WO2022081604A1 - Composition and method for treating cancer using a vaccine as a first therapueutic active ingredient in combination with a second active ingredient - Google Patents
Composition and method for treating cancer using a vaccine as a first therapueutic active ingredient in combination with a second active ingredient Download PDFInfo
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- WO2022081604A1 WO2022081604A1 PCT/US2021/054622 US2021054622W WO2022081604A1 WO 2022081604 A1 WO2022081604 A1 WO 2022081604A1 US 2021054622 W US2021054622 W US 2021054622W WO 2022081604 A1 WO2022081604 A1 WO 2022081604A1
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- hpv
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Definitions
- the invention relates to treating cancer, including skin cancer or malignant tumor and, more particularly, to a composition and method for treatment, or reducing the incidence or recurrence of, cancer or tumor by administration of a vaccine such as a conventional human papillomavirus (HPV) vaccine, as a first active therapeutic agent in combination with a second active therapeutic agent administered concomitantly or as a fixed- dose combination composition.
- a vaccine such as a conventional human papillomavirus (HPV) vaccine
- Skin cancer consists of three main types, namely, basal-cell carcinoma (BCC), squamous cell carcinoma (SCC) and melanoma.
- BCC basal-cell carcinoma
- SCC squamous cell carcinoma
- melanoma melanoma
- HPV human papillomavirus
- SCC squamous cell carcinoma
- HPV is a DNA virus that can infect certain types of tissues in humans.
- HPV16 and HPV18 HPV is not known to be a cause or to be associated with basal cell carcinoma (BCC) or melanoma.
- Basal-cell carcinoma (BCC) and melanoma are generally accepted as being unrelated to or independent from HPV infection.
- 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 having activity against HPV (types 6, 11, 16, and 18).
- GARDASIL® 9 is another commercially available vaccine marketed for prevention of HPV (types 16, 18, 31, 33, 45, 52, and 58). GARDASIL® is indicated for use in girls and boys from ages 9-26; GARDASIL® 9 is also indicated for use in girls from ages 9-26, and in boys from ages 9-15. [0006] Other vaccines have been produced, as well, for treating subtypes of HPV, particularly HPV16 and HPV18.
- preventive vaccines are typically administered for systemic action, being injected into a patient subcutaneously or intramuscularly (e.g., deltoid), remote from any particular target, such as the cervix. Moreover, they are generally accepted to be effective prior to exposure to HPV and are not commonly known to be effective for treatment after exposure to, or infection with, HPV.
- preventive vaccines include, for example, an improved vaccine composition as described in Chinese Pat App. No. 101890160 (CN’160) comprising certain LI proteins of HPV (as in GARDASIL®), and additional HPV-specific components.
- CN Chinese Pat App. No. 101890160
- Preventive vaccines comprising HPV-type 16 and 18 proteins are also suggested to provide cross-protection against other HPV types, as described in US Pub. No. 2005/0287161.
- Vaccines used for treatment are described. However, these therapeutic vaccines are understood in the art to require more than viral-specific components, such as the HPV LI proteins that comprise the commercially available preventive vaccines, such as GARDASIL®.
- US Pub. No. 2007/0218074 describes the use of a vaccine composition comprising host-cell peptides from an HPV-infected cell.
- the host-cell peptides e.g., the early antigens, E6 or E7, that present on the surface of cells infected with HPV, are fragments of host-cell proteins.
- the criticality of the polypeptides E6 or E7 in a vaccine used in treating certain cancer types is described 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 which includes a 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 a vaccine composition described in US Pub. No. 2011//0070252 which additionally requires Trojan antigen.
- US Pub. No. 2011/0110979 discloses therapeutic use of an HPV vaccine comprising E6 or E7 polypeptides (peptide fragments from host cells infected with HPV).
- US ‘538 describes that E6 and E7 are crucial to induce transformation into HPV-infected cells, and states that a vaccine composition which does not include 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 the US’979 publication additionally requires an immunostimulant or adjuvant.
- New immunotherapy drugs have led to breakthroughs against many cancers but there have been several failures over time.
- CAR T-cells and Immune Checkpoint Inhibitors (e.g., PD-1, PD-L1, and CTLA-4 inhibitors).
- CAR T-cells have not performed well with solid tumors.
- Immune Checkpoint Inhibitors (ICIs) have been used for solid tumors.
- ICIs Immune Checkpoint Inhibitors
- cemiplimab has been approved for advanced squamous cell carcinoma. Patients with complex skin squamous cell carcinomas, such as dystrophic epidermolysis bullosa patients, appear not to respond as well to cemiplimab which appears at least at some level due to immune based dysfunction.
- the subject invention concerns a method for treating a patient having skin cancer or malignant tumor, whether or not associated with or related to human papilloma virus (HPV) infection, said method comprising the steps of: administering to a patient having cancer or in need of treatment of a tumor, skin cancer or other cancerous lesion, a therapeutically effective dose of a commercially available HPV vaccine.
- the vaccine can be administered directly to the cancer, tumor, or lesion, either by direct application onto (topical) 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.
- a method 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 a conventional, approved dose of the vaccine per its label indication.
- the method can comprise: a) administering to a patient 27 years of age or older or a patient previously not immunized with an HPV vaccine, a first dose of an HPV vaccine which is free of host-cell peptide, polypeptide, or protein or a degradant product thereof; b) administering to the patient a second dose of the HPV vaccine about one month to about three months after the first administration; and c) optionally, administering to the patient a third dose of the HPV vaccine about five months to about seven months after the first dose.
- the second or third administrations according to steps b) and c), above can be by injection, or can be by topical administration of a composition comprising the vaccine.
- the second or third administrations of steps b) or c) can include both injection and by topical administration.
- 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.
- the HPV vaccine can be selected from HPV quadrivalent (types 6, 11, 16, and 18) recombinant vaccine comprising HPV LI proteins and HPV multivalent (types 16, 18, 31, 33, 45, 52, and 58) recombinant vaccine comprising HPV LI proteins, and preferably is free or substantially free of host-cell early antigen, e.g., E6 or E7.
- the method does not comprise or is without administering an additional or other immunostimulant or adjuvant.
- the method comprises administering an additional or other immunomodulatory agent, such as an immunostimulant or adjuvant.
- an immunomodulatory agent such as an adjuvant
- an immunomodulatory agent or adjuvant is generally not regarded as a second active ingredient.
- an immunomodulatory agent or adjuvant is distinguished from a second active ingredient used in combination with HPV vaccine in accordance with the subject invention.
- the size of the cancer or HPV-related lesion can be substantially reduced, or completely eliminated.
- the incidence of recurrence of the cancer or HPV-related lesion can be reduced.
- the method can be effective in treating or reducing the incidence of recurrence of a cancer, benign tumor, or HPV-related lesion such as squamous cell carcinoma, basal cell carcinoma, melanoma, verruca vulgaris, or condyloma accuminata.
- the method can comprise a single dose of the vaccine.
- a single dose of the vaccine can be administered topically, or by injection directly into a tumor or systemically to reduce the size or eliminate the tumor.
- a physician or healthcare professional can administer a second or subsequent dose, as needed or as determined by the physician or healthcare professional.
- the patient in need of treatment can be a person previously immunized with the vaccine. In another embodiment, the patient in need of treatment can be a person that has not been previously immunized with the vaccine. [00028]
- Each dose of HPV vaccine administered in the above method steps is preferably about 0.5 ml, and is more preferably 0.5 ml.
- the method can further comprise establishing a positive diagnosis of cancer, tumor, or HPV-related infection prior to administering the first dose of HPV vaccine.
- An alternative embodiment of the method according to the subject invention comprises treating a patient having cancer, tumor, or a human papilloma virus-related (HPV- related) or HPV-unrelated cancerous lesion, wherein the method comprises administering a dose of an HPV vaccine directly to the cancer, tumor, or lesion or an area immediately surrounding the tumor or lesion.
- HPV- related human papilloma virus-related
- HPV-unrelated cancerous lesion comprising a dose of an HPV vaccine directly to the cancer, tumor, or lesion or an area immediately surrounding the tumor or lesion.
- This alternative embodiment of the method according to the subject invention can further comprise the steps of: administering a second dose of the HPV vaccine directly to the tumor or lesion or an area immediately surrounding the tumor or lesion about one month to about three months after administering the first dose; and optionally, administering a third dose of the HPV vaccine directly to the tumor or lesion or an area immediately surrounding the tumor or lesion about five months to about seven months after administering the first dose.
