EP2094293A1 - Tissue targeted antigenic activation of the immune response to treat cancers - Google Patents
Tissue targeted antigenic activation of the immune response to treat cancersInfo
- Publication number
- EP2094293A1 EP2094293A1 EP07816065A EP07816065A EP2094293A1 EP 2094293 A1 EP2094293 A1 EP 2094293A1 EP 07816065 A EP07816065 A EP 07816065A EP 07816065 A EP07816065 A EP 07816065A EP 2094293 A1 EP2094293 A1 EP 2094293A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- cancer
- tissue
- antigenic
- patient
- situated
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Definitions
- the invention relates to immunological cancer therapies.
- the invention provides methods of formulating antigenic microbial composition and methods of using the antigenic compositions to treat cancers.
- cytokine therapy e.g., recombinant interleukin 2 and gamma interferon for kidney cancers
- dendritic cell therapy e.g., recombinant interleukin 2 and gamma interferon for kidney cancers
- dendritic cell therapy e.g., recombinant interleukin 2 and gamma interferon for kidney cancers
- autologous tumor vaccine therapy e.g., recombinant interleukin 2 and gamma interferon for kidney cancers
- genetically-altered vaccine therapy e.g., IL 2 and gamma interferon for kidney cancers
- lymphocyte therapy e.g., lymphocyte therapy
- microbial vaccines have been used to vaccinate subjects against pathogens that are associated with cancer, such as the human papillomavirus, lmmunostimulatory microbial vaccines that are not targeted to cancer-causing organisms, i.e.
- nonspecific immunostimulatory vaccines such as pyrogenic vaccines
- Coley's vaccine a combination of Streptococcus pyogenes and Serratia marcescens
- sarcomas and lymphomas
- lymphomas Naauts HC, Fowler GAA, Bogato FH.
- Intradermal BCG (Mycobacterium bovis) vaccine treatment has been reported to be effective for the treatment of stomach cancer (Ochiai T, Sato J, Hayashi R, et al: Postoperative adjuvant immunotherapy of gastric cancer with BCG-cell wall endoskeleton. Three- to six-year follow-up of a randomized clinical trial. Cancer Immunol lmmunother 1983; 14:167-171 ) and colon cancer (Smith RE, Colangelo L, Wieand HS, Begovic M, Wolmark N. Randomized trial of adjuvant therapy in colon carcinoma: 10-Year results of NSABP protocol C-01. J.
- Mycobacterium w vaccine therapy in combination with chemotherapy and radiation, was found to significantly improve quality of life and response to treatment in patients with lung cancer (Sur P, Dastidar A. Role of Mycobacterium w as adjuvant treatment of lung cancer [non-small cell lung cancer]. J Indian Med Assoc 2003 Feb; 101 [2]: 118-120).
- Mycobacterium vaccae vaccine therapy was found to improve quality of life (O'Brien M, Anderson H, Kaukel E, et al. SRL172 [killed Mycobacterium vaccae] in addition to standard chemotherapy improves quality of life without affecting survival, in patients with advanced non- small-cell lung cancer: phase III results.
- Corynebacterium parvum vaccine was linked with a trend towards improved survival for the treatment of melanoma (Balch CM, Smalley RV, Bartolucci AA, et al. A randomized prospective trial of adjuvant C. parvum immunotherapy in 260 patients with clinically localized melanoma [stage I]. Cancer 1982 Mar 15;49[6]: 1079-84).
- Intradermal Streptococcus pyogenes vaccine therapy was found to be effective for the treatment of stomach cancer (Hanaue H, Kim DY, Machimura T, et al. Hemolytic streptococcus preparation OK-432; beneficial adjuvant therapy in recurrent gastric carcinoma. Tokai J Exp Clin Med 1987 Nov;12[4]:209-14).
- Nocardia rubra vaccine was found to be effective for the treatment of lung cancer (Yasumoto K, Yamamura Y. Randomized clinical trial of non-specific immunotherapy with cell-wall skeleton of Nocardia rubra. Biomed Pharmacother 1984;38[1]:48-54; Ogura T. Immunotherapy of respectable lung cancer using Nocardia rubra cell wall skeleton. Gan To Kagaku Ryoho 1983 Feb;10[2 Pt 2]:366-72) and linked to a trend to improved survival for the treatment acute myelogenous leukemia (Ohno R, Nakamura H, Kodera Y, et al.
- Lactobacillus casei vaccine treatment combined with radiation was found to more effective for the treatment of cervical cancer than radiation alone.
- Pseudomonas aeruginosa vaccine treatment was found to increase the effectiveness of chemotherapy in the treatment of lymphoma and lung cancer (Li Z, Hao D, Zhang H, Ren L, et al. A clinical study on PA_MSHA vaccine used for adjuvant therapy of lymphoma and lung cancer. Hua Xi Yi Ke Da Xue Xue Bao 2000 Sep;31 [3]:334-7).
- Rabies virus vaccine was found to result in temporary remission in 8 of 30 patients with melanoma (Higgins G, Pack G. Virus therapy in the treatment of tumors. Bull Hosp Joint Dis 1951 ;12:379-382; Pack G. Note on the experimental use of rabies vaccine for melanomatosis. Arch Dermatol 1950;62:694-695).
