Methods and compositions for treating cancer or skin lesions using vaccines - Patents.com

Abstract

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

Description

[Technical Field]

[0001] The present invention relates to treating cancer, including skin cancer, or benign or malignant tumors, and more particularly to methods for treating cancer or tumors or reducing recurrence rates, including administering vaccines, including topical administration of vaccines as therapeutic agents. [Background technology]

[0002] Skin cancer consists of three major types: basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma, and is the most common form of cancer worldwide. Not surprisingly, for many years, research has been ongoing to find effective ways to treat, and potentially cure, these types of skin cancer.

[0003] It is generally accepted that human papillomavirus (HPV) is associated with causing certain types of skin cancer, particularly squamous cell carcinoma (SCC). HPV is a DNA virus that can infect certain types of tissue in humans. There are more than 30 subtypes of HPV, 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.

[0004] Vaccines have been developed and shown to prevent cervical cancer in women and other conditions caused by or associated with HPV infection. GARDASIL® is a commercially available vaccine with activity against HPV (types 6, 11, 16, and 18).

[0005] GARDASIL® 9 is another commercially available vaccine marketed for the prevention of HPV types 16, 18, 31, 33, 45, 52, and 58. GARDASIL® is indicated for use in girls and boys aged 9-26 years, and GARDASIL® 9 is also indicated for use in girls aged 9-26 years and boys aged 9-15 years.

[0006] 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 effect, i.e., injected subcutaneously or intramuscularly (e.g., deltoid muscle) into patients away from any specific target, such as the cervix. Furthermore, they are generally recognized as effective before exposure to HPV and are not generally known to be effective in treating HPV exposure or infection after HPV exposure.

[0007] Other prophylactic vaccines include, for example, improved vaccine compositions containing certain HPV L1 proteins (similar to GARDASIL®) and additional HPV-specific components, as described in Chinese Patent Application No. 101890160 (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 U.S. Patent Application Publication No. 2005 / 0287161.

[0008] Vaccines used for treatment (referred to herein as "therapeutic vaccines") have been described. However, these therapeutic vaccines are not limited to vaccines such as GARDASIL®. More virus-specific components are needed, such as the HPV L1 protein, which contains commercially available prophylactic vaccines.

[0009] U.S. Patent Application Publication No. 2007 / 0218074 describes the use of vaccine compositions containing host cell peptides derived from HPV-infected cells. The host cell peptides, e.g., early antigens E6 or E7 present on the surface of HPV-infected cells, are fragments of host cell proteins. The importance of polypeptides E6 or E7 in vaccines used to treat certain cancer types is discussed in "Development of HPV vaccines for HPV-associated head and neck squamous cell carcinoma," Devaraj, et al., Crit. Rev Oral Biol Med. 2003;14(5):345-62. Another vaccine containing a host cell protein (BAX) is described in US Pat. No. 8,399,610.

[0010] Yet another vaccine composition that includes other or additional antigens in combination with HPV-16 peptides is the vaccine composition described in U.S. Patent Application Publication No. 2011 / 0070252, which further requires a Trojan antigen.

[0011] U.S. Patent Application Publication No. 2011 / 0110979 (U.S. '979) and U.S. Patent Application Publication No. 2012 / 0288538 (U.S. '538) disclose the therapeutic use of HPV vaccines containing E6 or E7 polypeptides (peptide fragments derived from host cells infected with HPV). U.S. '538 describes that E6 and E7 are essential for inducing transformation in HPV-infected cells, and also describes that a vaccine composition that does not contain E6 or E7 would not be expected to work on cells that do not have E6 or E7, i.e., cells such as BCC that are not infected with HPV. The method described in U.S. '979 publication further requires an immunostimulant or adjuvant.

[0012] Although US '979 and US '538 publications describe the use of therapeutic vaccines against skin cancers such as SCC or epithelial SCC, they do not describe the use of vaccines against other skin cancers such as BCC or melanoma, presumably based on the proviso that BCC and melanoma are not associated with HPV infection.

[0013] The above-mentioned limitations and drawbacks of the use of vaccines can be overcome by the use of methods in accordance with the subject invention. There is a need in the medical and health fields for safe and effective cancer treatments (including skin cancers or cancers not generally associated with HPV infection) that are convenient for patients and medical professionals. Summary of the Invention [Means for solving the problem]

[0014] The subject invention relates to a method for treating a patient having skin cancer, benign or malignant tumor (whether related to or associated with human papillomavirus (HPV) infection), or other skin lesion, comprising administering a therapeutically effective dose of a commercially available HPV vaccine to a patient having or in need of treatment for a tumor, cancer, or other skin lesion. The vaccine can be administered directly to the cancer or lesion by direct (topical) 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. The therapeutically effective dose can be the conventional approved dose of the vaccine per its labeling.

[0015] In one embodiment, the method comprises: a) administering a first dose of an HPV vaccine that does not contain host cell peptides, polypeptides, or proteins, or degradation products thereof, to a patient 27 years of age or older or a patient who has not been previously immunized with an HPV vaccine; b) administering a second dose of the HPV vaccine to the patient about one month to about three months after the first dose; c) optionally administering a third dose of the HPV vaccine to the patient about 5 to about 7 months after the first dose; Includes:

[0016] 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 or by topical administration of a composition comprising the vaccine. Alternatively, the second or third administration of step b) or c) may include both injection and topical administration.

[0017] In one embodiment, the second dose of the HPV vaccine is administered about two months after the first dose, and the third dose of the HPV vaccine is administered about six months after the first dose.

[0018] The HPV vaccine can be selected from an HPV tetravalent (types 6, 11, 16, and 18) recombinant vaccine comprising the HPV L1 protein, and an HPV multivalent (types 16, 18, 31, 33, 45, 52, and 58) recombinant vaccine comprising the HPV L1 protein, preferably free of or substantially free of host cell early antigens, such as E6 or E7.

[0019] In certain preferred embodiments, the methods do not include or involve the administration of additional or other immunostimulants or adjuvants.

[0020] In certain preferred embodiments, the methods include administering additional or other immunomodulatory agents, such as immunostimulants or adjuvants.

[0021] By carrying out 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 can be effective for treating or reducing the recurrence rate of cancer, benign tumors, or HPV-related lesions, such as squamous cell carcinoma, basal cell carcinoma, melanoma, common warts, or condyloma acuminata.

[0022] In one embodiment, the method can include a single dose of vaccine. For example, the single dose of vaccine can be administered locally, by direct injection into the tumor, or systemically to reduce or eliminate the size of the tumor. A physician or medical professional can administer a second or subsequent dose as needed or as determined by the physician or medical professional.

[0023] In one embodiment, the patient in need of treatment may be one who has been previously immunized with the vaccine, hi another embodiment, the patient in need of treatment may be one who has not been previously immunized with the vaccine.

[0024] Each dose of HPV vaccine administered in the above method steps is preferably about 0.5 ml, more preferably 0.5 ml.

[0025] The method can further include confirming a positive diagnosis of cancer, benign tumor, or HPV infection prior to administering the first dose of HPV vaccine.

[0026] An alternative embodiment of a method according to the subject invention includes treating a patient having a cancer, benign tumor, or human papillomavirus-associated (HPV-associated) lesion, wherein the method includes administering a dose of an HPV vaccine directly to the cancer, tumor, or lesion, or to the area immediately surrounding the tumor or lesion.

[0027] This alternative embodiment of the method according to the subject invention comprises: administering a second dose of HPV vaccine directly to the tumor or lesion or to the area immediately surrounding the tumor or lesion about one to three months after administering the first dose; Optionally, administering a third dose of the HPV vaccine directly to the tumor or lesion or to the area immediately surrounding the tumor or lesion about 5 to about 7 months after administering the first dose. It may further include:

[0028] These direct second or third administrations of the vaccine-containing composition may be by topical application or by injection into the lesion.

[0029] In this alternative embodiment of the subject method, the second dose of the HPV vaccine can be administered about two months after the first dose, and the third dose of the HPV vaccine can be administered about six months after the first dose.

[0030] By practicing alternative embodiments of the methods according to the subject invention, the size of cancers, tumors, or HPV-associated lesions can be substantially reduced or completely eliminated, and the recurrence rate of cancers, tumors, or HPV-associated lesions can be reduced.

[0031] The preferred volume of each subsequent administration of HPV vaccine, if present, is 0.5 ml.

