, chemotherapeutic agents administered at least daily and HPV vaccines administered less frequently, such as once a week, once every two weeks, or once every three weeks, are particularly useful.

In some embodiments, the HPV vaccine is administered prior to administration of the chemotherapeutic agent, while in other embodiments the HPV vaccine is administered after administration of the chemotherapeutic agent. In another embodiment, the HPV vaccine is administered concurrently with a chemotherapeutic agent.

In some embodiments, at least one of the therapeutic agents in the combination therapy is the same dosing regimen (therapeutic dose, frequency, and duration). In other embodiments, the patient is given a lower total amount of at least one of the therapeutic agents in combination therapy than when the agents are used as monotherapy (e.g., lower doses, less frequent administration, and/or shorter duration of treatment).

Each therapeutic agent in the combination therapy of the invention can be administered orally or parenterally, including intravenous, intramuscular, intraperitoneal, subcutaneous, intrarectal, topical, and transdermal routes of administration.

The combination therapy of the invention can be used before or after surgery to remove a tumor,
It can also be used before, during, or after radiotherapy.

In some embodiments, the combination therapies of the invention are administered to patients who have not been previously treated with a biological or chemotherapeutic agent, ie, treatment-naive. In other embodiments, combination therapy is administered to treatment-experienced patients who have not had a sustained response after prior treatment with a biologic or chemotherapeutic agent.

The combination therapy of the invention is typically administered by palpation, visual observation or by MRI, ultrasound,
or to treat tumors so large as to be detected by imaging techniques well known in the art, such as CAT scans.

Any commercially available HPV vaccine can be used for direct administration to cancer or HPV-related lesions. For example, this embodiment of the subject method uses the commercially available GA, which is an HPV tetravalent (types 6, 11, 16, and 18) recombinant vaccine.
RDASIL®, or GARDASIL® 9, HPV multivalent (types 16, 18, 31, 33, 45, 52, and 58) recombinant vaccine, or CE
Vaccines containing purified, inactive viral or virus-like proteins, such as RVARIX®, an HPV bivalent (types 16 and 18) recombinant vaccine, are administered directly to or around the lesion. can include doing

Vaccines useful according to this embodiment of the subject method can also include host cell peptides, polypeptides or proteins such as early antigens E6 or E7, or host cell peptides, polypeptides or proteins such as early antigens It is also possible to exclude or not include E6 or E7 and so on. The vaccine may be in unimmunized patients, but will
It can be administered to treat benign tumors, or HPV-associated lesions, in patients of any age, even patients previously immunized with a vaccine.

The vaccine can be administered directly or locally to or around a lesion or tumor to reduce the recurrence rate of cancer, benign tumors, or HPV-related lesions in a patient.

In another embodiment, the vaccine treats cancer, benign tumors, or HPV-associated lesions in patients (e.g., infants, children, adolescents or young adults) up to the age of 26, or adult patients over the age of 27. or to reduce their recurrence rate.

More specifically, one preferred embodiment of the present invention is a method for the treatment of cancerous or non-cancerous tumors or lesions in a patient, comprising administering a dose of HPV recombinant vaccine to the lesion, tumor , or directly to a non-cancerous HPV-associated lesion.

Alternatively, the method can include any of the following steps:
i. about 1 to about 3 months after the first dose, administering a second dose of an HPV vaccine directly to a cancerous, benign, or non-cancerous HPV-associated lesion of the patient;
ii. About 5 to about 7 months after administering the first dose, administering a subsequent dose of the HPV vaccine directly to the patient's cancerous, benign, or non-cancerous HPV-associated lesion. or iii. about 1 to about 3 months after the first dose, administering a second dose of the HPV vaccine directly to the patient's cancerous lesion, benign tumor, or non-cancerous HPV-associated lesion; and About 5 to about 7 months after administering the first dose, administering a subsequent dose of the HPV vaccine directly to the patient's cancerous, benign, or non-cancerous HPV-associated lesion. .