- compositions comprising the vaccine can be topical applications, or can be by injection into the lesion.
- the second dose of HPV vaccine can be administered about two months after administering the first dose and the third dose of HPV vaccine can be administered about six months after administering the first dose.
- the size of the cancer, tumor, or HPV-related lesion can be substantially reduced or completely eliminated.
- the incidence of recurrence of the cancer, tumor, or HPV-related lesion can be reduced.
- the preferred dose of each subsequent administration of HPV vaccine if any, is 0.5 ml.
- the method according to any embodiment of the invention can be used for treating cancer, tumor, or malignant HPV-related lesion, including, but not limited to, a tumor associated or unassociated with HPV infection, squamous cell carcinoma, basal cell carcinoma, and melanoma.
- the method can further comprise establishing a positive diagnosis of cancer, cancerous tumor, or HPV infection-associated or HPV-unrelated malignant lesion prior to administering the first dose of HPV vaccine.
- the direct or local administration of the vaccine is administered by injection, and more preferably the method does not comprise administering an additional or other immunostimulant or adjuvant, with, during or following the administration of the vaccine.
- the subject method can comprise administering an additional or other immunomodulatory agent, e.g., and immunostimulant or adjuvant, with, during or following the administration of the vaccine.
- an additional or other immunomodulatory agent e.g., and immunostimulant or adjuvant
- Yet another embodiment of the invention includes a composition comprising, or a method of cancer treatment using, in combination, a first active agent which is an HPV vaccine and a second active agent which can be an immunotherapy cancer drug, e.g., an Immune Checkpoint Inhibitors, or “ICIs,” such as PD-1, PD-L1, or CTLA-4 inhibitors, or CAR T-cells.
- ICIs Immune Checkpoint Inhibitors
- a second active ingredient in accordance with the subject invention can be a semi-essential amino acid, such as N-acetyl cysteine (NAC.)
- NAC is administered orally, before, during or after injection of the vaccine composition.
- Another second active useful in accordance with the subject invention can be a messenger (m)RNA encoding a cytokine.
- Cytokine-encoding mRNA can produce one or more interleukins, such as IL-12 or IL-15, interferon (e.g., IFN-a), granulocyte-macrophage colonystimulating factor, or the like.
- Interleukins such as IL-12 or IL-15, interferon (e.g., IFN-a), granulocyte-macrophage colonystimulating factor, or the like.
- Effective antitumor activity of these cytokines involves multiple immune cell populations and can be accompanied by intratumoral IFN-y induction, systemic antigen-specific T cell expansion, increased granzyme B + T cell infiltration, and formation of immune memory.
- vaccine and mRNA encoding cytokine are formulated for injection.
- the vaccine and mRNA encoding cytokine can be formulated for intratumoral injection, and can be injected sequentially, concomitantly, or in a fixed-dose combination formulation injected together in a single composition.
- the vaccine can be formulated for topical administration and 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, or the like.
- a topical solution or suspension such as a liquid or spray, gel, cream, salve, ointment, foam or mousse, or the like.
- the subject invention can particularly concern a method for treating a tumor wherein the method comprises administering at least one dose of a commercially available HPV vaccine to a patient having a tumor.
- the subject method has been found to be effective for treating a tumor in glandular tissue, such as breast, pituitary (e.g., invasive pituitary adenoma), prostate, or pancreas.
- This embodiment can include at administering at least one dose of the vaccine directly into the tumor, itself.
- the subject invention can comprise administering at least one dose of the vaccine systemically, e.g., by intramuscular (IM) injection, alone, or in combination with (concomitantly or shortly before or after) the direct administration of the vaccine to the tumor.
- IM intramuscular
- this method can further comprise topical administration of at least one dose of the 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.
- compositions comprising the vaccine are also included as part of the invention.
- the HPV vaccine can be used or formulated with one or more additional active pharmaceutical ingredients for administration to the patient.
- Additional active pharmaceutical ingredients can be one or more immunomodulatory agent for modulating the effect of the vaccine, or one or more local anesthetic agent, e.g., lidocaine (with or without epinephrine), for reducing patient discomfort during the injection.
- a preferred embodiment can include the use of a first active agent which is an HPV vaccine and a second active agent which is an immunotherapy cancer drug, e.g., an Immune Checkpoint Inhibitors such as PD-1, PD-L1, or CTLA-4 inhibitors, or CAR T-cells.
- the first and second active agents can be formulated together in a fixed-dose combination composition, namely, a composition comprising a therapeutically effective amount of an HPV vaccine such as GARDASIL, GARDASIL-9, CERVARIX, or the like, and a therapeutically effective amount of an Immune Checkpoint Inhibitor or CAR T-cells.
- a fixed-dose combination composition namely, a composition comprising a therapeutically effective amount of an HPV vaccine such as GARDASIL, GARDASIL-9, CERVARIX, or the like, and a therapeutically effective amount of an Immune Checkpoint Inhibitor or CAR T-cells.
- the first and second active agents are formulated in an injectable dosage form.
- composition of the invention comprises a 1:1 (v/v) ratio 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)).
- the composition can be thoroughly mixed and injected into a patient for treatment.
- Ratios ranging from 1:10 (v/v) vaccine: anesthetic solution to 10:1 (v/v) vaccine: anesthetic solution can be used, as would be understood in the art.
- the mRNA encoding a cytokine can be admixed with the vaccine for injection or admixed with the vaccine and additional active ingredient, such as a local anesthetic at standard accepted doses.
- the HPV vaccine can also be formulated with one or more excipients or diluents for administration to the patient.
- Excipients and diluents can include one or more conventional pharmaceutically acceptable ingredients useful for formulating topical preparations, including but not limited to a bases for preparing a cream, emollient, gel, lotion, salve, or the like, and can optionally include penetration enhancers, preservatives, release-controlling agents, solubilizers, stabilizers, thickeners or thinners, or the like.
- Solutions for injection can also include one or more buffer, emollient, diluent, pH adjuster, preservative, solubilizer, stabilizer, or the like.
- compositions can be prepared as a manufactured product which can be shipped, stored, and used as needed, including a later time, or can be compounded at the point of care or remotely for immediate single-use treatment.
- a composition of the invention can include one or more additional active pharmaceutical ingredient without an excipient or diluent, or can include one or more active pharmaceutical ingredient and one or more excipient or diluent.
- a composition of the invention can include one or more excipient or diluent without an additional active pharmaceutical ingredient, or can include one or more excipient or diluent and one or more active pharmaceutical ingredient.
- HPV vaccines comprising only HPV antigens (being free of host-cell peptides), to a previously unimmunized patient, or an adult patient aged 27 or greater, to eliminate or reduce the incidence of recurrence of skin cancer, tumor or other malignant skin lesion that is not an HPV-associated lesion, has not been previously described.
- the present invention is directed to a method of treating cancer, benign or cancerous tumor, skin cancer, such as squamous cell carcinoma (SCC), or a cancerous skin lesion associated with or unassociated with human papilloma virus (HPV) infection, and includes treating a tumor originating in glandular tissue, such as breast, pituitary, prostate, or pancreatic tissue.
- skin cancer such as squamous cell carcinoma (SCC)
- HPV human papilloma virus
- One embodiment of a method in accordance with the subject invention comprises the administration of a commercially available HPV vaccine, such as an HPV quadrivalent (types 6, 11, 16, and 18) recombinant vaccine, and a second active agent which is an immunotherapy cancer drug, e.g., an Immune Checkpoint Inhibitors such as PD-1, PD-L1, or CTLA-4 inhibitors, CAR T-cells, a semi-essential amino acid such as N-acetyl cysteine, or an mRNA encoding a cytokine, to a patient having a cancer or tumor.
- a commercially available HPV vaccine such as an HPV quadrivalent (types 6, 11, 16, and 18) recombinant vaccine
- a second active agent which is an immunotherapy cancer drug e.g., an Immune Checkpoint Inhibitors such as PD-1, PD-L1, or CTLA-4 inhibitors, CAR T-cells, a semi-essential amino acid such as N-acetyl cysteine
- the subject method comprises administering at least one dose of the HPV vaccine to a patent that has not been previously immunized with an HPV vaccine, or to an adult patient aged 27 or older.