[0032] The methods according to any of the embodiments of the present invention can be used to treat cancer, benign tumors, or HPV-associated lesions, including, but not limited to, benign tumors, squamous cell carcinoma, basal cell carcinoma, melanoma, common warts, and condyloma acuminata, whether or not associated with HPV infection.

[0033] The method can further include confirming a positive diagnosis of cancer, benign tumor, or HPV infection prior to administering the first dose of HPV vaccine.

[0034] In one preferred embodiment, the direct or local administration of the vaccine is administered by injection, and more preferably, this method does not involve the administration of additional or other immunostimulants or adjuvants together with, during, or after administration of the vaccine.

[0035] Alternatively, the subject methods can involve administering additional or other immunomodulatory agents, such as immunostimulants or adjuvants, along with, during, or after administration of the vaccine.

[0036] In another preferred embodiment, the vaccine is formulated for topical administration and is applied directly to the lesion in the form of a topical solution or suspension, such as a liquid or spray, gel, cream, salve, ointment, foam, or mousse. This can be done.

[0037] The subject invention specifically relates to a method for treating a tumor, comprising administering to a patient having the tumor at least one dose of a commercially available HPV vaccine. Advantageously, the subject method has been found to be effective in treating tumors in glandular tissues such as the breast, pituitary gland (e.g., invasive pituitary adenoma), prostate, or pancreas. This embodiment can involve administering at least one dose of the vaccine directly to the tumor itself.

[0038] The subject invention can involve administering at least one dose of a vaccine systemically, for example, by intramuscular (IM) injection, either alone or in combination with (simultaneously with, immediately before, or after) administration of the vaccine directly to the tumor.

[0039] Alternatively, in certain cases, for example, when the tumor is on or near the surface of the body, the method can further include local administration of at least one dose of an HPV vaccine, alone or in combination with direct injection into the tumor, or in combination with systemic injection, or in combination with both direct and systemic injection.

[0040] Compositions containing vaccines are also included as part of the present invention.For example, HPV vaccines can be formulated with one or more additional active pharmaceutical ingredients for administration to patients.The additional active pharmaceutical ingredients can be one or more immunomodulators for adjusting the effect of vaccines, or one or more local anesthetics for reducing the discomfort of patients during injection, such as lidocaine (with or without epinephrine).

[0041] An example of a composition of the present invention comprises a 1:1 (v / v) mixture of 0.5 ml of a commercially available HPV vaccine and 0.5 ml of a commercially available lidocaine solution (e.g., 0.5% (w / v), 1% (w / v), or 2% (w / v)). This composition can be thoroughly mixed and injected into a patient for treatment. As will be understood in the art, ratios ranging from 1:10 (v / v) vaccine:anesthetic solution to 10:1 (v / v) vaccine:anesthetic solution can be used.

[0042] The HPV vaccine can also be formulated with one or more excipients or diluents for administration to a patient. The excipients and diluents can include one or more conventional pharmaceutically acceptable ingredients useful in formulating topical preparations, including, but not limited to, bases for preparing creams, emollients, gels, lotions, salves, etc., and can optionally include penetration enhancers, preservatives, release-controlling agents, solubilizers, stabilizers, thickeners, or thinners.

[0043] Solutions for injection may also contain one or more buffers, emollients, diluents, pH adjusters, preservatives, solubilizers, stabilizers, and the like.

[0044] These compositions can be prepared as products that can be shipped, stored, and used at any time, including at a later time, or can be compounded at the point of care or at a remote location for immediate, as-needed treatment.

[0045] The compositions of the present invention can include one or more additional active pharmaceutical ingredients without any excipients or diluents, or can include one or more active pharmaceutical ingredients and one or more excipients or diluents.

[0046] The compositions of the present invention contain one or more excipients or diluents without any additional active pharmaceutical ingredient. It may contain one or more excipients or diluents and one or more active pharmaceutical ingredients.

[0047] To the inventors' knowledge, administration of an HPV vaccine containing only HPV antigens (without host cell peptides) to previously unimmunized patients or adult patients 27 years of age or older to eliminate or reduce the recurrence rate of skin cancers, benign or malignant tumors, or other skin lesions that are not HPV-associated lesions has not previously been described. Direct or local injection of a vaccine by topical application or by direct injection into a lesion or tumor to eliminate the lesion or reduce the incidence of its recurrence has also not previously been described. DETAILED DESCRIPTION OF THE INVENTION

[0048] The present invention is directed to methods of treating cancer, benign tumors, skin cancers, such as squamous cell carcinoma (SCC), or skin lesions that may or may not be associated with human papillomavirus (HPV) infection, including treating tumors derived from glandular tissue, such as breast, pituitary, prostate, or pancreatic tissue. One embodiment of a method according to the subject invention involves administering to a patient with cancer or tumor a commercially available HPV vaccine, such as the HPV quadrivalent (types 6, 11, 16, and 18) recombinant vaccine.

[0049] In certain preferred embodiments, the subject methods involve administering at least one dose of an HPV vaccine to a patient who has not previously been immunized with an HPV vaccine, or to an adult patient who is 27 years of age or older. For purposes of the subject invention, a patient who has not previously been immunized with an HPV vaccine is referred to as an "unimmunized patient," regardless of whether the patient may have received other immunizations against other conditions or diseases.

[0050] The dosing regimen can be a single administration by direct injection, systemic injection, or topical application, or a combination of any of these routes of administration. Alternatively, the subject methods can include repeated (two or more) administrations, or repeated (simultaneous) administrations of the vaccine by direct injection, systemic injection, or topical application.

[0051] The subject method can also comprise administering according to the conventionally accepted dosing sequence for vaccines.For example, HPV vaccines are generally administered using a dosing regimen that includes the first dose, the second dose about 2 months after the first dose, and the third dose about 6 months after the first dose.These second, third or subsequent administrations can be systemic injections, for example, conventional intramuscular injections, or can be directly administered to lesions by intralesional injection or local administration.

[0052] Method embodiments of the present invention have surprisingly been found to provide beneficial results in treating or minimizing the occurrence, recurrence, and / or progression of cancerous lesions or benign tumors that are not associated with HPV infection, such as basal cell carcinoma (BBC) or melanoma.

[0053] Without being limited to any particular theory, it is proposed that the subject methods can increase or boost a patient's immune response (which can be clinically manifested as improved immune surveillance in skin cells), reducing the likelihood of the development and progression of abnormal skin cells that give rise to skin cancer, particularly, but not limited to, SCC.

[0054] Alternatively, the methods of the present invention can interfere with the intrinsic functional activity of viral and viral-like proteins by other mechanisms, which may include complete or partial functional inactivation of viral and viral-like proteins that are altered or activated by exogenous and / or environmental factors, such as ultraviolet light.

[0055] As used herein, the terms "HPV" and "human papillomavirus" refer to non-enveloped, double-stranded DNA viruses of the papillomavirus family. Their genomes are circular and approximately 8 kilobase pairs in size. Most HPVs encode eight major proteins, six located in the "early" region (E1-E2) and two in the "late" region (L1 (major capsid protein) and L2 (minor capsid protein)). Over 120 HPV types have been identified, which are designated numerically (e.g., HPV-16, HPV-18, etc.).

[0056] In one embodiment, the HPV vaccine of the subject invention comprises one or more proteins (e.g., recombinant L1 proteins) from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more different HPV types. Methods for expressing HPV L1 proteins and for producing HPV vaccines are known in the art and are described, for example, in U.S. Patent Nos. 5,820,870 and 6,251,678, which are incorporated by reference in their entireties for all purposes.

[0057] In one embodiment, the HPV vaccine used in the subject method contains purified, inactive viral and viral-like proteins, such as the commercially available GARDASIL®, which is an HPV quadrivalent (types 6, 11, 16, and 18) recombinant vaccine, or GARDASIL® 9, an HPV multivalent (types 16, 18, 31, 33, 45, 52, and 58) recombinant vaccine. In another embodiment, the HPV vaccine is the commercially available CERVARIX®, which is an HPV bivalent (types 16 and 18) recombinant vaccine. Vaccines useful according to this embodiment of the subject method preferably do not include host cell and / or non-L1 HPV peptides, polypeptides, or proteins, such as early antigens, E6, or E7, which are fragments of host cell peptides present on the surface of HPV-infected cells.