It will be understood by medical personnel that references to the timing of subsequent administrations of vaccines are broad and may vary from day to week or week to week. This variability is measured by the patient's adherence or non-adherence to the dosing schedule, clinically determined by the treating physician, who may decide to advance (for more aggressive treatment) or delay subsequent dosing for medical reasons. It may be due to knowledge. Generally, however, effective results are obtained by following a dosing schedule in which the second dose is administered about two months after the first dose and the third dose is administered about six months after the first dose. can be obtained. Additional (fourth or fifth) doses may also be administered if the physician believes that subsequent administrations may provide benefit to the patient.

Choosing a dosing regimen (also referred to herein as a dosing regimen) depends on the serum or tissue turnover rate of the substance, the severity of the symptoms, the immunogenicity of the substance, and the target cells, tissues, or Depends on several factors, including organ accessibility. Preferably, the dosing regimen maximizes the amount of therapeutic delivered to the patient while maintaining an acceptable level of side effects. Dosage and dosing frequency therefore depend to some extent on the particular therapeutic agent, the severity of the cancer being treated, and the characteristics of the patient. Guidelines are available in selecting appropriate doses of antibodies, cytokines, and small molecules. For example, Wawrz
ynczak (1996) Antibody Therapy, Bios Scientist
Ific Pub. Ltd, Oxfordshire, UK;
(1991) Monoclonal Antibodies, Cytokines an
d Arthritis, Marcel Dekker, New York, NY;
ch(ed.) (1993) Monoclonal Antibodies and P.
Epide Therapy in Autoimmune Diseases, Ma
Rcel Dekker, New York, NY; Baert et al. (200
3) New Engl. J. Med. 348:601-608; Milgrom et al.
al. (1999) New Engl. J. Med. 341:1966-1973;
amon et al. (2001) New Engl. J. Med. 344:783-
792; Beniaminovitz et al. (2000) New Engl. J.
. Med. 342:613-619; Ghosh et al. (2003) New E
ngl. J. Med. 348:24-32; Lipsky et al. (2000)N
ew Engl. J. Med. 343: 1594-1602; Physicians' D.
esk Reference 2003 (Physicians' Desk Reference
ence, 57th Ed); Medical Economics Company;
ISBN: 1563634457; 57th edition (November 20
02). Determination of an appropriate dosing regimen is, for example, using parameters or factors known or believed in the art to affect treatment, or predicted to affect treatment. , can be performed by a clinician and includes, for example, the patient's clinical history (e.g., prior therapy), the type and stage of cancer to be treated, and response to one or more therapeutic agents in combination therapy. of biomarkers.

The HPV viral or virus-like proteins of the invention are administered by continuous infusion or, for example, daily, every other day, three times a week, or once a week, once every two weeks, once every three weeks,
It can be administered by administration at intervals such as once a month, once every two months. The total weekly dose is generally at least 0.05 μg/kg, 0.2 μg/kg, 0.5 μg/kg, 1
μg/kg, 10 μg/kg, 100 μg/kg, 0.2 mg/kg, 1.0 mg/kg
, 2.0 mg/kg, 10 mg/kg, 25 mg/kg, 50 mg/kg of body weight, or more. For example, Yang et al. (2003) New Engl. J.
. Med. 349:427-434; Herold et al. (2002) New
Engl. J. Med. 346:1692-1698; Liu et al. (1999
) J. Neurol. Neurosurg. Psych. 67:451-456;
Tielji et al. (20003) Cancer Immunol. Immun
other. 52:133-144.

In some embodiments, the dosing regimen is about 14% over the course of the treatment regimen.
days (±2 days) or about 21 days (±2 days) or about 30 days (±2 days), or about 1 week (
± 2 days), 2 weeks (± 2 days), 3 weeks (± 2 days), or 4 weeks (± 2 days) intervals
, 3, 5, or 10 mg/kg of the HPV vaccine.