- a patient previously not immunized with an HPV vaccine is termed an “unimmunized patient” regardless of other immunizations the patient may have received against other conditions or diseases.
- the dosing regimen can be a single administration by direct injection, systemic injection, or topical application, or a combination of any of these administration routes.
- the subject method can comprise multiple (more than one) administration, or multiple (concomitant) administrations by direct injection, systemic injection, or topical application of the vaccine.
- the subject method can also comprise administering in accordance with the conventionally accepted dosing series for a vaccine.
- HPV vaccines are typically administered using a dosing regimen comprising a first dose, a second dose about two months following the first dose, and a third dose about six months following the first dose.
- These second, third, or subsequent administrations can be systemic injection, e.g., conventional intramuscular injection, or can be direct administration to the lesion by intralesional injection or by topical administration.
- the method embodiments of the present invention have surprisingly been found to have beneficial results in treating, or minimizing the occurrence, recurrence, and/or progression of, cancer lesions or benign tumors that are not associated with HPV infection, such as basal-cell carcinoma (BBC) or melanoma.
- BBC basal-cell carcinoma
- the subject method can increase, i.e., boost a patient’s immune response that may manifest clinically as increased surveillance in skin cells to decrease the likelihood of development and progression of abnormal skin cells that produce the skin cancer, particularly, but not exclusively, SCC.
- the method of the invention can interfere with inherent functional activities of viral and virus-like proteins by other mechanisms. This interference would include the complete or partial functional inactivation of viral and virus-like materials altered or activated by exogenous and/or environmental agents such as ultraviolet light.
- HPV human papillomavirus
- 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 (LI (the major capsid protein) and L2 (the minor capsid protein)).
- E1-E2 the “early” region
- LI the major capsid protein
- L2 the minor capsid protein
- an HPV vaccine of the subject invention comprises one or more proteins (e.g., a recombinant LI protein) from one, two, three, four, five, six, seven, eight, nine, ten or more different HPV types.
- proteins e.g., a recombinant LI protein
- Methods of expressing HPV LI proteins and methods of making HPV vaccines are known in the art and described in, e.g., U.S. Patent Nos. 5,820,870 and 6,251,678, which are incorporated herein by reference in their entireties for all purposes.
- the HPV vaccine employed in the subject method contains purified inactive viral or virus-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.
- the HPV vaccine is the commercially available CERVARIX®, which is an HPV bivalent (types 16 and 18) recombinant vaccine.
- a vaccine useful in accordance with this embodiment of the subject method is preferably free of host-cell and/or non-Ll HPV peptide, polypeptide, or protein, such as the early antigens, E6 or E7, which are fragments of host-cell peptides that present on the surface of an HPV-infected cell.
- the vaccine can be administered for treating cancerous or benign tumors, including cancer lesions not associated with HPV infection, cancer (tumors or lesions) associated with HPV infection, benign tumors not associated with HPV infection, or non- cancerous HPV-related lesions in an unimmunized patient.
- the vaccine can be administered to reduce the incidence of recurrence of cancer, a benign tumor, or an HPV-related or HPV-unrelated lesion in an unimmunized patient.
- the vaccine can be administered to treat cancer, benign tumor, or an HPV-related or HPV-unrelated lesion, or reduce the incidence of recurrence thereof, in an adult patient aged 27 or greater.
- one preferred embodiment of the invention comprises a method for the treatment of cancer, benign tumor, or HPV-related lesion, in a patient that is unimmunized, or an adult patient aged 27 or older, comprising the steps of: i. administering to the patient a first dose of an HPV recombinant vaccine free of host-cell peptides, polypeptides, or proteins; ii. administering to the patient a second dose of the HPV recombinant vaccine free of host-cell peptides, polypeptides, or proteins between about one month and about three months after the first dose; and iii. optionally, administering to the patient a third dose of the HPV vaccine free of host-cell peptides, polypeptides, or proteins between about five months to about seven months after administering the first dose.
- the second or third, or subsequent, administration of the vaccine dose can be systemic, e.g., intramuscular injection, or can be by direct administration to the lesion.
- the direct administration of the vaccine composition to the lesion can be by intralesional injection, or can be applied topically to the lesion.
- second, third or subsequent administrations are both systemic and by direct application of vaccine to the lesion.
- Such direct administration to the lesion can be intralesional injection or by topical application of a vaccine composition formulated for topical administration.
- a typical total dose for each administration according to the method of the subject invention is about 0.5 ml of the vaccine, and is preferably 0.5 ml of a commercially available HPV vaccine.
- cancer refers to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth.
- cancer include but are not limited to: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach
- the cancer is carcinoma, lymphoma, leukemia, blastoma, and sarcoma. More particular 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 myeloid leukemia (AML), multiple myeloma, gastrointestinal (tract) 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, stomach cancer, bladder cancer, hepatoma, breast cancer, colon carcinoma, and head and neck cancer.
- a cancer is an HPV- associated
- a particular example of cancer includes 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 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.
- oropharyngeal cancer e.g., cancer of the throat, soft palate, base of tongue, adenoids and/or tonsils).
- Yet another example of cancer includes renal cancer.
- Yet another example of cancer includes liver cancer.
- a cancer is associated with decreased expression of Bcl-2-associated X protein (BAX) and/or Bcl-2 homologous antagonist/killer (BAK1).
- BAX Bcl-2-associated X protein
- BAK1 Bcl-2 homologous antagonist/killer
- a cancer is associated with one or more aberrant mitochondrial activities.
- an HPV vaccine of the invention increases BAX and/or B AK1 expression in a tumor cell and/or promotes apoptosis of the tumor cell.
- the combination of vitamin D and an HPV vaccine of the invention increases BAX and/or BAK1 expression in a tumor cell and/or promotes apoptosis of a tumor cell.
- an HPV vaccine of the invention modulates one or more mitochondrial activities in a tumor cell.
- the above embodiments of a method of treatment according to the subject invention can be efficacious for treating skin cancer in the patient, and particularly squamous cell carcinoma, wherein a skin cancer lesion is reduced in size or eliminated following the three administrations of the vaccine.
- the treatment method in accordance with the subject invention can also reduce the incidence of recurrence of benign tumors or cancer tumors or lesions, including skin cancer, in the patient.
- the treatment method according to the subject invention comprises eliminating, or reducing the size or incidence of recurrence of a cancerous tumor of the breast, eliminating, or reducing the size or incidence of recurrence in a cancerous tumor of the prostate, eliminating, or reducing the size or incidence of recurrence of a cancerous tumor of the pancreas, or eliminating, or reducing the size or incidence of recurrence of a cancerous tumor of the pituitary gland, e.g., invasive pituitary adenoma.
- the method according to the subject invention can also be effective to reduce the size or eliminate an HPV-associated, but non-cancerous, lesion, such as warts, including genital warts, e.g., verruca vulgaris or condyloma accuminata
- Further unexpected results of the subject method of treatment comprise reducing the size of, eliminating, or reducing the incidence of recurrence of skin lesions that are not associated with HPV infection, such as basal cell carcinoma or melanoma.
- an HPV vaccine composition of the present invention is incorporated into pharmaceutical compositions suitable for administration.
- Such compositions typically comprise an HPV viral or viral-like protein and a pharmaceutically acceptable carrier.
- pharmaceutically acceptable carrier is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, 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, use thereof in the compositions is contemplated. Supplementary 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.
- routes of administration 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 include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases, 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.
- 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 dispersion.
- suitable carriers include physiological saline, bacteriostatic water, Cremophor ELTM (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS).
- the composition must be sterile and should be fluid to the extent that easy syringe-ability exists. 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, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof.
- the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion, or by the use of surfactants.
- Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.
- isotonic agents for example, sugars, polyalcohols such as mannitol, sorbitol, sodium chloride in the composition.
- Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.
- Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
- dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above.
- the preferred methods of preparation are vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
- 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, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials 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 com starch; a lubricant such as magnesium stearate or Sterotes; a glidant 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.
- 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 com starch
- a lubricant such as magnesium stearate or Sterotes
- a glidant such as colloidal silicon dioxide
- the compounds are delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.
- a suitable propellant e.g., a gas such as carbon dioxide, or a nebulizer.
- Systemic administration can also be by transmucosal or transdermal means.
- penetrants appropriate to the barrier to be permeated are used in the formulation.
- 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 accomplished through the use of nasal sprays or suppositories.