[0058] The vaccine can be administered to treat cancerous or benign tumors, including cancerous lesions not associated with HPV infection, cancers (tumors or lesions) associated with HPV infection, benign tumors not associated with HPV infection, or non-cancerous HPV-associated lesions in unimmunized patients.

[0059] Alternatively, the vaccine can be administered to reduce the recurrence rate of cancer, benign tumors, or HPV-associated lesions in unimmunized patients. In another embodiment, the vaccine can be administered to treat or reduce the recurrence rate of cancer, benign tumors, or HPV-associated lesions in adult patients 27 years of age or older.

[0060] More specifically, one preferred embodiment of the present invention is a method for the treatment of cancer, benign tumors, or HPV-associated lesions in a patient who is naive or an adult patient 27 years of age or older, comprising: i. administering to a patient a first dose of an HPV recombinant vaccine that does not contain a host cell peptide, polypeptide, or protein; ii. administering to the patient a second dose of an HPV recombinant vaccine that does not contain the host cell peptide, polypeptide, or protein about one month to about three months after the first dose; and iii. Optionally, about 5 to about 7 months after administration of the first dose, administering to the patient a third dose of an HPV vaccine that does not contain a host cell peptide, polypeptide, or protein. The method includes the method comprising:

[0061] The second or third or subsequent administration of the vaccine dose may be administered systemically, e.g., by intramuscular injection. The second, third, or subsequent administration may be systemic or by direct administration to the lesion. Direct administration of the vaccine composition to the lesion may be by intralesional injection or by local application to the lesion. In a further embodiment, the second, third, or subsequent administration is both systemic and by direct application of the vaccine to the lesion. Such direct administration to the lesion may be by intralesional injection or by local application of a vaccine composition formulated for local administration.

[0062] It will be understood by medical professionals that references to the timing of subsequent doses of vaccine are broad and may vary by day or week. This variation may be due to patient compliance or non-compliance with the dosing schedule, or clinical findings by the treating physician, who may decide to advance (for more aggressive treatment) or delay subsequent doses for medical reasons. However, in general, effective results can be obtained by following a dosing schedule in which the second dose is administered approximately two months after the first dose and the third dose is administered approximately six months after the first dose. Additional (fourth or fifth) doses may also be administered if the physician believes that subsequent administrations may provide benefit to the patient.

[0063] 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 a commercially available HPV vaccine.

[0064] The terms "cancer," "cancerous," or "malignant" refer to or describe a physiological condition in mammals that is typically characterized by uncontrolled cell growth. Examples of cancer include, but are not limited to, cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; pulmonary: bronchogenic lung carcinoma (squamous cell, small undifferentiated cell, large undifferentiated cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; gastrointestinal: esophageal (squamous cell carcinoma, adenocarcinoma, Leiomyosarcoma, lymphoma), 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, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma) Colorectal; Genitourinary: Kidney (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), Bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), Prostate (adenocarcinoma, sarcoma), Testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell tumor, fibroma, fibroadenoma, adenomatous tumor, lipoma); Liver: Hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Bone: Osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma , malignant giant cell tumor, chordoma, osteochondroma (osteochondroma), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma and giant cell tumor; nervous system: skull (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), meninges (meningiomas, meningeal sarcomas, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord (neurofibromas, meningiomas, gliomas, sarcomas); gynecology: uterus (endometrial cancer), cervix (cervical cancer, preneoplastic (pre) tumor) cervical dysplasia), ovary (ovarian cancer [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma], granulosa theca cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube (carcinoma), breast;Hematological system: blood (myeloid leukemia (acute and chronic), acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles, dysplastic nevi, lipomas, hemangiomas, dermatofibromas, keloids, psoriasis; and adrenal glands: 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, and glioma; Cancers include Hodgkin's lymphoma, non-Hodgkin's lymphoma, acute myeloid leukemia (AML), multiple myeloma, gastrointestinal cancer, renal cancer, ovarian cancer, liver cancer, lymphoblastic leukemia, lymphocytic leukemia, colorectal cancer, endometrial cancer, renal cancer, prostate cancer, thyroid cancer, melanoma, chondrosarcoma, neuroblastoma, pancreatic cancer, glioblastoma multiforme, cervical cancer, brain cancer, stomach cancer, bladder cancer, hepatoma, breast cancer, colon cancer, and head and neck cancer. In certain exemplary embodiments, the cancer is an HPV-associated cancer.

[0065] Specific examples of cancer include skin cancer, e.g., basal cell carcinoma and / or squamous cell carcinoma, among other known skin cancers. Another example of cancer includes breast cancer. Yet another example of cancer includes prostate cancer. Yet another example of cancer includes penile cancer. Yet another example of cancer includes 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 (e.g., cancer of the pharynx, soft palate, base of tongue, pharyngeal tonsil, and / or tonsil). Yet another example of cancer includes kidney cancer. Yet another example of cancer includes liver cancer.

[0066] In certain exemplary embodiments, the cancer is associated with decreased expression of Bcl-2 associated X protein (BAX) and / or Bcl-2 homologous antagonist / killer (BAK1). In other exemplary embodiments, the cancer is associated with one or more abnormal mitochondrial activities. In certain exemplary embodiments, the HPV vaccine of the present invention increases BAX and / or BAK1 expression in tumor cells and / or promotes apoptosis of tumor cells. In other aspects, the combination of vitamin D with the HPV vaccine of the present invention increases BAX and / or BAK1 expression in tumor cells and / or promotes apoptosis of tumor cells. In another embodiment, the HPV vaccine of the present invention modulates one or more mitochondrial activities in tumor cells.

[0067] The above-described embodiments of the treatment methods of the present invention may be effective in treating skin cancer, and in particular squamous cell carcinoma, in patients, where the skin cancer lesions reduce in size or disappear after three administrations of the vaccine.

[0068] Treatment methods according to the subject invention can also reduce the recurrence rate of benign or cancerous tumors or lesions (including skin cancers) in patients.

[0069] In particular, methods of treatment according to the subject invention include eliminating or reducing the size or recurrence rate of cancerous tumors of the breast, eliminating or reducing the size or recurrence rate of cancerous tumors of the prostate, eliminating or reducing the size or recurrence rate of cancerous tumors of the pancreas, or eliminating or reducing the size or recurrence rate of cancerous tumors of the pituitary gland, e.g., invasive pituitary adenomas.

[0070] Other specific types of cancers or tumors that may benefit from treatment using an HPV vaccine according to the methods of the subject invention 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, bladder cancer, lung cancer, kidney cancer, liver cancer, ovarian cancer, mucinous cystic neoplasm of the pancreas, and gastric (or stomach) cancer.

[0071] The methods of the invention may also be effective in reducing the size of or eliminating non-cancerous lesions associated with HPV, such as warts, including genital warts, eg, common warts or condyloma acuminata.

[0072] HPV quadrivalent (types 6, 11, 16, and 18) recombinant vaccine (wherein the vaccine is a recombinant HPV vaccine that binds to host cell peptides present on the surface of infected cells as a result of HPV infection of cells) 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 a compound (substantially free of steroids, polypeptides, or proteins) containing steroids. Further unexpected results of the subject treatment methods include reducing the size, disappearance, or recurrence rate of skin lesions not associated with HPV infection, such as basal cell carcinoma or melanoma.

[0073] The present invention relates to the use of the above-mentioned agents for the therapeutic treatment of cancer. Therefore, the HPV vaccine composition of the present invention is incorporated into a pharmaceutical composition suitable for administration. Such compositions typically contain HPV viral proteins or viral-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, and the like, that are compatible with pharmaceutical administration. 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, its use in the composition is anticipated. Additional active compounds can also be incorporated into the composition.