In another embodiment, the dosing regimen is about 0.005 mg/k using intrapatient dose escalation.
administering the HPV vaccine at a dose of from g to about 10 mg/kg. In other ascending dose embodiments, the interval between administrations is progressively shorter, e.g., about 30 days (±2 days) between the first dose and the second dose, and It will be about 14 days (±2 days) between. In certain embodiments, the dosing interval will be about 14 days (±2 days) for doses subsequent to the second dose. A typical total dose for each direct or topical administration by the methods of the subject invention is about 0.5 ml of vaccine, such as commercially available vaccines. Each 0.5 ml dose can be administered by intralesional injection, eg, as a total 0.5 ml bolus, or multiple 0.1 to 0.5 ml injections into the lesion, the area surrounding the lesion, or both. It can also be administered as divided doses as 2 ml sub-doses.

According to certain embodiments, multiple doses of HPV vaccine can be administered to a subject over a defined time course. The method includes, for example, sequentially administering repeated doses of the HPV vaccine to the subject. As used herein, "sequentially administering" means that each dose of HPV vaccine is administered at different times, e.g., separated by a predetermined interval (e.g., hours, days, weeks, or months). means administered to the subject on different days. The present invention provides a single priming dose of HPV vaccine, followed by one or more second doses of HPV vaccine, and optionally one or more third doses of HPV vaccine to be administered sequentially to a patient. It includes a method comprising administering.

The terms "first dose,""seconddose," and "third dose" refer to the timeline of administration of the HPV vaccine. Thus, a "priming dose" is the dose administered at the beginning of a treatment regimen (also referred to as a "baseline dose"); a "second dose" is a dose administered after the initial dose; A dose of" is the dose administered after the second dose. the first time, the second time,
and third doses can all contain the same amount of HPV vaccine (e.g., one or more HPV viral or virus-like proteins), but will generally differ from each other in the frequency of administration. . However, in certain embodiments, the first, second,
and/or the amount of HPV vaccine (e.g., one or more HPV viral or virus-like proteins) contained in the third dose differs from each other (e.g., is adjusted upwards or downwards as needed) during the course of treatment. The Rukoto.

In certain exemplary embodiments, each second and/or third dose is 1 to 14 weeks (e.g., 1, 1 and 1/2, 2, 2 and 1/2, 3, 3 and 1/2, 4, 4 and 1/2
, 5, 5 and 1/2, 6, 6 and 1/2, 7, 7 and 1/2, 8, 8 and 1/2, 9, 9 and 1/2
, 10, 10 and 1/2, 11, 11 and 1/2, 12, 12 and 1/2, 13, 13 and 1/2
, 14, 14½ weeks, or more) later. In another exemplary embodiment,
Each second and/or third dose is 1 to 14 months (e.g., 1, 1
and 1/2, 2, 2 and 1/2, 3, 3 and 1/2, 4, 4 and 1/2, 5, 5 and 1/2, 6, 6
and 1/2, 7, 7 and 1/2, 8, 8 and 1/2, 9, 9 and 1/2, 10, 10 and 1/2, 1
1, 11 and 1/2, 12, 12 and 1/2, 13, 13 and 1/2, 14, 14 and 1/2 months, or more) later. The phrase "immediate dose", as used herein, is
It means a dose of HPV vaccine administered to a patient immediately before the next dose in a series of repeated doses, in sequence with no doses in between.

These methods can include administering any number of second and/or third doses of the HPV vaccine to the patient. For example, in certain embodiments, only one second dose is administered to the patient. In other embodiments, two or more times (eg, 2, 3, 4, 5, 6
, 7, 8, or more) is administered to the patient. Similarly, in certain embodiments, only one third dose is administered to the patient. In other embodiments, two or more (eg, 2, 3, 4, 5, 6, 7, 8, or more) third doses are administered to the patient.