- the invention provides methods for formulating an immunogenic composition for treating a cancer situated in a specific organ or tissue in a mammal, such as human patient.
- the method may include selecting at least one microbial pathogen that is naturally pathogenic in the organ or tissue of the mammal within which the cancer is situated.
- An antigenic composition may be produced that includes antigenic determinants that together are specific for or characteristic of the microbial pathogen.
- a diagnostic step may be used to identify the specific organ or tissue within which the cancer is situated, prior to producing the antigenic composition targeted to the site of the cancer.
- the site of the cancer may be a primary site, or a secondary site of metastasis.
- the antigenic composition may be sufficiently specific that it would be capable of eliciting an immune response in the mammal specific to the microbial pathogen.
- the antigenic composition may be a bacterial composition, for example derived from a bacterial species or species that are endogenous to the flora of the patient or from an exogenous species or species.
- the antigenic composition may be derived from a virus or viruses. Accordingly, the microbial pathogen from which the antigenic composition is derived may be a virus.
- the microbial pathogen may be killed. In alternative embodiments, the microbial pathogen may be live or attenuated. Immunogenic compositions of the invention may also be formulated or administered with anti-inflammatory modalities, such as an NSAID.
- the site of administration may be at a site distant from the site of the cancer, for example in an organ or tissue that is not the organ or tissue within which the cancer is situated, for example the skin.
- the antigenic composition may for example be formulated for subcutaneous injection, intradermal injection or oral administration.
- the dosing or formulation of the antigenic composition may be adjusted in order to produce a localized immune reaction visible in the skin at the site of administration, for example an area of inflammation from 2mm to 100mm in diameter.
- the antigenic composition may be formulated for repeated subcutaneous or intradermal administration, for example at alternating successive sites.
- the invention involves methods of treating a mammal for a cancer situated in a tissue or an organ.
- the treatment may anticipate the development of the cancer in the tissue, for example if the site of a primary tumour suggests the likelihood of metastasis to a particular tissue or organ, then the patient may be prophylactically treated to prevent or ameliorate metastasis to that tissue or organ.
- the method may include administering to the subject an effective amount of an antigenic composition comprising antigenic determinants that together are specific for at least one microbial pathogen.
- An aspect of the invention involves the use of a microbial pathogen that is pathogenic in the specific organ or tissue of the mammal within which the cancer is situated.
- the antigenic composition may be administered, for example by subcutaneous or intradermal injection at an administration site, in successive doses given at a dosage interval, for example of between one hour and one month, over a dosage duration, for example of at least 2 weeks, 2 months, 6 months, 1 , 2, 3, 4, or 5 years.
- Each injection dose may for example be metered so that it is effective to cause visible localized inflammation at the administration site.
- the invention provides in part methods of treating cancers of a specific organ or tissue in a subject by administering one or more antigens of one or more microbial pathogens, such as bacterial or viral species that are pathogenic in the specific organ or tissue.
- one or more antigens of one or more microbial pathogens such as bacterial or viral species that are pathogenic in the specific organ or tissue.
- the pathogenic microbial species may be capable of causing infection naturally, (i.e. without human intervention) in the specific organ or tissue in a healthy subject, or may have caused an infection in the specific organ or tissue in a healthy subject.
- the antigen may be administered by administering a whole microbial species.
- the method may for example include administering at least two or more microbial species, or administering at least three or more microbial species, and the microbes may be bacteria or viruses.
- the method may further include administering a supplement or an adjuvant.
- An aspect of the invention involves administering antigenic compositions so as to elicit an immune response in said subject.
- the microbial pathogen in the antigenic composition may be killed, and thus rendered non-infectious.
- the antigenic composition is administered at a site distant from the cancer site, and in selected embodiments of this kind, methods of the invention may be carried out so that they do not produce infection at the cancer site.
- a "cancer” or "neoplasm,” as used herein, is any unwanted growth of cells serving no physiological function.
- a cancer cell has been released from its normal cell division control, i.e., a cell whose growth is not regulated by the ordinary biochemical and physical influences in the cellular environment.
- cancer is a general term for diseases characterized by abnormal uncontrolled cell growth.
- a cancer cell proliferates to form clonal cells that are malignant.
- the lump or cell mass, "neoplasm” or “tumor” is generally capable of invading and destroying surrounding normal tissues.
- malignancy is meant an abnormal growth of any cell type or tissue that has a deleterious effect in the organism having the abnormal growth.
- malignancy or “cancer” includes cell growths that are technically benign but which carry the risk of becoming malignant. Cancer cells may spread from their original site to other parts of the body through the lymphatic system or blood stream in a process known as "metastasis.” Many cancers are refractory to treatment and prove fatal. Examples of cancers or neoplasms include, without limitation, transformed and immortalized cells, tumors, carcinomas, in various organs and tissues as described herein or known to those of skill in the art.
- a "cell” is the basic structural and functional unit of a living organism. In higher organisms, e.g., animals, cells having similar structure and function generally aggregate into “tissues” that perform particular functions. Thus, a tissue includes a collection of similar cells and surrounding intercellular substances, e.g., epithelial tissue, connective tissue, muscle, nerve.