[0074] The pharmaceutical composition of the present invention is formulated to be compatible with its intended route of administration. Examples of administration routes include parenteral, e.g., intravenous (IV), intradermal, subcutaneous (SC or SQ), intraperitoneal, intramuscular, oral (e.g., inhalation), transdermal (topical), and transmucosal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can contain the following components: a sterile diluent, e.g., water for injection, saline, fixed oil, polyethylene glycol, glycerin, propylene glycol, or other synthetic solvent; an antibacterial agent, e.g., benzyl alcohol or methylparaben; an antioxidant, e.g., ascorbic acid or sodium bisulfite; a chelating agent, e.g., ethylenediaminetetraacetic acid; a buffer, e.g., acetate, citric acid, or phosphate, and an agent for adjusting osmotic pressure, e.g., sodium chloride or dextrose. pH can be adjusted with an acid or base, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

[0075] 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 physiological saline, bacteriostatic water, Cremophor E™ (BASF, Parsippany, NJ), or phosphate-buffered saline (PBS). In all cases, the composition must be sterile and fluid to the extent that easy syringability exists. The composition 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, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, or by the maintenance of the required particle size in the case of dispersions, or by the use of surfactants. Prevention of microbial action can be achieved by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc. In many cases, it will be preferable to include isotonic agents, such as sugars, polyalcohols such as mannitol, sorbitol, sodium chloride in the composition. Prolonged absorption of injectable compositions can be achieved by including agents that delay absorption, such as aluminum monostearate and gelatin in the composition.

[0076] Sterile injectable solutions may be prepared by administering a compound of formula (I) or (II) to a patient having the above-listed ingredients, or a combination of ingredients, as needed. Can be prepared by incorporating the required amount of active compound in suitable solvent, and then sterilize by filtration.Generally, dispersion system is prepared by incorporating active compound into sterile vehicle that contains basic dispersion medium and other required components from above-listed.For the sterile powder that is used to prepare sterile injection solution, the preferred method of preparation is vacuum drying and freeze-drying, which produces powder of active ingredient plus any additional desired component from its solution that has been previously sterilized and filtered.

[0077] Oral compositions generally contain an inert diluent or an edible carrier. These can be enclosed in gelatin capsules or compressed into tablets. For 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 liquid or suspension, or for use as a mouthwash. Here, the compound in the fluid carrier is applied orally, swished around the mouth, and expectorated or swallowed. Pharmaceutically compatible binders and / or adjuvants can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or sterote; a flow agent such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

[0078] For administration by inhalation, the compounds are delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, eg, a gas such as carbon dioxide, or a nebulizer.

[0079] Systemic administration can also be via transmucosal or transdermal means.For transmucosal or transdermal administration, a penetrant appropriate to the barrier to be permeated is used in the formulation.Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives.Transmucosal administration can be achieved through the use of nasal sprays or suppositories.For transdermal administration, the active compound is formulated into ointments, salves, gels, or creams generally known in the art.

[0080] 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.

[0081] In one embodiment, HPV viral or viral-like proteins are formulated with carriers that will protect the compound from rapid elimination from the body, such as controlled-release formulations, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid, can be used. Methods for preparing such formulations will be apparent to those skilled in the art. These materials are also commercially available from Alza Corporation and Nova Pharmaceuticals, Inc. 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 U.S. Pat. No. 4,522,811.

[0082] For ease of administration and dosage uniformity, it is particularly advantageous to prepare oral or parenteral compositions in dosage unit form.Dosage unit form as used herein refers to a physically separate unit that is suitable as a unit dosage for the subject that will be treated; each unit contains a predetermined amount of active compound, calculated to produce desired therapeutic effect together with required pharmaceutical carrier.The details of dosage unit form of the present invention are determined and directly depend on the unique properties of active compound and the specific therapeutic effect that should be achieved, and the limitation inherent in the art when preparing this active compound for individual treatment.

[0083] The toxicity and therapeutic efficacy of such compounds can be determined, for example, by LD 50 (a dose lethal to 50% of the population) and ED 50 The dose that is 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 LD 50 / ED 50 The therapeutic index can be expressed as: Compounds that exhibit large therapeutic indices are preferred. Compounds that exhibit toxic side effects can also be used, although care should be taken to design a delivery system that targets such compounds to the site of affected tissue in order to minimize the potential for damage to uninfected cells, thereby reducing side effects.

[0084] Data obtained from cell culture analysis and animal studies can be used to formulate a dosage range for use in humans. The dosage of such compounds is preferably within a circulating concentration range that includes the ED50 with little or no toxicity. Dosages can vary within this range depending on the dosage form used and the route of administration utilized. For any compound used in the method of the present invention, the therapeutically effective dose can be initially estimated from cell culture analysis. Dosages can be formulated in animal models to obtain a circulating plasma concentration range that includes the EC50 (i.e., the concentration of the test compound that achieves half of the maximum response) determined in cell culture. Such information can be used to more accurately determine useful doses in humans. Plasma levels can be measured, for example, by high-performance liquid chromatography.

[0085] The pharmaceutical compositions can be included in a container, pack, or dispenser together with any instructions for administration.

[0086] The route of delivery may depend on the patient's disorder. In certain exemplary embodiments, a subject diagnosed with skin cancer may be administered the HPV vaccine composition of the present invention by topical administration. In addition to the HPV vaccine composition of the present invention, the patient may be administered a second therapy, e.g., a palliative therapy and / or a disease-specific therapy. The second therapy may be, for example, palliative (e.g., to relieve symptoms), preventative (e.g., to slow or stop disease progression), or restorative (e.g., to reverse the disease process). For cancer treatment, for example, the palliative therapy may further include another chemotherapeutic agent used as a combination therapy, as further described herein.

[0087] Generally, the HPV vaccine composition of the present invention can be administered by any suitable method. As used herein, topical delivery can refer to the direct application of the HPV vaccine composition to any surface of the body, including the surface of the eye, mucous membrane, or body cavity, or to any internal surface. Formulations for topical administration can include transdermal patches, ointments, lotions, creams, gels, drops, sprays, and liquids. Conventional pharmaceutical carriers, aqueous, powder, or oily bases, thickeners, and the like may be necessary or desirable. Topical administration can also be used as a means to selectively deliver the HPV vaccine composition to the epidermis or dermis of a subject, or to specific layers thereof, or to underlying tissues.

[0088] Preparations 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 attached to a reservoir. For intravenous use, the total concentration of solutes should be controlled to render the preparation isotonic.

[0089] The HPV vaccine composition of the present invention can be administered to a subject by pulmonary delivery. Pulmonary delivery compositions can be delivered by inhalation of a dispersion so that the composition within the dispersion can reach the lungs (where it can be immediately absorbed directly into the blood circulation through the alveolar region). Pulmonary delivery can be effective for both systemic and localized delivery to treat lung diseases.

[0090] Pulmonary delivery can be achieved by a variety of techniques, including the use of nebulized, aerosolized, micellar, and dry-powder-based formulations. Delivery can be achieved using liquid nebulizers, aerosol-based inhalers, and dry-powder dispersion devices. Metered-dose inhalers are preferred. One advantage of using an atomizer or inhaler is that the device is self-contained, minimizing the potential for contamination. Dry-powder dispersion devices, for example, deliver drugs that can be easily formulated as dry powders. HPV vaccine compositions can be stably stored as lyophilized or spray-dried powders, either by themselves or in combination with a suitable powder carrier. Delivery of the composition for inhalation can be mediated by a dose-timing element. The dose-timing element can include a timer, dose counter, timing device, or time indicator that, when incorporated into the device, allows for dose tracking, compliance monitoring, and / or dose triggering for patients receiving the aerosolized pharmaceutical.

[0091] 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, etc. These carriers may be in crystalline or amorphous form, or a mixture of the two.

[0092] Particularly valuable bulking agents include compatible carbohydrates, polypeptides, amino acids, or combinations thereof.Suitable carbohydrates include monosaccharides such as galactose, D-mannose, sorbose, etc.; disaccharides such as lactose, trehalose, etc.; cyclodextrins such as 2-hydroxypropyl-β-cyclodextrin; and polysaccharides such as raffinose, maltodextrin, dextran, etc.; alditols such as mannitol, xylitol, etc.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.

[0093] 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.

[0094] One or more HPV viral proteins or viral-like proteins (i.e., HPV vaccines) of the present 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, avoid the first-pass effect of hepatic metabolism, and avoid exposing the drug to the harsh gastrointestinal (GI) environment. Additional advantages include easy access to the membrane site, allowing the drug to be easily applied, localized, and removed.

[0095] Another embodiment according to the subject invention involves administering an HPV vaccine to a patient by direct or local administration, e.g., injection, into a skin lesion or the area surrounding the skin lesion. This direct administration method may be useful in patients with cancer, particularly skin cancer. This embodiment of the method may also be useful in treating non-cancerous (benign) tumors, or non-cancerous lesions associated with HPV, such as warts, e.g., common warts or condyloma acuminata.