In embodiments with multiple second doses, each second dose can be administered with the same frequency as the other second doses. For example, each second dose can be administered to the patient one to three months after the immediately preceding dose. Similarly, in embodiments with multiple third doses, each third dose can be administered with the same frequency as the other third doses. For example, each third dose can be administered to the patient 1 to 3 months after the immediately preceding dose. Alternatively, the frequency with which the second and/or third dose is administered to the patient can vary over the course of the treatment regimen. The frequency of administration can also be adjusted during the course of treatment by the physician according to the individual patient's needs after clinical examination.

In certain embodiments, the initial dose (eg, "loading dose") is higher than either or both of the second and third doses. For example, the first dose is 1
. It can be 5×, 2×, 2.5×, 3×, or larger loading doses.

The above methods of treatment can be effective in treating skin cancer, and in particular squamous cell carcinoma, in patients where skin cancer lesions decrease in size or disappear after three doses of the vaccine. .

Direct or topical administration treatment methods according to the subject invention can also reduce the recurrence rate of cancer, including skin cancer, in patients.

Direct or local administration methods may also be used to treat benign tumors (whether or not associated with HPV infection), or HPV-related but non-cancerous lesions such as warts, including genital warts. For example, it can be effective in reducing the size of or eliminating common warts or condylomata acuminata.

Direct or local administration methods may also be used to treat benign tumors (whether or not associated with HPV infection), or HPV-related but non-cancerous lesions such as warts, including genital warts. For example, it may be effective in reducing the recurrence rate of warts vulgaris or condyloma acuminata.

HPV bivalent (types 16 and 18) recombinant vaccine, HPV tetravalent (types 6, 11, 16 and 18) recombinant vaccine or HPV polyvalent (types 16, 18, 31, 33, 45, 52 and 58) ) skin cancer after direct or topical administration of one or more injections of a recombinant vaccine;
It is a further unexpected result of the present invention to provide a method of eliminating or reducing the size of squamous cell carcinomas in particular.

A further unexpected result of direct or topical targeted administration methods of treatment is the reduction in size, elimination, or elimination of skin lesions unrelated to HPV infection, such as basal cell carcinoma or melanoma. Including reducing the recurrence rate.

In one embodiment of the subject invention, the direct or topical administration method is performed without the administration of additional or other immunostimulants or adjuvants.

In certain embodiments, the subject method can include administering an additional or other immunomodulatory agent, such as an immunostimulatory agent or an adjuvant, concurrently with, during, or after administration of the vaccine. . Non-limiting examples of immunomodulatory agents useful as part of the subject methods include:
1) Vitamin D and its analogues;
2) sirolimus;
3) interferons and their analogues;
4) Vitamin A and its analogues such as Soriatane (retinoids)
5) imiquimod;
6) ingenol mebutate; and 7) T4 endonuclease 8) antimetabolites such as 5 fluorouracil, methotrexate 9) cyclooxygenase inhibitors such as diclofenac.

These agents can be given locally or systemically in combination with the HPV vaccines as described herein or concurrently with the HPV vaccines as described herein to enhance the efficacy of the treatment. . For example, previously HPV with tumors (skin, lung, etc.)
A combination of interferon and HPV antigen vaccine may be given locally in patients immunized with Interferon may also be given systemically at the same time or not. This administration can promote local destruction of tumors or other lesions without the systemic side effects associated with interferon.

Although topical application can be beneficial for several reasons, including eliminating the risk of infection caused by injection, broad application over large areas is recommended to treat precancerous (actinic keratosis) as well as malignant tumors. can also be convenient. In addition, topical administration can provide cosmetic enhancement of the skin by reducing the appearance of its pigment irregularity, skin atrophy multiforme, and scaling.