- An "organ” is a fully differentiated structural and functional unit in a higher organism that may be composed of different types of tissues and is specialized for some particular function, e.g., kidney, heart, brain, liver, etc. Accordingly, by “specific organ, tissue, or cell” is meant herein to include any particular organ, and to include the cells and tissues found in that organ.
- Pathogenic agents are agents, such as microbes, such as bacteria or viruses, that are known to cause infection in a host in nature, and in this sense, "pathogenic” is used in the context of the present invention to mean “naturally pathogenic”. Although a wide variety of microbes may be capable of causing infection under artificial conditions, such as artificial innoculations of a microbe into a tissue, the range of microbes that natually cause infection is necessarily limited, and well established by medical practice.
- An "infection” is the state or condition in which the body or a part of it is invaded by a pathogenic agent (e.g., a microbe, such as a bacterium) which, under favorable conditions, multiplies and produces effects that are injurious (Taber's Cyclopedic Medical Dictionary, 14th Ed., CL. Thomas, Ed., F.A. Davis Company, PA, USA).
- a pathogenic agent e.g., a microbe, such as a bacterium
- An infection may not always be apparent clinically and may result in only localized cellular injury. Infections may remain subclinical, and temporary if the body's defensive mechanisms are effective. Infections may spread locally to become clinically apparent as an acute, a subacute, or a chronic clinical infection or disease state.
- a local infection may also become systemic when the pathogenic agent gains access to the lymphatic or vascular system (On-LJne Medical Dictionary, http://cancerweb.ncl.ac.uk/omd/). Infection is usually accompanied by inflammation, but inflammation may occur without infection.
- Inflammation is the characteristic tissue reaction to injury (marked by swelling, redness, heat, and pain), and includes the successive changes that occur in living tissue when it is injured. Infection and inflammation are different conditions, although one may arise from the other (Taber's Cyclopedic Medical Dictionary, supra). Accordingly, inflammation may occur without infection and infection may occur without inflammation (although inflammation typically results from infection by pathogenic bacteria or viruses).
- Inflammation is characterized by the following symptoms: redness (rubor), heat (calor), swelling (tumor), pain (dolor). Localized visible inflammation on the skin may be apparent from a combination of these symptoms, particularly redness at a site of administration.
- a subject is an animal, e.g, a mammal, to whom the specific pathogenic bacteria, bacterial antigens, viruses, viral antigens or compositions thereof of the invention may be administered. Accordingly, a subject may be a patient, e.g., a human, suffering from a cancer, or suspected of having a cancer, or at risk for developing a cancer. A subject may also be an experimental animal, e.g., an animal model of a cancer.
- the terms "subject” and “patient” may be used interchangeably, and may include a human, a non-human mammal, a non-human primate, a rat, mouse, dog, etc.
- a healthy subject may be a human who is not suffering from a cancer or suspected of having a cancer, or who is not suffering from a chronic disorder or condition.
- a "healthy subject” may also be a subject who is not immunocompromised.
- immunocompromised is meant any condition in which the immune system functions in an abnormal or incomplete manner, lmmunocompromisation may be due to disease, certain medications, or conditions present at birth. Immunocompromised subjects may be found more frequently among infants, the elderly, and individuals undergoing extensive drug or radiation therapy.
- an “immune response” includes, but is not limited to, one or more of the following responses in a mammal: induction or activation of antibodies, neutrophils, monocytes, macrophages, B cells, T cells (including helper T cells, natural killer cells, cytotoxic T cells, ⁇ T cells), such as induction or activation by the antigen(s) in a composition or vaccine, following administration of the composition or vaccine.
- An immune response to a composition or vaccine thus generally includes the development in the host animal of a cellular and/or antibody-mediated response to the composition or vaccine of interest. In some embodiments, the immune response is such that it will also result in slowing or stopping the progression of a cancer in the animal.
- Figure 1 shows a survival curve for a cumulative series of patients diagnosed with stage 3B or 4 inoperable lung cancer (all patients), comparing patients treated with MRV, patients not treated with the MRV, and a standard SEER survival curve.
- Figure 2 shows a survival curve for a cumulative series of patients diagnosed with stage 3B or 4 inoperable lung cancer (patients treated for at least 2 months with MRV), comparing patients treated with MRV, patients not treated with the MRV, and a standard SEER survival curve.
- Figure 3 shows a survival curve for a cumulative series of patients diagnosed with stage 3B or 4 lung cancer, illustrating the benefits of treatment with the MRV composition of the invention, comparing patients treated with MRV, patients not treated with the MRV, and a standard SEER survival curve.
- Figure 4 shows a survival curve for a cumulative series of patients diagnosed with stage 3B or 4 lung cancer, illustrating the effect of treatments for at least 2 months, comparing patients treated with MRV, patients not treated with the MRV, and a standard SEER survival curve.
- Figure 5 shows a survival curve for a cumulative series of patients diagnosed with stage 3B or 4 lung cancer, illustrating the effect of treatments for at least 6 months duration, comparing patients treated with MRV, patients not treated with the MRV, and a standard SEER survival curve.
- Figure 6 shows a survival curve for a cumulative series of 52 breast cancer patients with metastases to bone and/or lung, comparing patients treated with MRV, patients not treated with the MRV, and a standard SEER survival curve.