- the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art.
- the compounds can also be prepared in the form of suppositories (e.g., with conventional suppository bases such as cocoa butter and other glycerides) or retention enemas for rectal delivery.
- suppositories e.g., with conventional suppository bases such as cocoa butter and other glycerides
- retention enemas for rectal delivery.
- the HPV viral or viral-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.
- a controlled release formulation including implants and microencapsulated delivery systems.
- Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, poly anhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art.
- the materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc.
- Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to 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.
- Dosage unit form refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
- the specification for the dosage unit forms of the invention is dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of individuals.
- Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population).
- the dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50/ED50.
- Compounds that exhibit large therapeutic indices are preferred. Although compounds that exhibit toxic side effects may be used, care should be taken to design a delivery system that targets such compounds to the site of affected tissue in order to minimize potential damage to uninfected cells and, thereby, reduce side effects.
- the data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage for use in humans.
- the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity.
- the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
- the therapeutically effective dose can be estimated initially from cell culture assays.
- a dose may be formulated in animal models to achieve a circulating plasma concentration range that includes the EC50 (i.e., the concentration of the test compound which achieves a half-maximal response) as determined in cell culture.
- EC50 i.e., the concentration of the test compound which achieves a half-maximal response
- levels in plasma may be measured, for example, by high performance liquid chromatography.
- compositions can be included in a container, pack, or dispenser together with optional instructions for administration.
- a subject diagnosed with skin cancer can be administered an HPV vaccine composition of the invention by topical administration.
- a patient can be administered a second therapy, e.g., a palliative therapy and/or disease- specific therapy.
- the secondary therapy can be, for example, symptomatic (e.g., for alleviating symptoms), protective (e.g., for slowing or halting disease progression), or restorative (e.g., for reversing the disease process).
- symptomatic therapies can further include another chemotherapeutic agent used as a combination therapy as described further herein.
- an HPV vaccine composition of the invention can be administered by any suitable method.
- topical delivery can refer to the direct application of an HPV vaccine composition to any surface of the body, including the eye, a mucous membrane, surfaces of a body cavity, or to any internal surface.
- Formulations for topical administration may 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 an HPV vaccine composition to the epidermis or dermis of a subject, or to specific strata thereof, or to an underlying tissue.
- Formulations for parenteral administration may include sterile aqueous solutions which may also contain buffers, diluents, and other suitable additives.
- Intraventricular injection may be facilitated by an intraventricular catheter, for example, attached to a reservoir.
- the total concentration of solutes should be controlled to render the preparation isotonic.
- An HPV vaccine composition of the 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 lung where it can be readily absorbed through the alveolar region directly into blood circulation. Pulmonary delivery can be effective both for systemic delivery and for localized delivery to treat diseases of the lungs.
- Pulmonary delivery can be achieved by different approaches, including the use of nebulized, aerosolized, micellular and dry powder-based formulations. Delivery can be achieved with liquid nebulizers, aerosol-based inhalers, and dry powder dispersion devices. Metered-dose devices are preferred. One of the benefits of using an atomizer or inhaler is that the potential for contamination is minimized because the devices are self-contained. Dry powder dispersion devices, for example, deliver drugs that may be readily formulated as dry powders. An HPV vaccine composition may be stably stored as lyophilized or spray-dried powders by itself or in combination with suitable powder carriers.
- the delivery of a composition for inhalation can be mediated by a dosing timing element which can include a timer, a dose counter, time measuring device, or a time indicator which when incorporated into the device enables dose tracking, compliance monitoring, and/or dose triggering to a patient during administration of the aerosol medicament.
- a dosing timing element which can include a timer, a dose counter, time measuring device, or a time indicator which when incorporated into the device enables dose tracking, compliance monitoring, and/or dose triggering to a patient during administration of the aerosol medicament.
- the 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; and the like. These carriers may be in a crystalline or amorphous form or may be a mixture of the two.
- HSA Human Serum Albumin
- bulking agents such as carbohydrates, amino acids, and polypeptides
- pH adjusters or buffers such as sodium chloride
- salts such as sodium chloride
- Bulking agents that are particularly valuable 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-P-cyclodextrin; and polysaccharides, such as raffinose, maltodextrins, dextrans, and the like; alditols, such as mannitol, xylitol, and the like.
- a preferred group of carbohydrates includes lactose, trehalose, raffinose maltodextrins, 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.
- HPV viral or viral-like proteins of the invention i.e., an HPV vaccine
- GI hostile gastrointestinal
- Another embodiment in accordance with the subject invention comprises administering an HPV vaccine administered to a patient by direct or local administration, e.g., injection, into a skin lesion or surrounding area of the lesion.
- This direct administration method can be useful in patients suffering from cancer, particularly skin cancer.
- This embodiment of the method can also be useful for treating non-cancerous (benign) tumors, or non-cancerous lesions associated with HPV, such as warts, e.g., verruca vulgaris or condyloma accuminata.
- the dosing regimen can comprise a single administration or more than one administration.
- a three-administration dosing series as above, can be followed.
- a physician can administer a subsequent dose as needed (prn) following an initial dose directly into or surrounding the lesion. Divided dosing of the vaccine for any particular single time point is considered to be a single administration.
- This direct-administration embodiment of the invention can have beneficial results in treating, or minimizing the occurrence, recurrence, and/or progression of, cancer lesions or tumors such as basal-cell carcinoma (BBC) or melanoma, or non-cancerous (benign) tumors that are not associated with HPV infection.
- cancer lesions or tumors such as basal-cell carcinoma (BBC) or melanoma, or non-cancerous (benign) tumors that are not associated with HPV infection.
- the method is carried out without the administration of an additional or other immunostimulant or adjuvant either with, during, or following the treatment method of the invention.
- the subject method can comprise administering an additional or other immunomodulatory agent, e.g., and immunostimulant or adjuvant, with, during or following the administration of the vaccine.
- additional or other immunomodulatory agent e.g., and immunostimulant or adjuvant
- immunomodulatory agents include:
- Vitamin A and its analogues e.g., Soriatane (a retinoid)
- Antimetabolites e.g., 5 Fluorouracil, Methotrexate
- Cyclooxygenase inhibitors e.g., Diclofenac
- these agents can be given in combination locally or systemically with, or contemporaneous with, the HPV vaccine as described herein, to enhance the effect of the treatment.
- a combination of interferon and HPV antigen vaccine could be given locally.
- Interferon may or may not also be given at the same time systemically. This administration can enhance local destruction of the tumor or other lesion without the systemic side effects associated with interferon.
- the invention provides a method for treating cancer in an individual comprising administering to the individual a combination therapy which comprises an HPV vaccine and one or more additional chemotherapeutic agents other than the HPV vaccine.
- the specific dosage and dosage schedule of the additional therapeutic agent can further vary, and the optimal dose, dosing schedule and route of administration will be determined based upon the specific therapeutic agent that is being used.
- chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziri dines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylolomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including the synthetic analogue topotecan); bryostatin; cally statin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); cryptophycins (particularly cryptophy cin 1 and cryptophy cin 8); dolastatin; duocar
- calicheamicin especially calicheamicin gammall and calicheamicin phill, see, e.g., Agnew, Chem. Inti. Ed. Engl., 33 : 183-186 (1994); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromomophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (including morpholino- doxorubicin,
- paclitaxel and doxetaxel 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; topoisomerase inhibitor RFS 2000; difluoromethylormthine (DMFO); retinoids such as retinoic acid; capeci tabine; and pharmaceutically acceptable salts, acids or derivatives of any of the above.
- platinum analogs such as cisplatin and carboplatin
- vinblastine platinum
- anti-hormonal agents that act to regulate or inhibit hormone action on tumors
- SERMs selective estrogen receptor modulators
- aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)- imidazoles, aminoglutethimide, megestrol acetate, exemestane, formestane, fadrozole, vorozole, letrozole, and anastrozole
- anti- androgens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; and pharmaceutically acceptable salts, acids or derivatives of any of the above.
- a method of treatment according to the invention comprises administering a first active agent being an HPV vaccine as described herein, and a second active agent which is an Immune Checkpoint Inhibitor or CAR T-cells.