Accordingly, one object of the subject invention is a cost-effective, safe and effective method for reducing or ameliorating the growth or size of cancer tumors or lesions, including skin cancer lesions such as SCC, BCC, or melanoma tumors or lesions. It is to provide simple treatment with Another object of the subject invention is to provide a cost-effective, effective and convenient treatment for curing skin cancer lesions, and yet another object of the present invention is to treat cancers, including skin cancer lesions. To provide a cost-effective, effective and convenient method for reducing the recurrence rate of cancer.

A subject method of treating or reducing the recurrence rate of skin cancer comprises treating a patient with HPV at one or more doses.
Including administering the vaccine. In one embodiment, the method comprises administering a first dose of HP to the patient
V tetravalent (types 6, 11, 16, and 18) recombinant vaccine, a second dose of HPV tetravalent (types 6, 11, 16, and 18) recombinant vaccine approximately two months later, and a second including administration of a third dose of HPV tetravalent (types 6, 11, 16, and 18) recombinant vaccine approximately four months after dose two. In preferred embodiments, each dose is 0.5 ml.

A subject method is to use commercially available HPV bivalent (types 16 and 18) recombinant vaccines, HPV tetravalent vaccines as therapeutics, but not or in addition to their use as prophylactic vaccines. (Types 6, 11, 16 and 18) or HPV multivalent (Types 16, 18, 31, 33, 45, 52 and 58) recombinant vaccines may be used.

A prophylactic vaccine is understood to be a vaccine composition administered prior to exposure or infection with an agent such as human papillomavirus (HPV). Prophylactic vaccines for protection or prevention from HPV infection and related cancers are commercially available and therefore known to be safe. GARDASIL® is marketed in the United States by Mer
ck & Co. , Inc. Whitehouse Station, NJ 08889 U
The HPV tetravalent (types 6, 11, 16, and 18) recombinant vaccine currently marketed by SA as a prophylactic vaccine, GARDASIL® 9 is an HPV multivalent (
16, 18, 31, 33, 45, 52, and 58) are recombinant vaccines. CERV
ARIX® is manufactured by GlaxoSmithKline (Brentford, Enr.).
HPV bivalent (types 16 and 18) recombinant vaccine available from S.p.A. grand.

Through the use of commercially available vaccines, vaccines are readily available to physicians or medical personnel. In addition, HPV bivalent (16 and 18) recombinant vaccines, HPV tetravalent (6, 11, 16 and 18) recombinant vaccines or HPV multivalent (16, 18, 31, 33, 45, 16, 18, 31, 33, 45, 52, and 58) The use of recombinant vaccines does not require a second or additional immunostimulant or adjuvant. These commercially available HPV bivalent (types 16 and 18), HPV tetravalent (6, 11
, 16, and 18) or HPV multivalent (types 16, 18, 31, 33, 45, 52, and 58) recombinant vaccines contain host cells and/or non-L1 viral peptides, polypeptides, or proteins, such as Free or substantially free of antigens, such as E6 or E7.

Advantageously, using the subject methods as described herein, cancers, benign tumors, or HPV-related skin lesions (including skin cancers) associated with HPV infection, or Treating skin cancer without any unexpected results can be achieved.

Another embodiment of the subject invention includes compositions for practicing the methods of treatment as described. Vaccines and additional ingredients - such as one or more active pharmaceutical ingredients, excipients, or diluents -
are also included as part of the invention. In the compositions of the present invention, HPV
Vaccines can be formulated with one or more additional active pharmaceutical ingredients for administration to a patient. Additional active pharmaceutical ingredients may include one or more immunomodulators to modulate the efficacy of the vaccine, or one or more local anesthetics to reduce patient discomfort during injection, such as lidocaine (epinephrine). with or without).

One embodiment of the composition of the subject invention comprises a commercially available HPV vaccine formulated with one or more immunomodulatory agents. The one or more immunomodulatory agents can be selected from the group consisting of:
1) Vitamin D and its analogues;
2) sirolimus;
3) interferons and their analogues;
4) Vitamin A and its analogues such as Soriatane (retinoids)
5) imiquimod;
6) ingenol mebutate; and 7) T4 endonuclease 8) antimetabolites such as 5 fluorouracil, methotrexate 9) cyclooxygenase inhibitors such as diclofenac.