- Figure 7 is a comparison of survival of a cumulative series of metastatic prostate cancer patients who had surgery or radiation to destroy their prostate gland (and thus, the primary tumour) and who had detectable cancer limited to bone metastases, comparing patients treated with MRV, patients not treated with the MRV, and a standard SEER survival curve.
- Figure 8 shows a survival curve for a cumulative series of patients initially diagnosed with Stage 4 colorectal cancer, comparing patients treated with PVF, patients treated with MRV, patients not treated with an antigenic composition and a standard SEER survival curve.
- Figure 9 shows a survival curve for a cumulative series of patients initially diagnosed with Stage 4 Colorectal Cancer, with date from patients receiving treatment within 3 months of diagnosis, comparing patients treated with PVF, patients treated with MRV, patients not treated with an antigenic composition and a standard SEER survival curve.
- Figure 10 shows a survival curve for a cumulative series of stage 3B lung cancer patients who were treated with an oral antigen therapy, Respivax, compared to patients who did not use an antigenic composition.
- Figure 11 shows a survival curve for a cumulative series of patients diagnosed with stage 3B lung cancer, illustrating the benefits of treatment with the MRV composition of the invention, comparing patients treated with MRV, patients not treated with the MRV, and a standard SEER survival curve.
- Figure 12 shows a survival curve measured from date of first visit for a cumulative series of patients diagnosed with stage 3B lung cancer, illustrating the benefits of treatment with the MRV composition of the invention, comparing patients treated with MRV, patients not treated with the MRV, and a standard SEER survival curve.
- Figure 13 shows a survival curve for a cumulative series of patients diagnosed with stage 3B lung cancer whose first visit was within 3 months of diagnosis, illustrating the benefits of early treatment with the MRV composition of the invention, comparing patients treated with MRV, patients not treated with the MRV, and a standard SEER survival curve.
- the invention relates to the surprising discovery that administration, for example at a site distant from the cancer, of microbial pathogens, such as killed microbial pathogens, that are pathogenic in a particular tissue or organ is effective in treating cancer situated in that specific tissue or organ. Accordingly, the invention provides antigenic compositions derived from these microbial pathogens, including whole killed bacterial or viral species, or components thereof, for the treatment of cancer, and methods for using the same.
- microbial pathogens such as killed microbial pathogens
- compositions including many of the most common pathogenic bacteria that cause lung infection were surprisingly and unexpectedly effective in improving the clinical course of cancer of the lung.
- administering compositions including Staphylococcus aureus one of the most common causes of bone, breast, skin, perineal and lymph node infection and septicemia was surprising and unexpectedly effective in improving the clinical course of cancer of the bone, breast, skin, perineum, and lymphoma (cancer of the lymph glands) and multiple myeloma (a type of hematological cancer).
- composition including antigens of pathogenic microbial species that cause infection in a particular tissue or organ will be an effective formulation for treating a cancer in that tissue or organ.
- cancer in the lung is effectively treated with a microbial composition including pathogenic species that commonly cause lung infection
- cancer in the colon is effectively treated with a composition including pathogenic microbial species that commonly cause colon infections.
- Antigenic compositions of the invention may be produced that include antigenic determinants that together are specific for or characteristic of a microbial pathogen.
- specific it is meant that the antigenic determinants are sufficiently characteristic of the pathogen that they could be used to raise an immune response, such as an adaptive immune response, against the pathogen in the patient, if the antigenic determinants were to be administered in an appropriate manner to have that effect.
- the antigenic determinants need not be so specific that they are characteristic of only one particular strain or species of pathogen, since even a specific immune response against a particular pathogen may be cross reactive with other closely related organisms that are also naturally pathogenic in the tissue or organ in which the cancer is situated and that the antigenic composition is formulated or selected to target.
- the compositions of pathogenic microbes may be used for treating primary cancer sites and/or sites of metastasis.
- the microbial compositions may be used for the treatment of a cancer at a particular site, regardless of whether the cancer is the primary cancer or the mestastatic site.
- the composition may be directed to the treatment of each cancer site, or may be a combined composition for both the primary cancer and the metastatic site(s).
- each cancer site or may be a combined composition for both the primary cancer and the metastatic site(s).
- three different compositions including species that are known to be kidney pathogens, species that are known to be lung pathogens and species that are known to be bone pathogens, or a combined composition thereof may be used.
- the compositions may be administered in different locations at the same time or at different times.
- both a microbial composition including bacteria (or viruses) which commonly cause lung infection and a microbial composition including bacteria (or viruses) which commonly cause bone infection may be used.
- a pathogenic bacterial (or viral) composition including bacteria (or viruses) which commonly cause colon infection and a microbial composition including bacteria (or viruses) which commonly cause lung infection may be used;
- a pathogenic bacterial (or viral) composition including bacteria (or viruses) which commonly cause prostate infection and a pathogenic bacterial (or viral) composition including bacteria (or viruses) that commonly cause bone infection may be used.
- Primary cancer Common sites for metastases prostate bone, lungs breast bone, lungs, skin, liver, brain lung bone, brain, liver, lungs colon liver, lungs, bone, brain kidney lungs, bone, brain pancreas liver, lungs melanoma lungs, skin, liver, brain uterus lungs, bones, ovaries ovary liver, lung bladder bone, lung, liver head and neck bone, lungs sarcoma lungs, brain stomach liver cervix bone, lungs testes lungs thyroid bone, lungs
- the antigenic compositions may be used for treating or preventing cancers at primary sites or for treating or preventing metastasis.