- An Immune Checkpoint Inhibitor can include a Programed Death 1 (PD-1) inhibitor; or a Programed Death 1 Ligand (PD-1L) inhibitor. Examples of PD-1 and PD-1L inhibitors are:
- CTLA-4 Cytotoxic T-lymphocyte- Associated Protein 4
- CAR T-cells is the abbreviation for Chimeric Antigen Receptor T cells and can include a bispecific antibody, such as Catumaxomab, or a monoclonal antibody, such as Campath, Brutuximab, Vismodigib, or the BRAF inhibitors, Vemurafenib, Dabrfenib, or ecorafenib.
- a bispecific antibody such as Catumaxomab
- a monoclonal antibody such as Campath, Brutuximab, Vismodigib, or the BRAF inhibitors, Vemurafenib, Dabrfenib, or ecorafenib.
- an HPV vaccine being inhibitory on multiple levels, can advantageously boost eh efficacy of the immune-based therapy.
- Vaccination to HPV infection results in resistance to a naturally occurring, commonly encountered, infectious agent and can unexpectedly provide an immune response more complex than inhibition of a select few pathways as produced by immune-based therapies, used alone.
- the response to vaccine seen in elderly patients indicates an immune based effect in subjects with failing immune surveillance function.
- Intralesional injection of HPV vaccine also indicates a direct local effect on treated tumors.
- Another second active ingredient useful for administration in combination with HPV vaccine to a patient having cancer in accordance with the subject invention can be a semiessential amino acid, such as N-acetyl cysteine (NAC.)
- NAC N-acetyl cysteine
- the NAC is administered orally, before, during or after dosing of the vaccine composition via injection.
- NAC is typically administered as an oral dosage form, 600-1200 mg per day, preferably 600 mg administered orally, BID, and can be administered long-term, e.g., for the life of the patient, due to its low toxicity.
- the NAC can be administered following a complete series of HPV vaccine injections.
- NAC can be prescribed for administration prior to the patient starting a complete series of HPV vaccine injections.
- the time prior to HPV vaccine administration is not critical and can be 1 day up to one year prior to the first HPV vaccine injection.
- Another alternative is to start the patient on NAC therapy simultaneous with the initiation of the HPV vaccine injection series, for example, initiating daily dosing of NAC on the first day of injecting a first HPV vaccine injection or at any time during the course of the series of HPV vaccine injections.
- HPV vaccine in another embodiment, can be administered in combination with administration of an mRNA encoding a cytokine.
- Cytokineencoding mRNA can produce one or more interleukins, such as IL-12 or IL-15, interferon (e.g., IFN-a), granulocyte-macrophage colony-stimulating factor, or the like.
- Interleukins such as IL-12 or IL-15, interferon (e.g., IFN-a), granulocyte-macrophage colony-stimulating factor, or the like.
- Effective antitumor activity of these cytokines involves multiple immune cell populations and can be accompanied by intratumoral IFN-y induction, systemic antigen-specific T cell expansion, increased granzyme B+ T cell infiltration, and formation of immune memory.
- vaccine and mRNA encoding cytokine are formulated for injection.
- the vaccine and mRNA encoding cytokine can be formulated for intratumoral injection, and can be injected sequentially, concomitantly, or in a fixed-dose combination formulation injected together in a single composition.
- Each therapeutic agent in a combination therapy of the invention may be administered either alone or in a medicament (also referred to herein as a pharmaceutical composition or a fixed-dose combination product) which comprises the therapeutic agent and one or more pharmaceutically acceptable carriers, excipients, and diluents, according to standard pharmaceutical practice.
- a medicament also referred to herein as a pharmaceutical composition or a fixed-dose combination product
- the therapeutic agent comprises the therapeutic agent and one or more pharmaceutically acceptable carriers, excipients, and diluents, according to standard pharmaceutical practice.
- Each therapeutic agent in a combination therapy of the invention may be administered simultaneously (i.e., in the same medicament), concurrently (i.e., in separate medicaments administered one right after the other in any order) or sequentially in any 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 agent is a sterile liquid) and/or are administered on different dosing schedules, e.g., a chemotherapeutic that is administered at least daily and an HPV vaccine that is administered less frequently, such as once weekly, once every two weeks, or once every three weeks.
- the HPV vaccine is administered before 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 the chemotherapeutic agent.
- At least one of the therapeutic agents in the combination therapy is administered using the same dosage regimen (dose, frequency, and duration of treatment) that is typically employed when the agent is used as monotherapy for treating the same cancer.
- the patient receives a lower total amount of at least one of the therapeutic agents in the combination therapy than when the agent is used as monotherapy, e.g., smaller doses, less frequent doses, and/or shorter treatment duration.
- Each therapeutic agent in a combination therapy of the invention can be administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal, topical, and transdermal routes of administration.
- a combination therapy of the invention may be used prior to or following surgery to remove a tumor and may be used prior to, during or after radiation therapy.
- a combination therapy of the invention is administered to a patient who has not been previously treated with a biotherapeutic or chemotherapeutic agent, i.e., is treatment-naive.
- the combination therapy is administered to a patient who failed to achieve a sustained response after prior therapy with a biotherapeutic or chemotherapeutic agent, i.e., is treatment-experienced.
- a combination therapy of the invention is typically used to treat a tumor that is large enough to be found by palpation, visual observation or by imaging techniques well known in the art, such as MRI, ultrasound, or CAT scan.
- any commercially available HPV vaccine can be employed for administration directly to a cancer or HPV-related lesion.
- this embodiment of the subject method can comprise directly administering into or surrounding a lesion, a vaccine comprising purified inactive viral or virus-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.
- GARDASIL® is an HPV quadrivalent (types 6, 11, 16, and 18) recombinant vaccine or GARDASIL® 9
- HPV multivalent types 16, 18, 31, 33, 45, 52, and 58
- CERVARIX® an HPV bivalent (types 16 and 18) recombinant vaccine.
- a vaccine useful in accordance with this embodiment of the subject method can include host-cell peptides, polypeptides, or proteins, such as the early antigens, E6 or E7 or exclude or be free of host-cell peptides, polypeptides, or proteins, such as the early antigens, E6 or E7.
- the vaccine can be administered for treating cancer, a benign tumor, or HPV-related lesion in a patient of any age, whether an unimmunized patient or a patient previously immunized with an HPV vaccine.
- the vaccine can be directly or locally administered into or surrounding a lesion or tumor to reduce the incidence of recurrence of cancer, benign tumor, or an HPV-related lesion in a patient.
- the vaccine can be administered to treat cancer, benign tumor, or an HPV-related lesion, or reduce the incidence of recurrence thereof, in a patient up to 26 years old (e.g., an infant, a child, an adolescent or a young adult) or, alternatively, an adult patient aged 27 or greater.
- one preferred embodiment of the invention comprises a method for the treatment of cancerous or non-cancerous tumor or lesion in a patient comprising the step of administering to the patient a dose of an HPV recombinant vaccine directly to the lesion, tumor, or non-cancerous HPV-related lesion.
- the method can comprise the following optional steps: i. administering directly to a cancer lesion, benign tumor, or non-cancerous HPV-related lesion of a patient a second dose of the HPV vaccine between about one month and about three months after the first dose; ii. administering directly to a cancer lesion, benign tumor, or non-cancerous HPV-related lesion of a patient a subsequent dose of the HPV vaccine between about five months to about seven months after administering the first dose; or iii.
- a dosage regimen (also referred to herein as an administration regimen) depends on several factors, including the serum or tissue turnover rate of the entity, the level of symptoms, the immunogenicity of the entity, and the accessibility of the target cells, tissue or organ in the individual being treated.
- a dosage regimen maximizes the amount of therapeutic agent delivered to the patient consistent with an acceptable level of side effects.
- the dose amount and dosing frequency depends in part on the particular therapeutic agent, the severity of the cancer being treated, and patient characteristics.
- Guidance in selecting appropriate doses of antibodies, cytokines, and small molecules is available. See, e.g., Wawrzynczak (1996) Antibody Therapy, Bios Scientific Pub.
- Determination of the appropriate dosage regimen may be made by the clinician, e.g., using parameters or factors known or suspected in the art to affect treatment or predicted to affect treatment, and will depend, for example, the patient’s clinical history (e.g., previous therapy), the type and stage of the cancer to be treated and biomarkers of response to one or more of the therapeutic agents in the combination therapy.
- HPV viral or viral-like proteins of the invention may be administered by continuous infusion, or by doses at intervals of, e.g., daily, every other day, three times per week, or one time each week, two weeks, three weeks, monthly, bimonthly, etc.