A composition comprising an HPV vaccine and at least one immunomodulatory agent advantageously comprises
It can provide enhanced efficacy of the anti-cancer therapeutic activity of HPV vaccines.

One embodiment of the composition of the subject invention comprises a commercially available HPV vaccine formulated with one or more local anesthetics. The one or more local anesthetics can be selected from the group consisting of: Ester-type local anesthetics i.e. procaine, benzocaine, chloroprocaine, cocaine, cyclomethicaine, dimethocaine/larocaine, pipelocaine, propoxycaine, procaine. , proparacaine, and tetracaine, or amide-type local anesthetics, namely lidocaine, articaine, bupivacaine, syncocaine, etidocaine, levobupivacaine, lignocaine, mepivacaine, prilocaine, ropivacaine, and trimecaine.

An example of a composition of the present invention contains 0.5 ml of commercially available HPV vaccine and 0
. 5 ml of commercially available lidocaine solution (e.g. 0.5% (w/v), 1%
(w/v), or 2% (w/v)) in a 1:1 (v/v) ratio. The composition can be mixed thoroughly and injected into the patient for treatment. As will be understood in the art, ratios ranging from 1:10 (v/v) vaccine:anesthetic to 10:1 (v/v) vaccine:anesthetic can be used.

HPV vaccines can also be formulated with one or more excipients or diluents for administration to a patient. Excipients and diluents are one or more useful in formulating topical preparations, including but not limited to bases for preparing creams, emollients, gels, lotions, salves, and the like. can contain conventional pharmaceutically acceptable ingredients of
Penetration enhancers, preservatives, controlled release agents, solubilizers, stabilizers, thickeners or thinners may optionally be included.

Solutions for injection may also contain one or more buffers, emollients, diluents, pH adjusting agents, preservatives, solubilizers, stabilizers, and the like. Topical compositions, including vaccines useful in accordance with the subject invention, can be formulated as conventionally known in the pharmaceutical arts, including one or more additional ingredients or excipients such as organic or inorganic solvents ( aqueous or non-aqueous), stabilizers,
Penetration enhancers, buffers, gelling agents, polymeric agents, lubricants, glidants, creams, waxes, suspending agents, surfactants, and the like can be included. The formulation can further include a penetration enhancer such as DMSO. The formulations include topical solutions, lotions or shake lotions, ointments, creams, gels, foams, transdermal patches, biofrequency chips, powders, solids, sponges, tapes, pastes. It can be provided as a drug, tincture, micelle, liposome, or the like.

These compositions can be prepared as articles of manufacture that can be shipped, stored and used at any time, including at a later point in time, or can be stored away at the point of care or for immediate as-needed treatment. You can also synthesize at a certain place.

Compositions of the present invention can contain one or more additional active pharmaceutical ingredients without excipients or diluents, or can contain one or more active pharmaceutical ingredients and one or more excipients. Agents or diluents may also be included.

The compositions of the present invention can contain one or more excipients or diluents without additional active pharmaceutical ingredients, or one or more excipients or diluents and one or more It can also contain an active pharmaceutical ingredient.

Example 1 - Skin Cancer The following table shows treatments performed in three groups of patients experiencing relatively high recurrence rates of skin cancer, including squamous cell carcinoma (SCC) and basal cell carcinoma. provide results from the subject method of

The data presented below represent the average number of characteristic recurrences of skin cancer per month before and after receiving the methods of treatment described herein.