[0096] In one embodiment involving direct injection into or around a lesion, the dosing regimen can include a single dose or multiple doses. For example, as described above, a third dose series can be followed. Alternatively, the physician can administer the first dose followed by subsequent doses as needed (prn) directly into or around the lesion. Split doses of vaccine for any particular single time point are considered a single dose.

[0097] This direct administration embodiment of the present invention can provide beneficial results in treating or minimizing the occurrence, recurrence, and / or progression of cancerous lesions or tumors not associated with HPV infection, such as basal cell carcinoma (BBC) or melanoma, or non-cancerous (benign) tumors.

[0098] In one embodiment of the subject invention, the method is performed without the administration of additional or other immunostimulants or adjuvants simultaneously with, during, or after the therapeutic methods of the invention.

[0099] Alternatively, the subject methods can include administering additional or other immunomodulatory agents, such as immunostimulants or adjuvants, simultaneously 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) Interferon and its analogues; 4) Vitamin A and its analogues, such as Soriatane (retinoids) 5) Imiquimod; 6) ingenol mebutate; and 7) T4 endonuclease 8) Antimetabolites, e.g., 5-fluorouracil, methotrexate 9) Cyclooxygenase inhibitors, e.g., diclofenac

[0100] These agents can be administered locally or systemically in combination with an HPV vaccine as described herein, or simultaneously with an HPV vaccine as described herein, to enhance the effectiveness of treatment. For example, in patients with tumors (skin, lung, etc.) who have been previously immunized with HPV, a combination of interferon and an HPV antigen vaccine may be administered locally. Interferon may also be administered systemically at the same time, or not. This administration can promote the local destruction of tumors or other lesions without the systemic side effects associated with interferon.

[0101] In another aspect, the present invention provides a method for treating cancer in an individual, the method comprising administering to the individual a combination therapy comprising an HPV vaccine and one or more additional chemotherapeutic agents other than the HPV vaccine. The specific dosage and dosing schedule of the additional therapeutic agent may further vary, and the optimal dose, dosing schedule, and route of administration will be determined based on the specific therapeutic agent used.

[0102] Examples of chemotherapeutic agents include alkylating agents, such as thiotepa and cyclosphosphamide; alkyl sulfonates, such as busulfan, improsulfan, and piposulfan; aziridines, such as benzodopa, carboquone, meturedopa, and uredopa; ethyleneimines and methylamelamine (altretamine, triethylenemelamine, triethylene ethylenethiophosphoramide, triethylenethiophosphoramide, and trimethylolomelamine); acetogenins (especially bullatacin and bullatacinone); camptothecin (including the synthetic analog topotecan); bryostatin; kallistatin; CC-1065 (including its adozelesin, carzelesin, and bisceresin synthetic analogs); cryptophycins (especially cryptophycin 1 and cryptophycin 8); dolastatins; duocarmycins (synthetic analogs , KW-2189 and CBI-TMI); eluterobin; pancratistatin; sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, fenesterine, prednisone nitrosoureas, e.g., carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics, e.g., enediyne antibiotics (e.g., calicheamicins, particularly calicheamicin gamma II and calicheamicin phi II (see, e.g., Agnew, Chem. Intl. Ed. Engl., 33:183-186 (1994)); dynemicins (including dynemicin A); bisphosphonates, e.g., clodronate; esperamicin;and neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromomophores), aclacinomycin, actinomycin, authramycin, azaserine, bleomycin, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazomethanesulfonyl esters, Zo-5-oxo-L-norleucine, doxorubicin (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcelomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, potfiromycin, puromycin, queramicin quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites, e.g., methotrexate and 5-fluorouracil (5-FU); folic acid analogues, e.g., denopterin, methotrexate, pteropterin, trimetrexate; purine analogues, e.g., fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogues, e.g., for example, ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens, for example, calsterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals, for example, aminoglutethimide, mitotane, trilostane; folic acid replenishers, for example, florinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestravcil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone;Elformithine; elliptinium acetate; epothilones; etoglucide; gallium nitrate; hydroxyurea; lentinan; lonidamine; maytansinoids, e.g., Maytan; ansamitocins and ansamitocins; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllic acid; 2-ethylhydrazide; procarbazine; razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid; triaziconazole; 2,2',2''-trichlorotriethylamine; trichothecines (especially T-2 toxin, verracurin A, roridin A, and anguidine); urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; ga Cytosine (gacytosine); arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids, such as paclitaxel and doxetaxel; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs, such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopterin; Xeloda; ibandronate; CPT-11; the topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids, such as retinoic acid; capecitabine; and pharmaceutically acceptable salts, acids, or derivatives of any of the foregoing.Also included are anti-hormonal agents that act to regulate or inhibit hormone action on tumors, such as antiestrogens and selective estrogen receptor modulators (SERMs) (e.g., tamoxifen, raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and toremifene (Fareston)); aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands (e.g., 4(5)-imidazole, aminoglutethimide, megestrol acetate, exemestane, formestane, fadrozole, vorozole, letrozole, and anastrozole); and anti-androgens, such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; and pharmaceutically acceptable salts, acids, or derivatives of any of the above.

[0103] Each therapeutic agent in the combination therapy of the invention can be administered in accordance with standard pharmaceutical practice either alone or in a pharmaceutical preparation comprising the therapeutic agent and one or more pharmaceutically acceptable carriers, excipients, and diluents (also referred to herein as a pharmaceutical composition).

[0104] Each therapeutic agent in the combination therapy of the invention can be administered simultaneously (i.e., in the same pharmaceutical agent), concurrently (i.e., in separate pharmaceutical agents, one administered immediately after the other, in either order), or sequentially in either order. Sequential administration is particularly useful when the therapeutic agents in the combination therapy are in different dosage forms (one agent is a tablet or capsule and another is a sterile liquid) and / or are administered on different dosing schedules (e.g., a chemotherapy agent administered at least daily and an HPV vaccine administered less frequently, e.g., once a week, every two weeks, or every three weeks).

[0105] In some embodiments, the HPV vaccine is administered before the administration of the chemotherapeutic agent, while in other embodiments, the HPV vaccine is administered after the administration of the chemotherapeutic agent, hi another embodiment, the HPV vaccine is administered concurrently with the chemotherapeutic agent.

[0106] In some embodiments, at least one of the therapeutic agents in the combination therapy is administered using the same dosing regimen (dosage, frequency, and duration of treatment) as would typically be used if the agent were used as a monotherapy to treat the same cancer. In other embodiments, the patient receives a lower total amount of at least one of the therapeutic agents in the combination therapy than if the agent were used as a monotherapy (e.g., a lower dose, less frequent administration, and / or a shorter duration of treatment).

[0107] Each therapeutic agent in the combination therapy of the present invention can be administered orally or parenterally, including intravenous, intramuscular, intraperitoneal, subcutaneous, rectal, topical, and transdermal routes of administration.

[0108] The combination therapy of the present invention can be used before or after surgery to remove the tumor, and can be used before, during, or after radiation therapy.

[0109] In some embodiments, the combination therapy of the present invention is administered to patients who have not been previously treated with a biologic or chemotherapeutic agent, i.e., are treatment-naive. In other embodiments, the combination therapy is administered to patients who have not achieved a durable response after prior treatment with a biologic or chemotherapeutic agent, i.e., are treatment-experienced.

[0110] The combination therapy of the present invention is typically used to treat tumors large enough to be detected by palpation, visual observation, or by imaging techniques well known in the art, such as MRI, ultrasound, or CAT scan.

[0111] Any commercially available HPV vaccine can be used for direct administration to cancer or HPV-associated lesions. For example, this embodiment of the subject method can include administering directly to or around the lesion a vaccine containing purified inactive viral or viral-like proteins, such as the commercially available GARDASIL®, which is an HPV quadrivalent (types 6, 11, 16, and 18) recombinant vaccine, or GARDASIL® 9, an HPV multivalent (types 16, 18, 31, 33, 45, 52, and 58) recombinant vaccine, or CERVARIX®, an HPV bivalent (types 16 and 18) recombinant vaccine.

[0112] Vaccines useful according to this embodiment of the subject method can include, or can exclude or not include, host cell peptides, polypeptides, or proteins, such as the early antigens E6 or E7, such as the early antigens E6 or E7. The vaccines can be administered to treat benign tumors or HPV-associated lesions in patients of any age, whether unimmunized or previously immunized with an HPV vaccine.