- an antigenic composition specific for cancer of the lung for example including antigenic determinants of bacteria or viruses which commonly cause lung infection
- an antigenic composition specific for cancer of the breast for example including antigenic determinants of bacteria which commonly cause breast infection
- an antigenic composition including bacteria which commonly cause bone infection may be used to prevent or treat bone metastases in a patient with prostate cancer.
- an antigenic composition including bacteria or viruses which commonly cause lung infection may be used to prevent or treat lung metastases in a patient with malignant melanoma.
- carcinomas which are the predominant cancers and are cancers of epithelial cells or cells covering the external or internal surfaces of organs, glands, or other body structures (e.g., skin, uterus, lung, breast, prostate, stomach, bowel), and which tend to metastasize; sarcomas, which are derived from connective or supportive tissue (e.g., bone, cartilage, tendons, ligaments, fat, muscle); and hematologic tumors, which are derived from bone marrow and lymphatic tissue.
- carcinomas which are the predominant cancers and are cancers of epithelial cells or cells covering the external or internal surfaces of organs, glands, or other body structures (e.g., skin, uterus, lung, breast, prostate, stomach, bowel), and which tend to metastasize
- sarcomas which are derived from connective or supportive tissue (e.g., bone, cartilage, tendons, ligaments, fat, muscle); and hematologic tumors, which are derived from bone marrow and
- Carcinomas may be adenocarcinomas (which generally develop in organs or glands capable of secretion, such as breast, lung, colon, prostate or bladder) or may be squamous cell carcinomas (which originate in the squamous epithelium and generally develop in most areas of the body).
- adenocarcinomas which generally develop in organs or glands capable of secretion, such as breast, lung, colon, prostate or bladder
- squamous cell carcinomas which originate in the squamous epithelium and generally develop in most areas of the body.
- Sarcomas may be osteosarcomas or osteogenic sarcomas (bone), chondrosarcomas (cartilage), leiomyosarcomas (smooth muscle), rhabdomyosarcomas (skeletal muscle), mesothelial sarcomas or mesotheliomas (membranous lining of body cavities), fibrosarcomas (fibrous tissue), angiosarcomas or hemangioendotheliomas (blood vessels), liposarcomas (adipose tissue), gliomas or astrocytomas (neurogenic connective tissue found in the brain), myxosarcomas (primitive embryonic connective tissue), or mesenchymous or mixed mesodermal tumors (mixed connective tissue types).
- Hematologic tumors may be myelomas, which originate in the plasma cells of bone marrow; leukemias which may be "liquid cancers" and are cancers of the bone marrow and may be myelogenous or granulocytic leukemia (myeloid and granulocytic white blood cells), lymphatic, lymphocytic, or lymphoblastic leukemias (lymphoid and lymphocytic blood cells) or polycythemia vera or erythremia (various blood cell products, but with red cells predominating); or lymphomas, which may be solid tumors and which develop in the glands or nodes of the lymphatic system, and which may be Hodgkin or Non-Hodgkin lymphomas.
- mixed type cancers such as adenosquamous carcinomas, mixed mesodermal tumors, carcinosarcomas, or teratocarcinomas also exist.
- Cancers may also be named based on the organ in which they originate i.e., the "primary site,” for example, cancer of the breast, brain, lung, liver, skin, prostate, testicle, bladder, colon and rectum, cervix, uterus, etc. This naming persists even if the cancer metastasizes to another part of the body that is different from the primary site.
- treatment is directed to the site of the cancer, not type of cancer, so that a cancer of any type that is situated in the lung, for example, would be treated on the basis of this localization in the lung.
- lung cancers are generally small cell lung cancers or non-small cell lung cancers, which may be squamous cell carcinoma, adenocarcinoma, or large cell carcinoma; skin cancers are generally basal cell cancers, squamous cell cancers, or melanomas. Lymphomas may arise in the lymph nodes associated with the head, neck and chest, as well as in the abdominal lymph nodes or in the axillary or inguinal lymph nodes.
- Identification and classification of types and stages of cancers may be performed by using for example information provided by the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute, which is an authoritative source of information on cancer incidence and survival in the United States and is recognized around the world.
- SEER Program currently collects and publishes cancer incidence and survival data from 14 population-based cancer registries and three supplemental registries covering approximately 26 percent of the US population.
- the program routinely collects data on patient demographics, primary tumor site, morphology, stage at diagnosis, first course of treatment, and follow-up for vital status, and is the only comprehensive source of population- based information in the United States that includes stage of cancer at the time of diagnosis and survival rates within each stage.
- the incidence and survival data of the SEER Program may be used to access standard survival for a particular cancer site and stage.
- specific criteria may be selected from the database, including date of diagnosis and exact stage (for example, in the case of the lung cancer example herein, the years were selected to match the time-frame of the retrospective review, and stage 3B and 4 lung cancer were selected; and in the case of the colon cancer example herein, the years were also selected to match the time-frame of the retrospective review, and the stage 4 colon cancer was selected).