A. patient 1
Patient 1 received three doses, including a first 0.5 ml dose, a second 0.5 ml dose 2 months later, and a third 0.5 ml dose 4 months after the second dose. A 0.5 ml dose was administered. HP
At a follow-up examination 3 months after administration of the third dose of the V tetravalent (types 6, 11, 16, and 18) recombinant vaccine, patient 1 was diagnosed with SCC type for a period of 3 months. There was no recurrence of skin cancer, including both BCC types. Prior to initiation of treatment regimen, Patient 1 had over 300 characteristic occurrences of skin cancer during her lifetime.

B. patient 2
Patient 2 received three doses, including a first 0.5 ml dose, a second 0.5 ml dose 2 months later, and a third 0.5 ml dose 4 months after the second dose. HPV tetravalent (6
, 11, 16, and 18) were administered with recombinant vaccines.

C. patient 3
Patient 3 received three doses, including a first 0.5 ml dose, a second 0.5 ml dose 2 months later, and a third 0.5 ml dose 8 months after the second dose. HPV tetravalent (6
, 11, 16, and 18) were administered with recombinant vaccines.

As a population, patients who received a regimen of treatment using HPV tetravalent (types 6, 11, 16, and 18) recombinant vaccines each had a significant reduction in the number of skin cancer recurrences and a reduction in desquamation. and improved skin texture and appearance, with increased generalized skin flexibility.

In general, the methods of treatment described herein effectively increase, i.e. boost, a patient's immune surveillance of skin cells to reduce the likelihood of developing abnormal skin cells that give rise to skin cancer. Helpful. The methods of the invention treat and prevent recurrence of SCC, and
It has been shown to significantly reduce recurrence of BCC. Enhanced immune surveillance as a result of therapeutic modalities may also result in a concomitant reduction in the incidence of malignant melanoma.

In one embodiment, a method of treatment to eliminate or reduce the recurrence rate of skin cancer includes HPV tetravalent (types 6, 11, 16, and 18) recombinant vaccine in the form of an injection, cancer tissue, Alternatively, direct administration to an area of tissue directly surrounding the cancerous tissue is included.

Example 2 - Breast Cancer A 32-year-old female (no history of breast cancer, no family history, no risk factors) with previous HPV vaccination was diagnosed with metastatic breast cancer. Her primary tumor was measured by ultrasound to be approximately 4.1 centimeters in diameter. These metastatic tumors can double in size in about 12 weeks.

With the patient's fully informed consent and understanding, a standard initial dose (approximately 0.5 ml) of commercially available HPV vaccine was injected directly into the tumor. A second dose of 0.5 ml diluted with saline and lidocaine to approximately 3 ml was administered directly to the tumor approximately two weeks after the first injection. At that point it is more difficult to find a tumor to inject,
thought to be reduced in size.

Follow-up ultrasound recently showed that the size of the tumor had decreased to approximately 2.7 centimeters in diameter, representing an approximately 35% reduction in diameter and tumor volume (volume for a sphere is 4/3
calculated as π x radius ³ ) decreased by 75%.

Using the size doubling projection, the tumor should have grown approximately 40% to a tumor diameter of approximately 4.6 centimeters.

Example 3 - Metastatic Basal Squamous Cell Carcinoma A 99 year old female presented with metastatic basal squamous cell carcinoma of the lower extremities. The metastatic basal squamous cell carcinoma was severe enough that she was referred to a dermatologist for palliative therapy, and no further options were available other than amputation of the limb to prevent further spread of the cancer.

The patient received a single injection intramuscularly (systemically) of a conventional dose (approximately 0.5 ml) of commercially available HPV vaccine. An additional standard dose of HPV vaccine was injected at each of two or more sites of the larger lesion.

Within 4 weeks of treatment with the HPV vaccine, these lesions visually improved substantially,
No further spread of cancer to the lower extremities was seen. This patient is currently in remission from a lesion of greater or increased size of the lesion.

Example 4 Penile Cancer A 45-year-old HIV-positive male with a 2-year history of squamous cell carcinoma of the penis that was refractory to treatment with various topical and surgical modalities was treated with label instructions. Treated with 3 equal doses of GARDASIL® intramuscularly according to.