[0113] 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-associated lesions in a patient.

[0114] In another embodiment, the vaccine can be administered to treat or reduce the recurrence rate of cancer, benign tumors, or HPV-associated lesions in patients up to 26 years of age (e.g., infants, children, adolescents, or young adults), or in adult patients 27 years of age or older.

[0115] More specifically, certain preferred embodiments of the present invention include methods for treating a cancerous or non-cancerous tumor or lesion in a patient, comprising administering to the patient a dose of an HPV recombinant vaccine directly to the lesion, tumor, or non-cancerous HPV-associated lesion.

[0116] Alternatively, the method may include the following optional steps: i. administering a second dose of an HPV vaccine directly to the patient's cancerous lesion, benign tumor, or non-cancerous HPV-associated lesion about one month to about three months after the first dose; ii. A subsequent dose of HPV vaccine is administered approximately 5 to 7 months after the first dose. directly into a cancerous lesion, benign tumor, or non-cancerous HPV-associated lesion in a patient; or iii. administering a second dose of the HPV vaccine directly to the patient's cancerous lesion, benign tumor, or non-cancerous HPV-associated lesion about 1 month to about 3 months after the first dose, and administering a subsequent dose of the HPV vaccine directly to the patient's cancerous lesion, benign tumor, or non-cancerous HPV-associated lesion about 5 months to about 7 months after administration of the first dose.

[0117] It will be understood by medical professionals that references to the timing of subsequent doses of vaccine are broad and may vary by day or week. This variation may be due to patient compliance or non-compliance with the dosing schedule, or clinical findings by the treating physician, who may decide to advance (for more aggressive treatment) or delay subsequent doses for medical reasons. However, in general, effective results can be obtained by following a dosing schedule in which the second dose is administered approximately two months after the first dose and the third dose is administered approximately six months after the first dose. Additional (fourth or fifth) doses may also be administered if the physician believes that subsequent administrations may provide benefit to the patient.

[0118] The selection of a dosing regimen (also referred to herein as an administration regimen) depends on several factors, including the serum or tissue turnover rate of the substance in the individual being treated, the severity of symptoms, the immunogenicity of the substance, and the accessibility of target cells, tissues, or organs. Preferably, the dosing regimen maximizes the amount of therapeutic agent delivered to the patient while maintaining an acceptable level of side effects. Therefore, the dosage and frequency of administration depend to some extent on the specific therapeutic agent, the severity of the cancer being treated, and the characteristics of the patient. Guidelines are available for selecting the appropriate dose of antibodies, cytokines, and small molecules. For example, Wawrzynczak (1996) Antibody Therapy, Bios Scientific Pub. Ltd, Oxfordshire, UK; Kresina (ed.) (1991) Monoclonal Antibodies, Cytokines and Arthritis, Marcel Dekker, New York, NY; Bach (ed.) (1993) Monoclonal Antibodies and Peptide Therapy in Autoimmune Diseases, Marcel Dekker,New York,NY;Baert et al.(2003)New Engl.J.Med.348:601-608;Milgrom et al.(1999)New Engl.J.Med.341:1966-1973;Slamon et al.(2001)New Engl.J.Med.344:783-792;Beniaminovitz et al. al.(2000)New Engl.J.Med.342:613-619;Ghosh et al.(2003)New Engl.J.Med.348:24-32;Lipsky et al.(2000)New Engl.J.Med.343:1594-1602;Physicians'Desk Reference 2003(Physicians'Desk Reference,57th Ed);Medical See Economics Company; ISBN:1563634457;57th edition (November 2002).Determining an appropriate dosing regimen can be made by the clinician using, for example, parameters or factors known or suspected in the art to affect treatment, or predicted to affect treatment, and will depend, for example, on the patient's clinical history (e.g., previous treatments), the type and stage of the cancer being treated, and biomarkers of response to one or more therapeutic agents in the combination therapy.

[0119] The HPV viral or viral-like proteins of the invention can be administered by continuous infusion or by administration at intervals such as daily, every other day, three times a week, or once a week, once every two weeks, once every three weeks, once a month, once every two months, etc. 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 (body weight), or more. See, e.g., 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; Portielji et al. (2003) Cancer Immunol. Immunother. 52:133-144.

[0120] In some embodiments, the dosing regimen will involve administering the HPV vaccine at a dose of 1, 2, 3, 5, or 10 mg / kg at intervals of about 14 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) throughout the course of the treatment regimen.

[0121] In other embodiments, the dosing regimen will involve administering the HPV vaccine at doses from about 0.005 mg / kg to about 10 mg / kg using intrapatient dose escalation. In other ascending dose embodiments, the interval between doses will be increasingly shorter, e.g., about 30 days (± 2 days) between the first and second doses, and about 14 days (± 2 days) between the second and third doses. 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 according to the subject invention method is about 0.5 ml of vaccine, e.g., a commercially available vaccine. Each 0.5 ml dose can be administered, e.g., by intralesional injection as a full 0.5 ml bolus, or as divided doses as multiple 0.1-0.2 ml sub-doses to the lesion, the area surrounding the lesion, or both.

[0122] According to certain embodiments, multiple doses of an HPV vaccine can be administered to a subject over a defined time course. This method includes, for example, sequentially administering multiple doses of an HPV vaccine to a subject. As used herein, "sequentially administering" means that each dose of an HPV vaccine is administered to a subject at different time points, for example, on separate days separated by a predetermined interval (e.g., hours, days, weeks, or months). The present invention includes methods that include sequentially administering to a patient a single initial dose of an HPV vaccine, followed by one or more second doses of an HPV vaccine, and optionally followed by one or more third doses of an HPV vaccine.

[0123] The terms "first dose," "second dose," and "third dose" refer to the time sequence of administration of the HPV vaccine. Thus, the "first dose" is the dose administered at the beginning of a treatment regimen (also referred to as the "baseline dose"); the "second dose" is the dose administered after the first dose; and the "third dose" is the dose administered after the second dose. The first, second, and third doses can all contain the same amount of HPV vaccine (e.g., one or more HPV viral proteins or viral-like proteins), but will generally differ from one another in terms of frequency of administration. However, in certain embodiments, the amount of HPV vaccine (e.g., one or more HPV viral proteins or viral-like proteins) contained in the first, second, and / or third dose will differ from one another during the course of treatment (e.g., adjusted upward or downward as needed).

[0124] In an exemplary embodiment, each second and / or third dose is administered 1 to 14 weeks (e.g., 1, 1 1 / 2, 2, 2 1 / 2, 3, 3 1 / 2, 4, 4 1 / 2) after the immediately preceding dose. , 5, 5.5 1 / 2, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5 weeks, or more). In another exemplary embodiment, each second and / or third dose is administered 1 to 14 months (e.g., 1, 1 1 / 2, 2, 2 1 / 2, 3, 3 1 / 2, 4, 4 1 / 2, 5, 5 1 / 2, 6, 6 1 / 2, 7, 7 1 / 2, 8, 8 1 / 2, 9, 9 1 / 2, 10, 10 1 / 2, 11, 11 1 / 2, 12, 12 1 / 2, 13, 13 1 / 2, 14, 14 1 / 2 months, or more) after the immediately preceding dose. The phrase "immediately preceding dose," as used herein, refers to the dose of HPV vaccine that is administered to a patient before the immediately following dose in a series of repeated administrations, in sequence with no intervening doses.

[0125] These methods can include administering any number of second and / or third doses of an HPV vaccine to a patient. For example, in certain embodiments, only one second dose is administered to a patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) second doses are administered to a patient. Similarly, in certain embodiments, only one third dose is administered to a patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) third doses are administered to a patient.

[0126] In embodiments involving multiple second doses, each second dose can be administered at the same frequency as the other second doses. For example, each second dose can be administered to a patient 1 to 3 months after the immediately preceding dose. Similarly, in embodiments involving multiple third doses, each third dose can be administered at the same frequency as the other third doses. For example, each third dose can be administered to a patient 1 to 3 months after the immediately preceding dose. Alternatively, the frequency with which the second and / or third doses are administered to a patient can vary throughout the course of the treatment regimen. The frequency of administration can also be adjusted during the course of treatment by a physician according to the needs of individual patients after clinical examination.

[0127] In certain embodiments, the first dose (e.g., "loading dose") is higher than either or both of the second and third doses. For example, the first dose can be a loading dose that is 1.5x, 2x, 2.5x, 3x, or more greater than the second dose.