- Bacteria that are generally harmless can cause infection in healthy subjects, with results ranging from mild to severe infection to death. Whether or not a bacterium is pathogenic (i.e., causes infection) depends to some extent on factors such as the route of entry and access to specific host cells, tissues, or organs; the intrinsic virulence of the bacterium; the amount of the bacteria present at the site of potential infection; or the health of the host animal. Thus, bacteria that are normally harmless can become pathogenic given favorable conditions for infection, and even the most virulent bacterium requires specific circumstances to cause infection.
- microbial species that are members of the normal flora can be pathogens, when they move beyond their normal ecological role in the endogenous flora.
- endogenous species can cause infection outside of their ecological niche in regions of anotomical proximity, for example by contiguous spread. When this occurs, these normally harmless endogenous bacteria are considered pathogenic.
- Specif ic pathogenic bacterial species and viruses are known to cause infections in specific cells, tissues, or organs in otherwise healthy subjects.
- Infections of the skin are commonly caused by the following bacterial species: Staphylococcus aureus, Beta hemolytic streptococci group A, B, C or G, Corynebacterium diptheriae, Corynebacterium ulcerans, or Pseudomonas aeruginosa; or viral pathogens: rubeola, rubella, varicella-zoster, echoviruses, coxsackieviruses, adenovirus, vaccinia, herpes simplex, or parvo B19.
- Infections of the soft tissue are commonly caused by the following bacterial species: Streptococcus pyogenes, Staphylococcus aureus, Clostridium perfringens, or other Clostridium spp.; or viral pathogens: influenza, or coxsackieviruses
- Infections of the breast are commonly caused by the following bacterial species: Staphylococcus aureus, or Streptococcus pyogenes.
- Infections of the lymph nodes of the head and neck are commonly caused by the following bacterial species: Staphylococcus aureus, Streptococcus pyogenes; or viral pathogens: Epstein-Barr, cytomegalovirus, adenovirus, measles, rubella, herpes simplex, coxsackieviruses, or varicella-zoster.
- Infections of the lymph nodes of the arm/axillae are commonly caused by the following bacterial species: Staphylococcus aureus, Streptococcus pyogenes; or viral pathogens: measles, rubella, Epstein-Barr, cytomegalovirus, adenovirus, or varicella-zoster.
- Infections of the lymph nodes of the mediastinum are commonly caused by the following bacterial species: viridans streptococci, Peptococcus spp., Peptostreptococcus spp., Bacteroides spp., Fusobacterium spp.; or Mycobacterium tuberculosis; or viral pathogens: measles, rubella, Epstein-Barr, cytomegalovirus, varicella-zoster, or adenovirus.
- Infections of the pulmonary hilar lymph nodes are commonly caused by the following bacterial species: Streptococcus pneumoniae, Moraxella catarrhalis, Mycoplasma pneumoniae, Klebsiella pneumoniae, Haemophilus influenza, Chlamydophila pneumoniae, Bordetella pertussis or Mycobacterium tuberculosis; or viral pathogens: influenza, adenovirus, rhinovirus, coronavirus, parainfluenza, respiratory syncytial virus, human metapneumovirus, or coxsackievirus.
- Infections of the intra-abdominal lymph nodes are commonly caused by the following bacterial species: Yersinia enterocolitica, Yersinia pseudotuberculosis, Salmonella spp., Streptococcus pyogenes, Escherichia coli, Staphylococcus aureus or Mycobacterium tuberculosis; or viral pathogens: measles, rubella, Epstein-Barr, cytomegalovirus, varicella-zoster, adenovirus, influenza, or coxsackieviruses.
- Infections of the lymph nodes of the leg/inguinal region are commonly caused by the following bacterial species: Staphylococcus aureus, or Streptococcus pyogenes; or viral pathogens: measles, rubella, Epstein-Barr, cytomegalovirus, or herpes simplex.
- Infections of the blood are commonly caused by the following bacterial species: Staphylococcus aureus, Streptococcus pyogenes, coagulase-negative staphylococci, Enterococcus spp., Escherichia coli, Klebsiella spp., Enterobacter spp., Proteus spp., Pseudomonas aeruginosa, Bacteroides fragilis, Streptococcus pneumoniae, or group B streptococci; or viral pathogens: rubeola, rubella, varicella-zoster, echoviruses, coxsackieviruses, adenovirus, Epstein-Barr, herpes simplex or cytomegalovirus.
- Infections of the bone are commonly caused by the following bacterial species: Staphylococcus aureus, coagulase-negative staphylococci, Streptococcus pyogenes, Streptococcus pneumoniae, Streptococcus agalactiae, other streptococci spp., Escherichia coli, Pseudomonas spp., Enterobacter spp., Proteus spp., or Serratia spp.; or viral pathogens: parvovirus B19, rubella, or hepatitis B.
- Infections of the meninges are commonly caused by the following bacterial species: Haemophilus influenzae, Neisseria meningitidis, Streptococcus pneumoniae, Streptococcus agalactiae, or Listeria monocytogenes; or viral pathogens: echoviruses, coxsackieviruses, other enteroviruses, or mumps.
- Infections of the brain are commonly caused by the following bacterial species: Streptococcus spp. (including S. anginosus, S. constellatus, S.