Within 4 days, the patient's pain began to decrease and within a few weeks the improvement was 9 to 10 scale ratings.
Pain scale rating of 10 reduced to 0.

A recent examination with confocal microscopy shows no evidence of malignancy. Confocal photography can be used to detect cancer on the skin without the need for a biopsy.

Example 5 - Aggressive Squamous Cell Carcinoma Aggressive, rapidly growing, recurrent squamous cell carcinoma on the lower extremities of an elderly male (history of renal cell carcinoma and prior chemotherapy) mixed with lidocaine 1% with epinephrine GARDASIL (
®) were treated with two intralesional injections.

This patient had previously received GARDASIL® intramuscularly.

This tumor completely regressed and disappeared immediately after the first treatment, without further malignancy.

Example 6 - Prostate Cancer Prostate cancer treatment would involve treating the patient with intramuscular HPV. Direct injection into the prostate can also be included.

Example 7 - Glioblastoma Multiforme Glioblastoma multiforme treatment would involve treating the patient with intramuscular HPV followed by direct injection of glioblastoma multiforme into the tumor.

Example 8 Cervical Cancer Cervical cancer treatment would involve treating the patient with intramuscular HPV. It can also include direct injection into the cervix.

Example 9 - Anal Cancer Treatment for anal cancer would involve treating the patient with intramuscular HPV. It can also include direct injection or topical application to the anus.

The use of other HPV vaccines in treating cancer or tumors according to the methods described herein is also fully contemplated and within the scope of the invention.

While this invention has been shown according to several preferred and practical embodiments thereof, it will be appreciated that departures from this disclosure are considered well within the spirit and scope of the invention.

Claims (13)

at least one purified viral L1 protein or fragment thereof;
A pharmaceutical composition comprising a second active pharmaceutical ingredient and a pharmaceutically acceptable carrier. A pharmaceutical composition according to claim 1, wherein said second active pharmaceutical ingredient is a local anesthetic. The local anesthetic is procaine, benzocaine, chloroprocaine, cocaine, cyclomethicaine, dimethocaine/larocaine, pipelocaine, propoxycaine, procaine, proparacaine and tetracaine, lidocaine, articaine, bupivacaine, syncocaine, etidocaine, levobupivacaine, lignocaine , mepivacaine, prilocaine, ropivacaine and trimecaine. 3. The pharmaceutical composition of claim 2, wherein said local anesthetic is lidocaine. wherein said second active pharmaceutical ingredient is vitamin D, vitamin D analogues, vitamin A, vitamin A analogues, sirolimus, interferon, interferon analogues, imiquimod, ingenol mebutate, T4 endonuclease, antimetabolites and 2. The pharmaceutical composition of claim 1, which is an immunomodulatory agent selected from the group consisting of cyclooxygenase inhibitors. 6. The pharmaceutical composition according to claim 5, wherein said antimetabolite is 5-fluorouracil or methotrexate. 6. The pharmaceutical composition according to claim 5, wherein said cyclooxygenase inhibitor is diclofenac. 8. The pharmaceutical composition according to any one of claims 1 to 7, which is in injectable form. 8. A pharmaceutical composition according to any one of claims 1 to 7 in topical form. 10. The pharmaceutical composition of any one of claims 1-9, wherein said at least one purified viral L1 protein or fragment thereof is a human papillomavirus (HPV) L1 protein or fragment thereof. 11. A pharmaceutical composition according to claim 10, comprising purified viral L1 proteins or fragments thereof obtained from each of HPV types 6, 11, 16 and 18. 11. A pharmaceutical composition according to claim 10, comprising a purified viral L1 protein or fragment thereof obtained from each of HPV types 16, 18, 31, 33, 45, 52 and 58. 13. The pharmaceutical composition of any one of claims 1-12, wherein said at least one purified viral L1 protein or fragment thereof is present in a virus-like particle (VLP).