[0128] The above method of treatment may be effective in treating skin cancer, and particularly squamous cell carcinoma, in patients, where the skin cancer lesions reduce in size or disappear after three doses of the vaccine.

[0129] Direct or topical administration treatment methods according to the subject invention can also reduce the recurrence rate of cancer, including skin cancer, in patients.

[0130] Direct or topical administration methods may also be effective in reducing the size of or eliminating benign tumors (whether or not associated with HPV infection), or non-cancerous lesions that are associated with HPV, such as warts, including genital warts, e.g., common warts or condyloma acuminata.

[0131] Direct or topical administration methods may also be effective in reducing the recurrence rate of benign tumors (whether or not associated with HPV infection), or non-cancerous lesions that are associated with HPV, such as warts, including genital warts, e.g., common warts or condyloma acuminata.

[0132] HPV bivalent (types 16 and 18) recombinant vaccine, HPV quadrivalent (types 6, 11, 16, and It is a further unexpected result of the present invention to provide a method of eliminating or reducing the size of skin cancers, and in particular squamous cell carcinomas, following direct or topical administration of one or more injections of an HPV (types 16, 18, 31, 33, 45, 52, and 58) recombinant vaccine or an HPV multivalent (types 16, 18, 31, 33, 45, 52, and 58) recombinant vaccine.

[0133] Further unexpected results of the direct or topically targeted administration method of treatment include reducing the size, disappearance, or recurrence rate of skin lesions not associated with HPV infection, such as basal cell carcinoma or melanoma.

[0134] In one embodiment of the subject invention, the direct or local administration method is performed without the administration of additional or other immunostimulants or adjuvants.

[0135] In certain embodiments, the subject methods can include administering additional or other immunomodulatory agents, such as immunostimulants or adjuvants, simultaneously 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) Interferon and its analogues; 4) Vitamin A and its analogues, such as Soriatane (retinoids) 5) Imiquimod; 6) ingenol mebutate; and 7) T4 endonuclease 8) Antimetabolites, e.g., 5-fluorouracil, methotrexate 9) Cyclooxygenase inhibitors, e.g., diclofenac

[0136] These agents can be administered locally or systemically in combination with an HPV vaccine as described herein, or simultaneously with an HPV vaccine as described herein, to enhance the effectiveness of treatment. For example, in patients with tumors (skin, lung, etc.) who have been previously immunized with HPV, a combination of interferon and an HPV antigen vaccine can be administered locally. Interferon can also be administered systemically at the same time, or not. This administration can promote the local destruction of tumors or other lesions without the systemic side effects associated with interferon.

[0137] Topical application can be beneficial for several reasons, including eliminating the risk of infection caused by injection, but also by widespread application over large areas to treat precancerous (actinic keratoses) as well as malignant tumors. Additionally, topical administration can provide cosmetic improvement to the skin by reducing its pigment irregularity, poikiloderma, and scaling appearance.

[0138] Accordingly, one object of the subject invention is to provide a cost-effective, safe, effective, and convenient treatment for reducing or remission of the growth or size of cancer tumors or lesions, including skin cancer lesions such as SCC, BCC, or melanoma tumors or lesions. 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 invention is to provide a cost-effective, effective, and convenient method for reducing the recurrence rate of cancer, including skin cancer lesions.

[0139] A subject method for treating or reducing the recurrence rate of skin cancer comprises administering to a patient one or more doses of an HPV vaccine. In one embodiment, the method involves administering to a patient a first dose of an HPV tetravalent (types 6, 11, 16, and 18) recombinant vaccine, followed approximately two months later by a second dose of an HPV tetravalent (types 6, 11, 16, and 18) recombinant vaccine. The vaccine comprises administering a dose of a tetravalent (types 6, 11, 16, and 18) recombinant HPV vaccine approximately four months after the second dose, and a third dose of a tetravalent (types 6, 11, 16, and 18) recombinant HPV vaccine approximately four months after the second dose. In a preferred embodiment, each dose is 0.5 ml.

[0140] The subject methods can be advantageous in that they can be practiced using commercially available HPV bivalent (types 16 and 18) recombinant vaccines, HPV quadrivalent (types 6, 11, 16, and 18) vaccines, or HPV multivalent (types 16, 18, 31, 33, 45, 52, and 58) recombinant vaccines as therapeutics, rather than or in addition to their use as prophylactic vaccines.

[0141] A prophylactic vaccine is understood to be a vaccine composition administered before exposure to 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 a quadrivalent (types 6, 11, 16, and 18) recombinant HPV vaccine currently sold as a prophylactic vaccine in the United States by Merck & Co., Inc., Whitehouse Station, NJ 08889 USA, and GARDASIL® 9 is a multivalent (types 16, 18, 31, 33, 45, 52, and 58) recombinant HPV vaccine. CERVARIX® is a bivalent (types 16 and 18) recombinant HPV vaccine available from GlaxoSmithKline (Brentford, England).

[0142] The use of commercially available vaccines allows the vaccines to be easily administered by physicians or medical personnel. Furthermore, the use of HPV bivalent (types 16 and 18) recombinant vaccines, HPV quadrivalent (types 6, 11, 16, and 18) recombinant vaccines, or HPV multivalent (types 16, 18, 31, 33, 45, 52, and 58) recombinant vaccines according to the subject methods does not require a second or additional immunostimulant or adjuvant. These commercially available HPV bivalent (types 16 and 18), HPV quadrivalent (types 6, 11, 16, and 18) or HPV multivalent (types 16, 18, 31, 33, 45, 52, and 58) recombinant vaccines are free or substantially free of host cells and / or non-L1 viral peptides, polypeptides, or proteins, such as antigens, E6, or E7.

[0143] Advantageously, the subject methods as described herein can be used to achieve unexpected results in treating cancers, benign tumors, or HPV-associated skin lesions (including skin cancers) associated with HPV infection, or skin cancers not associated with HPV infection.

[0144] Another embodiment of the subject invention includes compositions for carrying out the methods of treatment as described. Compositions comprising a vaccine and additional components, such as one or more active pharmaceutical ingredients, excipients, or diluents, are also included as part of the invention. In the compositions of the invention, the HPV vaccine can be formulated with one or more additional active pharmaceutical ingredients for administration to a patient. The additional active pharmaceutical ingredients can be one or more immunomodulators to modulate the effectiveness of the vaccine, or one or more local anesthetics, such as lidocaine (with or without epinephrine), to reduce patient discomfort during injection.

[0145] One embodiment of the composition of the subject invention comprises a commercially available HPV vaccine formulated with one or more immunomodulatory agents, which may be selected from the group consisting of: 1) Vitamin D and its analogues; 2) sirolimus; 3) Interferon and its analogues; 4) Vitamin A and its analogues, such as Soriatane (retinoids) 5) Imiquimod; 6) ingenol mebutate; and 7) T4 endonuclease 8) Antimetabolites, e.g., 5-fluorouracil, methotrexate 9) Cyclooxygenase inhibitors, e.g., diclofenac

[0146] Compositions comprising an HPV vaccine and at least one immunomodulatory agent can advantageously provide enhanced efficacy of the anti-cancer therapeutic activity of the HPV vaccine.

[0147] One embodiment of the composition of the subject invention comprises a commercially available HPV vaccine formulated with one or more local anesthetics, which may be selected from the group consisting of ester-type local anesthetics, i.e., procaine, benzocaine, chloroprocaine, cocaine, cyclomethycaine, dimethocaine / larocaine, piperocaine, propoxycaine, procaine, proparacaine, and tetracaine, or amide-type local anesthetics, i.e., lidocaine, articaine, bupivacaine, cinchocaine, etidocaine, levobupivacaine, lignocaine, mepivacaine, prilocaine, ropivacaine, and trimecaine.

[0148] An example of a composition of the present invention comprises a 1:1 (v / v) mixture of 0.5 ml of a commercially available HPV vaccine and 0.5 ml of a commercially available lidocaine solution (e.g., 0.5% (w / v), 1% (w / v), or 2% (w / v)). This composition can be thoroughly mixed and injected into a patient for treatment. As will be understood in the art, ratios ranging from 1:10 (v / v) vaccine:anesthetic solution to 10:1 (v / v) vaccine:anesthetic solution can be used.