- Infections of the spinal cord are commonly caused by the following bacterial species: Haemophilus influenzae, Neisseria meningitidis, Streptococcus pneumoniae, Streptococcus agalactiae, Listeria monocytogenes, or Borrelia burgdorferi; or viral pathogens: coxsackieviruses, echoviruses, poliovirus, other enteroviruses, mumps, herpes simplex, varicella-zoster, flaviviruses, or bunyaviruses.
- Infections of the eye/orbit are commonly caused by the following bacterial species: Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumoniae, Streptococcus milleri, Escherichia coli, Bacillus cereus, Chlamydia trachomatis, Haemophilus influenza, Pseudomonas spp., Klebsiella spp., or
- Treponema pallidum or viral pathogens: adenoviruses, herpes simplex, varicella- zoster, or cytomegalovirus.
- Infections of the salivary glands are commonly caused by the following bacterial species: Staphylococcus aureus, viridans streptococci (e.g.,
- Streptococcus salivarius Streptococcus sanguis, Streptococcus mutans
- Peptostreptococcus spp. or Bacteroides spp., or other oral anaerobes
- viral pathogens mumps, influenza, enteroviruses, or rabies.
- Infections of the mouth are commonly caused by the following bacterial species: Prevotella melaninogenicus, anaerobic streptococci, viridans streptococci, Actinomyces spp., Peptostreptococcus spp., or Bacteroides spp., or other oral anaerobes; or viral pathogens: herpes simplex, coxsackieviruses, or Epstein-Barr.
- Infections of the tonsils are commonly caused by the following bacterial species: Streptococcus pyogenes, or Group C or G B-hemolytic streptococci; or viral pathogens: rhinoviruses, influenza, coronavirus, adenovirus, parainfluenza, respiratory syncytial virus, or herpes simplex.
- Infections of the sinuses are commonly caused by the following bacterial species: Streptococcus pneumoniae, Haemophilus influenza, Moraxella catarrhalis, ⁇ -streptococci, anaerobic bacteria (e.g., Prevotella spp.), or Staphylococcus aureus; or viral pathogens: rhinoviruses, influenza, adenovirus, or parainfluenza.
- Infections of the nasopharynx are commonly caused by the following bacterial species: Streptococcus pyogenes, or Group C or G B-hemolytic streptococci; or viral pathogens: rhinoviruses, influenza, coronavirus, adenovirus, parainfluenza, respiratory syncytial virus, or herpes simplex.
- Infections of the thyroid are commonly caused by the following bacterial species: Staphylococcus aureus, Streptococcus pyogenes, or Streptococcus pneumoniae; or viral pathogens: mumps, or influenza.
- Infections of the larynx are commonly caused by the following bacterial species: Mycoplasma pneumoniae, Chlamydophila pneumoniae, or Streptococcus pyogenes; or viral pathogens: rhinovirus, influenza, parainfluenza, adenovirus, corona virus, or human metapneumovirus.
- Infections of the trachea are commonly caused by the following bacterial species: Mycoplasma pneumoniae; or viral pathogens: parainfluenza, influenza, respiratory syncytial virus, or adenovirus.
- Infections of the bronchi are commonly caused by the following bacterial species: Mycoplasma pneumoniae, Chlamydophila pneumoniae, Bordetella pertussis, Streptococcus pneumoniae, or Haemophilus influenzae; or viral pathogens: influenza, adenovirus, rhinovirus, coronavirus, parainfluenza, respiratory syncytial virus, human metapneumovirus, or coxsackievirus.
- Infections of the lung are commonly caused by the following bacterial species: Streptococcus pneumoniae, Moraxella catarrhalis, Mycoplasma pneumoniae, Klebsiella pneumoniae, or Haemophilus influenza; or viral pathogens: influenza, adenovirus, respiratory syncytial virus, or parainfluenza.
- Infections of the pleura are commonly caused by the following bacterial species: Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumoniae, Haemophilus influenzae, Bacteroides fragilis, Prevotella spp., Fusobacterium nucleatum, peptostreptococcus spp., or Mycobacterium tuberculosis; or viral pathogens: influenza, adenovirus, respiratory syncytial virus, or parainfluenza.
- Infections of the mediastinum are commonly caused by the following bacterial species: viridans streptococci, Peptococcus spp., Peptostreptococcus spp., Bacteroides spp., or Fusobacterium spp. or Mycobacterium tuberculosis; or viral pathogens: measles, rubella, Epstein-Barr, or cytomegalovirus.
- Infections of the heart are commonly caused by the following bacterial species: Streptococcus spp. (including S. mitior, S. bovis, S. sanguis, S. mutans, S. anginosus), Enterococcus spp., Staphylococcus spp., Corynebacterium diptheriae, Clostridium pe ⁇ ringens, Neisseria meningitidis, or Salmonella spp.; or viral pathogens: enteroviruses, coxsackieviruses, echoviruses, poliovirus, adenovirus, mumps, rubeola, or influenza.
- Streptococcus spp. including S. mitior, S. bovis, S. sanguis, S. mutans, S. anginosus
- Enterococcus spp. Staphylococcus spp.
- Corynebacterium diptheriae Clostridium pe ⁇
- Infections of the esophagus are commonly caused by the following bacterial species: Actinomyces spp., Mycobacterium avium, Mycobacterium tuberculosis, or Streptococcus spp.; or viral pathogens: cytomegalovirus, herpes simplex, or varicella-zoster.