- a total weekly dose is generally at least 0.05 pg/kg, 0.2 pg/kg, 0.5 pg/kg, 1 pg/kg, 10 pg/kg, 100 pg/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.
- the dosing regimen will comprise 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 one week ( ⁇ 2 days), two weeks ( ⁇ 2 days), three weeks ( ⁇ 2 days) or four weeks ( ⁇ 2 days) throughout the course of treatment.
- the dosing regimen will comprise administering the HPV vaccine at a dose of from about 0.005 mg/kg to about 10 mg/kg, with intra-patient dose escalation.
- the interval between doses will be progressively shortened, e.g., about 30 days ( ⁇ 2 days) between the first and second dose, about 14 days ( ⁇ 2 days) between the second and third doses.
- 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 local administration according to the method of the subject invention is about 0.5 ml of the vaccine, e.g., of a commercially available vaccine.
- Each 0.5 ml dose can be administered, e.g., by intralesional injection, as a bolus of the entire 0.5 ml or can be administered as a divided dose as a plurality of 0.1 -0.2 ml partial administrations into the lesion, an area surrounding the lesion, or both.
- multiple doses of an HPV vaccine may be administered to a subject over a defined time course.
- the methods include, for example, sequentially administering to a subject multiple doses of an HPV vaccine.
- sequentially administering means that each dose of an HPV vaccine is administered to the subject at a different point in time, e.g., on different days separated by a predetermined interval (e.g., hours, days, weeks, or months).
- the present invention includes methods which comprise sequentially administering to the patient a single initial dose of an HPV vaccine, followed by one or more secondary doses of an HPV vaccine, and optionally followed by one or more tertiary doses of an HPV vaccine.
- the terms “initial dose,” “secondary doses,” and “tertiary doses,” refer to the temporal sequence of administration of an HPV vaccine.
- the “initial dose” is the dose which is administered at the beginning of the treatment regimen (also referred to as the “baseline dose”);
- the “secondary doses” are the doses which are administered after the initial dose;
- the “tertiary doses” are the doses which are administered after the secondary doses.
- the initial, secondary, and tertiary doses may all contain the same amount of an HPV vaccine (e.g., of the one or more HPV viral or viral-like proteins), but will generally differ from one another in terms of frequency of administration.
- the amount of an HPV vaccine (e.g., of the one or more HPV viral or viral-like proteins) contained in the initial, secondary and/or tertiary doses will vary from one another (e.g., adjusted up or down as appropriate) during the course of treatment.
- each secondary and/or tertiary dose is administered 1 to 14 (e.g., 1, 116, 2, 2%, 3, 316, 4, 416, 5, 516, 6, 616, 7, 716, 8, 816, 9, 916, 10, 1016, 11, 1116, 12, 1216, 13, 1316, 14, 1416, or more) weeks after the immediately preceding dose.
- 1 to 14 e.g., 1, 116, 2, 2%, 3, 316, 4, 416, 5, 516, 6, 616, 7, 716, 8, 816, 9, 916, 10, 1016, 11, 1116, 12, 1216, 13, 1316, 14, 1416, or more
- each secondary and/or tertiary dose is administered 1 to 14 (e.g., 1, 116, 2, 216, 3, 316, 4, 416, 5, 516, 6, 616, 7, 716, 8, 816, 9, 916, 10, 1016, 11, 1116, 12, 1216, 13, 1316, 14, 1416, or more) months after the immediately preceding dose.
- the phrase “the immediately preceding dose,” as used herein, means, in a sequence of multiple administrations, the dose of an HPV vaccine which is administered to a patient prior to the administration of the very next dose in the sequence with no intervening doses.
- These methods may include administering to a patient any number of secondary and/or tertiary doses of an HPV vaccine.
- any number of secondary and/or tertiary doses of an HPV vaccine may include administering to a patient any number of secondary and/or tertiary doses of an HPV vaccine.
- only a single secondary dose is administered to the patient.
- two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) secondary doses are administered to the patient.
- only a single tertiary dose is administered to the patient.
- two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) tertiary doses are administered to the patient.
- each secondary dose may be administered at the same frequency as the other secondary doses. For example, each secondary dose may be administered to the patient 1 to 3 months after the immediately preceding dose.
- each tertiary dose may be administered at the same frequency as the other tertiary doses. For example, each tertiary dose may be administered to the patient 1 to 3 months after the immediately preceding dose.
- the frequency at which the secondary and/or tertiary doses are administered to a patient can vary over the course of the treatment regimen. The frequency of administration may also be adjusted during the course of treatment by a physician depending on the needs of the individual patient following clinical examination.
- the initial dose (e.g., a “loading dose”) is higher than either or both of the secondary and tertiary doses.
- the initial dose can be a loading dose, which is 1.5x, 2x, 2.5x, 3x or more, greater than the secondary dose.
- the above direct or local administration method of treatment can be efficacious for treating skin cancer in the patient, and particularly squamous cell carcinoma, wherein a skin cancer lesion is reduced in size or eliminated following the three administrations of the vaccine.
- the direct or local administration treatment method according to the subject invention can also reduce the incidence of recurrence of cancer, including skin cancer, in the patient.
- the direct or local administration method can also be effective to reduce the size or eliminate a benign tumor, whether or not associated with HPV infection, or an HPV- associated, but non-cancerous, lesion, such as warts, including genital warts, e.g., verruca vulgaris or condyloma accuminata.
- the direct or local administration method can also be effective to reduce the incidence of recurrence of a benign tumor, whether or not associated with HPV infection, or an HPV-associated, but non-cancerous, lesion, such as warts, including genital warts, e.g., verruca vulgaris or condyloma accuminata.
- HPV bivalent types 16 and 18
- HPV quadrivalent types 6, 11, 16, and 18
- HPV multivalent types 16, 18, 31, 33, 45, 52, and 58
- Further unexpected results of the subject direct or local administration method of treatment comprise reducing the size of, eliminating, or reducing the incidence of recurrence of skin lesions that are not associated with HPV infection, such as basal cell carcinoma or melanoma.
- the direct or local administration method is carried out without the administration of an additional or other immunostimulant or adjuvant.
- the subject method can comprise administering an additional or other immunomodulatory agent, e.g., and immunostimulant or adjuvant, with, during or following the administration of the vaccine.
- immunomodulatory agents useful as part of the subject method include:
- Vitamin A and its analogues e.g., Soriatane (a retinoid)
- Antimetabolites e.g., 5 Fluorouracil, Methotrexate
- cyclooxygenase inhibitors e.g., Diclofenac [000150]
- these agents can be given in combination locally or systemically with, or contemporaneous with, the HPV vaccine as described herein, to enhance the effect of the treatment.
- a combination of interferon and HPV antigen vaccine could be given locally.
- Interferon may or may not also be given at the same time systemically. This administration can enhance local destruction of the tumor or other lesion without the systemic side effects associated with interferon.
- Topical application can be beneficial for several reasons, including the elimination of infection risk caused by injection, but can also be advantageous by wide-spread application over large areas in order to treat precancerous (actinic keratoses) as well as malignant tumors.
- topical administration can provide cosmetic enhancement of the skin, by decreasing that appearance of pigment irregularities, poikiloderma, and scaling.
- the subject method of treating or reducing the incidence of recurrence of skin cancer comprises administering an HPV vaccine in one or more doses to a patient.
- the method includes administration of a first dose of HPV quadrivalent (types 6, 11, 16, and 18) recombinant vaccine to a patient, a second dose of HPV quadrivalent (types 6, 11, 16, and 18) recombinant vaccine approximately two months thereafter, and a third dose of HPV quadrivalent (types 6, 11, 16, and 18) recombinant vaccine approximately four months after the second dose.
- each dose is 0.5 ml.
- the subject method can be advantageous in that it can be performed using a commercially available HPV bivalent (types 16 and 18) recombinant vaccine, HPV quadrivalent (types 6, 11, 16, and 18) vaccine or HPV multivalent (types 16, 18, 31, 33, 45, 52, and 58) recombinant vaccine as a therapeutic agent rather than or in addition to its use as a preventive vaccine.
- HPV bivalent (types 16 and 18) recombinant vaccine HPV quadrivalent (types 6, 11, 16, and 18) vaccine or HPV multivalent (types 16, 18, 31, 33, 45, 52, and 58) recombinant vaccine as a therapeutic agent rather than or in addition to its use as a preventive vaccine.