[0149] The HPV vaccine can also be formulated with one or more excipients or diluents for administration to a patient. The excipients and diluents can include one or more conventional pharmaceutically acceptable ingredients useful in formulating topical preparations, including, but not limited to, bases for preparing creams, emollients, gels, lotions, salves, etc., and can optionally include penetration enhancers, preservatives, release-controlling agents, solubilizers, stabilizers, thickeners, or thinners.

[0150] Solutions for injection may also include one or more buffers, emollients, diluents, pH adjusters, preservatives, solubilizers, stabilizers, etc. Topical compositions containing useful vaccines according to the subject invention may be formulated as conventionally known in the pharmaceutical arts and may include one or more additional ingredients or excipients, such as organic or inorganic solvents (aqueous or non-aqueous), stabilizers, penetration enhancers, buffers, gelling agents, polymers, lubricants, flow agents, creams, waxes, suspending agents, surfactants, etc. The formulations may further include a penetration enhancer such as DMSO. The formulations may be provided as topical solutions, lotions or shake lotions, ointments, creams, gels, foams, transdermal patches, biofrequency chips, powders, solids, sponges, tapes, pastes, tinctures, micelles, or liposomes, etc.

[0151] These compositions can be prepared as products that can be shipped, stored, and used at any time, including at a later time, or can be compounded at the point of care or at a remote location for immediate, as-needed treatment.

[0152] The compositions of the present invention can contain one or more additional active pharmaceutical ingredients without any excipients or diluents, or they can contain one or more active pharmaceutical ingredients and one or more excipients or diluents. It can also be done as follows.

[0153] The compositions of the present invention can include one or more excipients or diluents without any additional active pharmaceutical ingredient, or they can include one or more excipients or diluents and one or more active pharmaceutical ingredients. [Example]

[0154] Example 1 - Skin Cancer The following table provides results by subject method of treatment administered in three groups of patients experiencing relatively high rates of recurrence of skin cancer, including squamous cell carcinoma (SCC) and basal cell carcinoma.

[0155] The data presented below represents the average number of characteristic recurrences of skin cancer per month for the periods before and after receiving the methods of treatment described herein.

[0156] A. Patient 1 Patient 1 received three 0.5 ml doses, including a first 0.5 ml dose, a second 0.5 ml dose two months later, and a third 0.5 ml dose four months after the second dose. At follow-up examination three months after administration of the third dose of the HPV quadrivalent (types 6, 11, 16, and 18) recombinant vaccine, Patient 1 had no recurrence of skin cancer, including both SCC and BCC types, during the three-month period. Prior to the initiation of the treatment regimen, Patient 1 had experienced more than 300 distinct incidences of skin cancer during her lifetime.

[0157] [Table 1]

[0158] B. Patient 2 Patient 2 received three 0.5 ml doses of the HPV quadrivalent (types 6, 11, 16, and 18) recombinant vaccine, including a first 0.5 ml dose, a second 0.5 ml dose two months later, and a third 0.5 ml dose four months after the second dose.

[0159] [Table 2]

[0160] C. Patient 3 Patient 3 received three 0.5 ml doses of the HPV quadrivalent (types 6, 11, 16, and 18) recombinant vaccine, including a first 0.5 ml dose, a second 0.5 ml dose two months later, and a third 0.5 ml dose eight months after the second dose.

[0161] [Table 3]

[0162] As a group, patients who received a regimen of treatment using the quadrivalent (6, 11, 16, and 18) recombinant HPV vaccine each experienced a significant reduction in the number of skin cancer recurrences and improved skin texture and appearance, with reduced scaling and increased overall skin softness.

[0163] Generally, the methods of treatment described herein effectively increase or boost a patient's immune surveillance of skin cells, reducing the likelihood of developing abnormal skin cells that can lead to skin cancer. The methods of the present invention have been shown to treat and prevent the recurrence of SCC, and to significantly reduce the recurrence of BCC. The improved immune surveillance resulting from the treatment methods may also result in a concomitant reduction in the incidence of malignant melanoma.

[0164] In one embodiment, a method of treatment to eliminate or reduce the recurrence rate of skin cancer includes administering an HPV quadrivalent (types 6, 11, 16, and 18) recombinant vaccine in the form of an injection directly to the cancerous tissue or to the area of ​​tissue immediately surrounding the cancerous tissue.

[0165] Example 2 - Breast Cancer A 32-year-old woman (with no history of breast cancer, no family history, and no risk factors) who had previously received the HPV vaccine was diagnosed with metastatic breast cancer. Her primary tumor was approximately 4.1 cells in diameter by ultrasound. These metastatic tumors can double in size in about 12 weeks.

[0166] With the patient's 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 0.5 ml dose, diluted to approximately 3 ml with saline and lidocaine, was administered directly into the tumor approximately two weeks after the first injection, at which point the tumor was considered more difficult to find and had decreased in size for injection.

[0167] Follow-up ultrasound recently showed that the tumor size had decreased to approximately 2.7 centimeters in diameter, representing an approximately 35% decrease in diameter and tumor volume (volume for a sphere is 4 / 3π x radius). 3 This corresponds to a 75% reduction in the oxidative stress (calculated as

[0168] Using a predicted doubling in size, the tumor should increase by approximately 40%, resulting in a tumor diameter of approximately 4.6 centimeters.

[0169] Example 3 - Metastatic basal squamous cell carcinoma A 99-year-old woman presented with metastatic basal squamous cell carcinoma of the lower extremity, which was severe enough that she was referred to a dermatologist for palliative care, and no further options were available other than limb amputation to prevent further spread of the cancer.

[0170] The patient received a single injection of a conventional dose (approximately 0.5 ml) of commercially available HPV vaccine intramuscularly (systemically). Additional standard doses of HPV vaccine were injected into each of two or more sites of larger lesions.

[0171] Within 4 weeks of treatment with the HPV vaccine, these lesions had visually improved substantially, and there was no further spread of the cancer to the lower extremities. The patient is now in remission from further or increased size of the lesions.

[0172] Example 4 - Penile Cancer A 45-year-old HIV-positive man with a 2-year history of squamous cell carcinoma of the penis that had been refractory to various topical and surgical treatments was treated with three equal doses of GARDASIL® administered intramuscularly according to label instructions.

[0173] Within four days, the patient's pain began to decrease, and over the course of several weeks, the pain scale rating decreased from 9-10 to 0 on a 10 scale.

[0174] Modern examination with a confocal microscope shows no evidence of malignancy. Confocal photography can be used to detect cancer on the skin without the need for a biopsy.

[0175] Example 5 - Invasive squamous cell carcinoma An elderly man with a history of renal cell carcinoma and prior chemotherapy presented with an aggressive, rapidly growing, recurrent squamous cell carcinoma on the lower extremity, and was treated with two intralesional injections of GARDASIL® mixed with lidocaine 1% containing epinephrine.

[0176] The patient had previously been vaccinated intramuscularly with GARDASIL®.

[0177] The tumor completely regressed and disappeared shortly after the first treatment without further evidence of malignancy.

[0178] Example 6 - Prostate Cancer Prostate cancer treatment will involve treating patients with intramuscular HPV, and may also involve direct injection into the prostate.

[0179] Example 7 - Glioblastoma multiforme Glioblastoma multiforme treatment would involve treating patients with intramuscular HPV followed by injection directly into the glioblastoma multiforme tumor.

[0180] Example 8 - Cervical Cancer Cervical cancer treatment will involve treating patients with intramuscular HPV, and may also involve injection directly into the cervix.

[0181] Example 9 - Anal cancer Anal cancer treatment will involve treating patients with intramuscular HPV, and may also involve direct injection or topical application to the anus.

[0182] The use of other HPV vaccines in treating cancer or tumors according to the methods described herein is also fully anticipated and within the scope of the present invention.

[0183] While the present invention has been shown in accordance with certain preferred and working embodiments thereof, it will be recognized that departures from this disclosure are considered well within the spirit and scope of the present invention.

Claims

[Claim 1] A pharmaceutical composition for treating cancer, said composition comprising: an injectable composition, the cancer is skin cancer, squamous cell carcinoma, basal cell carcinoma, or penile cancer; HPV (types 6, 11, 16 and 18) recombinant vaccines containing HPV L1 protein; a second active pharmaceutical ingredient which is lidocaine; and A pharmaceutical composition which is a mixture containing a pharmaceutically acceptable carrier.

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