- HPV human papilloma virus
- Preventive vaccines for protection against or prevention of HPV infection and associated cancers are commercially available are therefore known to be safe.
- GARDASIL® is an HPV quadrivalent (types 6, 11, 16, and 18) recombinant vaccine and GARDASIL® 9, is an HPV multivalent (types 16, 18, 31, 33, 45, 52, and 58) recombinant vaccine currently marketed as a preventive vaccine in the United States by Merck & Co., Inc. Whitehouse Station, NJ 08889 USA.
- CERVARIX® is an HPV bivalent (types 16 and 18) recombinant vaccine available from GlaxoSmithKline (Brentford, England).
- the vaccine can be readily accessed by a physician or healthcare practitioner.
- an HPV bivalent (types 16 and 18) recombinant vaccine, an HPV quadrivalent (types 6, 11, 16, and 18) recombinant vaccine or HPV multivalent (types 16, 18, 31, 33, 45, 52, and 58) recombinant vaccine in accordance with the subject method do not require secondary or additional immunostimulants or adjuvants.
- 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-cell and/or non-Ll viral peptides, polypeptides, or proteins, such as the antigens, E6 or E7.
- the unexpected result of treating cancer, benign tumor, or HPV-related skin lesions, including skin cancers that are associated with HPV infection or skin cancers that are not associated with HPV infection can be achieved using the subject method as described herein.
- compositions for carrying out a method of treatment as described.
- Compositions comprising the vaccine and an added ingredient - one or more of an active pharmaceutical ingredients, excipient, or diluents, for example - are also included as part of the invention.
- HPV vaccine can be formulated with one or more additional active pharmaceutical ingredients for administration to the patient.
- Additional active pharmaceutical ingredients can be one or more immunomodulatory agent for modulating the effect of the vaccine, or one or more local anesthetic agent, e.g., lidocaine (with or without epinephrine), for reducing patient discomfort during the injection.
- One embodiment of a composition of the subject invention comprises commercially available HPV vaccine formulated with one or more immunomodulatory agent.
- the one or more immunomodulatory agent can be selected from the group consisting of:
- Vitamin A and its analogues e.g., Soriatane (a retinoid)
- Antimetabolites e.g., 5 Fluorouracil, Methotrexate
- cyclooxygenase inhibitors e.g., Diclofenac
- a composition comprising HPV vaccine and at least one immunomodulatory agent can advantageously provide enhanced effect of the anti-cancer therapeutic activity of the HPV vaccine.
- a composition according to the invention comprises HPV vaccine formulated with an mRNA encoding a cytokine in a single, fixed dose combination composition.
- composition of the subject invention comprises commercially available HPV vaccine formulated with one or more local anesthetic agent.
- the one or more local anesthetic agent can be selected from the group consisting of: the ester local anesthetics, namely procaine, benzocaine, chloroprocaine, cocaine, cyclomethycaine, dimethocaine/larocaine, piperocaine, propoxycaine, procaine, proparacaine, and tetracaine, or the amide local anesthetics, namely, lidocaine, articaine, bupivacaine, cinchocaine, etidocaine, levobupivacaine, lignocaine, mepivacaine, prilocaine, ropivacaine, and trimecaine.
- the ester local anesthetics namely procaine, benzocaine, chloroprocaine, cocaine, cyclomethycaine, dimethocaine/larocaine, piperocaine, propoxycaine,
- composition of the invention comprises a 1:1 (v/v) ratio 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)).
- the composition can be thoroughly mixed and injected into a patient for treatment. Ratios ranging from 1:10 (v/v) vaccine: anesthetic solution to 10:1 (v/v) vaccine: anesthetic solution can be used, as would be understood in the art.
- One embodiment of a composition of the subject invention comprises commercially available HPV vaccine formulated in a fixed-dose combination product with one or more anti-cancer agent selected from the group consisting of an Immune Checkpoint Inhibitors and CAR T-cells.
- Immune Checkpoint Inhibitors of the invention include, but are not limited to, the PD-1/PD-L1 Inhibitors Cemiplimab, Atezolizumab, Avelumab, Bavencio, Durvalumab, Imfinzi, Keytruda, Nivolumab, Opdivo, Pembrolizumab, and Tecentriq, or can include the CRLA-4 inhibitor Ipilumumab.
- bispecific antibodies such as Catumaxomab
- monoclonal antibodies such as Campath, Brutuximab, or Vismodigib
- BRAF inhibitors Vemurafenib, Dabrfenib, or ecorafenib.
- HPV vaccine and second active agent such as Immune Checkpoint Inhibitors and CAR T-cells can also be formulated with one or more excipients or diluents for administration to the patient.
- Solutions for injection can also include one or more buffer, emollient, diluent, pH adjuster, preservative, solubilizer, stabilizer, or the like.
- Excipients and diluents can include one or more conventional pharmaceutically acceptable ingredients useful for formulating topical preparations, including but not limited to, a base for preparing a cream, emollient, gel, lotion, salve, or the like, and can optionally include penetration enhancers, preservatives, release-controlling agents, solubilizers, stabilizers, thickeners or thinners, or the like.
- a topical composition comprising a vaccine useful in accordance with the subject invention can be formulated as is conventionally known in the pharmaceutical arts, and can comprise one or more additional ingredients or excipients, such as an organic or inorganic solvent (aqueous or non-aqueous), stabilizing agent, penetration enhancer, buffer, gelling agent, polymeric agent, lubricant, glidant, cream, wax, suspending agent, surfactant, or the like.
- the formulation can further include a penetration enhancer, such as DMSO.
- the formulation can be provided as a topical solution, lotion or shake lotion, ointment, cream, gel, foam, transdermal patch, biofrequency chip, powder, solid, sponge, tape, paste, tincture, micelle or liposome, or the like.
- These compositions can be prepared as a manufactured product which can be shipped, stored, and used as needed, including a later time, or can be compounded at the point of care or remotely for immediate single-use treatment.
- a composition of the invention can include one or more additional active pharmaceutical ingredient without an excipient or diluent, or can include one or more active pharmaceutical ingredient and one or more excipient or diluent.
- a composition of the invention can include one or more excipient or diluent without an additional active pharmaceutical ingredient, or can include one or more excipient or diluent and one or more active pharmaceutical ingredient
- Example 1 skin cancer
- SCC squamous cell carcinoma
- Patient 1 was administered three 0.5ml doses, including a first 0.5ml dose, a second 0.5ml dose two months later, and a third 0.5ml dose four months after the second dose.
- a follow-up exam three months after administration of the third dose of HPV quadrivalent (types 6, 11, 16, and 18) recombinant vaccine, Patient 1 had experienced zero recurrences of skin cancer, including both SCC and BCC types, during the three-month period.
- Prior to commencement of the treatment method Patient 1 had more than 300 distinctive occurrences of skin cancer during his lifetime.
- Patient 2 was administered three 0.5ml doses of HPV quadrivalent (types 6, 11, 16, and 18) recombinant vaccine, including a first 0.5 ml dose, a second 0.5ml dose two months later, and a third 0.5ml dose four months after the second dose.
- HPV quadrivalent types 6, 11, 16, and 18
- Patient 3 was administered three 0.5ml doses of HPV quadrivalent (types 6, 11, 16, and 18) recombinant vaccine, including a first 0.5ml dose, a second 0.5ml dose two months later, and a third 0.5ml dose eight months after the second dose.
- HPV quadrivalent types 6, 11, 16, and 18
- the method of treatment described herein serves to effectively increase, i.e., boost, the patient’s immune surveillance in skin cells in order to decrease the likelihood of a development of abnormal skin cells that produce the skin cancer.
- the method of the present invention has been shown to treat and prevent recurrence of SCC, and to significantly reduce recurrence of BCC. It is also possible that the increase in immune surveillance, as a result of the treatment method, will concomitantly decrease the incidence of malignant melanoma.
- the method of treatment for eliminating or reducing the incidence of recurrence of skin cancer includes administering the HPV quadrivalent (types 6, 11, 16, and 18) recombinant vaccine in the form of an injection directly into the cancerous tissue or an area of tissue immediately surrounding the cancerous tissue.
- HPV quadrivalent types 6, 11, 16, and 18
- the tumor was directly injected with a standard initial dose (about 0.5 ml) of a commercially available HPV vaccine.
- a second dose 0.5 ml, diluted with saline and lidocaine to about 3 ml, was directly administered to the tumor about two weeks after the first injection. At that time, it was harder to find the tumor to inject, and was believed to have been reduced in size.
- the tumor should have increased by about 40%. to a tumor diameter of about 4.6 centimeters.
- a single injection of a conventional dose (about 0.5 ml) of a commercially available HPV vaccine was administered to the patient, intramuscularly (systemically). Additional standard doses of the HPV vaccine were injected into each of two or more sites of the larger lesions.
- the lesions were substantially visually improved, and the cancer had no further spreading on the leg. The patient is currently in remission from further or increased size of the lesions.
- Example 5 aggressive squamous cell carcinoma
- Example 6 prostate cancer
- Prostate cancer treatment would involve treating the patient with intramuscular HPV, and can also include direct injection into the prostate.
- Glioblastoma multiforme treatment would involve treating the patient with intramuscular HPV, and then direct injection into a tumor of glioblasotma multiforme.
- Cervical cancer treatment would involve treating the patient with intramuscular HPV, and can also include direct injection into the cervix.
- Example 9 anal cancer
- Anal cancer treatment would involve treating the patient with intramuscular HPV, and can also include direct injection or topical application to the anus.
- the patient is a 74-year old woman who has an approximately 20 year history of more than 70 keratinocyte carcinomas.
- the patient received the Gardasil vaccine in a series of three doses. This course was repeated two years later.
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KR1020237016232A KR20230117106A (ko) | 2020-10-12 | 2021-10-12 | 제1 치료 활성 성분으로서의 백신을 제2 활성 성분과 조합하여 사용하여 암을 치료하기 위한 조성물 및 방법 |
AU2021360676A AU2021360676A1 (en) | 2020-10-12 | 2021-10-12 | Composition and method for treating cancer using a vaccine as a first therapueutic active ingredient in combination with a second active ingredient |
ES21880926T ES2962700T1 (es) | 2020-10-12 | 2021-10-12 | Composición y método para tratar el cáncer, usando una vacuna como un primer ingrediente activo terapéutico en combinación con un segundo ingrediente activo |
MX2023004285A MX2023004285A (es) | 2020-10-12 | 2021-10-12 | Composicion y metodo para tratar el cancer utilizando una vacuna como primer principio activo terapeutico en combinacion con un segundo principio activo. |
CA3195478A CA3195478A1 (en) | 2020-10-12 | 2021-10-12 | Composition and method for treating cancer using a vaccine as a first therapeutic active ingredient in combination with a second active ingredient |
EP21880926.7A EP4225351A1 (en) | 2020-10-12 | 2021-10-12 | Composition and method for treating cancer using a vaccine as a first therapueutic active ingredient in combination with a second active ingredient |
DE21880926.7T DE21880926T1 (de) | 2020-10-12 | 2021-10-12 | Zusammensetzung und verfahren zur behandlung von krebs mit einem impfstoff als erster therapeutischer wirkstoff in kombination mit einem zweiten wirkstoff |
PL21880926.7T PL4225351T1 (pl) | 2020-10-12 | 2021-10-12 | Kompozycja i sposób leczenia nowotworu z zastosowaniem szczepionki jako pierwszego składnika terapeutycznie czynnego w połączeniu z drugim składnikiem czynnym |
US18/248,861 US20230414741A1 (en) | 2014-10-24 | 2021-10-12 | Method and compositon for treating cancer using a vaccine |
DK21880926.7T DK4225351T1 (da) | 2020-10-12 | 2021-10-12 | Sammensætning og fremgangsmåde til behandling af kræft under anvendelse af en vaccine som en første terapeutisk aktiv ingrediens i kombination med en anden aktiv ingrediens |
JP2023522489A JP2023546073A (ja) | 2020-10-12 | 2021-10-12 | 第1の治療有効成分としてのワクチンを、第2の有効成分と組み合わせて使用する、癌を治療するための組成物及び方法 |
FIEP21880926.7T FI4225351T1 (fi) | 2020-10-12 | 2021-10-12 | Koostumus ja menetelmä syövän hoitamiseksi käyttämällä rokotetta ensimmäisenä terapeuttisesti aktiivisena ainesosana yhdessä toisen aktiivisen ainesosan kanssa |
IL302098A IL302098A (en) | 2020-10-12 | 2021-10-12 | The composition and method for treating cancer using a vaccine as a first active therapeutic ingredient in combination with a second active ingredient |
CONC2023/0006083A CO2023006083A2 (es) | 2020-10-12 | 2023-05-12 | Composición y método para el tratamiento del cáncer utilizando una vacuna como un primer ingrediente activo terapéutico en combinación con un segundo ingrediente activo |
CY20232200001T CY20232200001T2 (el) | 2020-10-12 | 2023-10-19 | Συνθεση και μεθοδος για τη θεραπεια ενος καρκινου χρησιμοποιωντας ενα εμβολιο ως ενα πρωτο θεραπευτικο δραστικο συστατικο σε συνδυασμο με ενα δευτερο δραστικο συστατικο |
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JP (1) | JP2023546073A (ko) |
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Citations (6)
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US20150297530A1 (en) * | 2012-01-12 | 2015-10-22 | Pharma Two B Ltd. | Fixed dose combination therapy of parkinson's disease |
US20160095912A1 (en) * | 2001-12-19 | 2016-04-07 | Curevac Ag | APPLICATION OF mRNA FOR USE AS A THERAPEUTIC AGAINST TUMOUR DISEASES |
US20170165351A1 (en) * | 2014-10-24 | 2017-06-15 | Hpvvax, Llc | Method and composition for treating cancer or skin lesion using a vaccine |
US20190161530A1 (en) * | 2016-04-07 | 2019-05-30 | Bluebird Bio, Inc. | Chimeric antigen receptor t cell compositions |
US20190388369A1 (en) * | 2012-04-26 | 2019-12-26 | Sentient Lifesciences, Inc. | Use of N-acetylcysteine Amide in the Treatment Of Disease and Injury |
US20200108142A1 (en) * | 2016-04-01 | 2020-04-09 | Kite Pharma, Inc. | Chimeric antigen and t cell receptors and methods of use |
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- 2021-10-12 JP JP2023522489A patent/JP2023546073A/ja active Pending
- 2021-10-12 PL PL21880926.7T patent/PL4225351T1/pl unknown
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Patent Citations (6)
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US20160095912A1 (en) * | 2001-12-19 | 2016-04-07 | Curevac Ag | APPLICATION OF mRNA FOR USE AS A THERAPEUTIC AGAINST TUMOUR DISEASES |
US20150297530A1 (en) * | 2012-01-12 | 2015-10-22 | Pharma Two B Ltd. | Fixed dose combination therapy of parkinson's disease |
US20190388369A1 (en) * | 2012-04-26 | 2019-12-26 | Sentient Lifesciences, Inc. | Use of N-acetylcysteine Amide in the Treatment Of Disease and Injury |
US20170165351A1 (en) * | 2014-10-24 | 2017-06-15 | Hpvvax, Llc | Method and composition for treating cancer or skin lesion using a vaccine |
US20200108142A1 (en) * | 2016-04-01 | 2020-04-09 | Kite Pharma, Inc. | Chimeric antigen and t cell receptors and methods of use |
US20190161530A1 (en) * | 2016-04-07 | 2019-05-30 | Bluebird Bio, Inc. | Chimeric antigen receptor t cell compositions |
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DK4225351T1 (da) | 2023-10-23 |
IL302098A (en) | 2023-06-01 |
JP2023546073A (ja) | 2023-11-01 |
HUE21880926T1 (hu) | 2024-04-28 |
ES2962700T1 (es) | 2024-03-20 |
KR20230117106A (ko) | 2023-08-07 |
FI4225351T1 (fi) | 2023-10-20 |
CY20232200001T2 (el) | 2024-02-16 |
MX2023004285A (es) | 2023-06-19 |
PL4225351T1 (pl) | 2023-12-11 |
DE21880926T1 (de) | 2024-01-11 |
CA3195478A1 (en) | 2022-04-21 |
AU2021360676A1 (en) | 2023-06-15 |
CO2023006083A2 (es) | 2023-08-18 |
EP4225351A1 (en) | 2023-08-16 |
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