- Infections of the stomach are commonly caused by the following bacterial species: Streptococcus pyogenes or Helicobacter pylori; or viral pathogens: cytomegalovirus, herpes simplex, Epstein-Barr, rotaviruses, noroviruses, or adenoviruses.
- Infections of the small bowel are commonly caused by the following bacterial species: Escherichia coli, Clostridium difficile, Bacteroides fragilis, Bacteroides vulgatus, Bacteroides thetaiotaomicron, Clostridium perfringens, Salmonella enteriditis, Yersinia enterocolitica, or Shigella flexneri; or viral pathogens: adenoviruses, astroviruses, caliciviruses, noroviruses, rotaviruses, or cytomegalovirus.
- Infections of the colon/rectum are commonly caused by the following bacterial species: Escherichia coli, Clostridium difficile, Bacteroides fragilis, Bacteroides vulgatus, Bacteroides thetaiotaomicron, Clostridium perfringens, Salmonella enteriditis, Yersinia enterocolitica, or Shigella flexneri; or viral pathogens: adenoviruses, astroviruses, caliciviruses, noroviruses, rotaviruses, or cytomegalovirus.
- Infections of the anus are commonly caused by the following bacterial species: Streptococcus pyogenes, Bacteroides spp., Fusobacterium spp., anaerobic streptococci, Clostridium spp., Escherichia coli, Enterobacter spp., Pseudomonas aeruginosa, or Treponema pallidum; or viral pathogens: herpes simplex.
- Infections of the perineum are commonly caused by the following bacterial species: Escherichia coli, Klebsiella spp., Enterococcus spp., Bacteroides spp., Fusobacterium spp., Clostridium spp., Pseudomonas aeruginosa, anaerobic streptococci, Clostridium spp., or Enterobacter spp.; or viral pathogens: herpes simplex.
- Infections of the liver are commonly caused by the following bacterial species: Escherichia coli, Klebsiella spp., Streptococcus (anginosus group), Enterococcus, spp. other viridans streptococci, or Bacteroides spp.; or viral pathogens: hepatitis A, Epstein-Barr, herpes simplex, mumps, rubella, rubeola, varicella-zoster, coxsackieviruses, or adenovirus.
- Infections of the gallbladder are commonly caused by the following bacterial species: Escherichia coli, Klebsiella spp., Enterobacter spp., enterococci, Bacteroides spp., Fusobacterium spp., Clostridium spp., Salmonella enteriditis, Yersinia enterocolitica, or Shigella flexneri.
- Infections of the biliary tract are commonly caused by the following bacterial species: Escherichia coli, Klebsiella spp., Enterobacter spp., enterococci, Bacteroides spp., Fusobacterium spp., Clostridium spp., Salmonella enteriditis, Yersinia enterocolitica, or Shigella flexneri; or viral pathogens: hepatitis A, Epstein-Barr, herpes simplex, mumps, rubella, rubeola, varicella-zoster, cocsackieviruses, or adenovirus.
- Infections of the pancreas are commonly caused by the following bacterial species: Escherichia coli, Klebsiella spp., Enterococcus spp., Pseudomonas spp., Staphylococcal spp., Mycoplasma spp., Salmonella typhi, Leptospirosis spp., or Legionella spp.; or viral pathogens: mumps, coxsackievirus, hepatitis B, cytomegalovirus, herpes simplex 2, or varicella-zoster.
- Infections of the spleen are commonly caused by the following bacterial species: Streptococcus spp., Staphylococcus spp., Salmonella spp.,
- Pseudomonas spp. Escherichia coli, or Enterococcus spp.; or viral pathogens: Epstein-Barr, cytomegalovirus, adenovirus, measles, rubella, coxsackieviruses, or varicella-zoster.
- Infections of the adrenal gland are commonly caused by the following bacterial species: Streptococcus spp., Staphylococcus spp., Salmonella spp., Pseudomonas spp., Escherichia coli, or Enterococcus spp.; or viral pathogens: varicella-zoster.
- Infections of the kidney are commonly caused by the following bacterial species: Escherichia coli, Proteus mirabilis, Proteus vulgatus, Providentia spp., Morganella spp., Enterococcus faecalis, or Pseudomonas aeruginosa; or viral pathogens: BK virus, or mumps.
- Infections of the ureter are commonly caused by the following bacterial species: Escherichia coli, Proteus mirabilis, Proteus vulgatus, Providentia spp., Morganella spp., or Enterococcus spp.
- Infections of the bladder are commonly caused by the following bacterial species: Escherichia coli, Proteus mirabilis, Proteus vulgatus,
- Infections of the peritoneum are commonly caused by the following bacterial species: Staphylococcus aureus, Streptococcus pyogenes,
- Streptococcus pneumonia Escherichia coli, Klebsiella spp., Proteus spp., enterococci, Bacteroides fragilis, Prevotella melaninogenica, Peptococcus spp., Peptostreptococcus spp., Fusobacterium spp., or Clostridium spp.
- Infections of the retroperitoneal area are commonly caused by the following bacterial species: Escherichia coli, or Staphylococcus aureus.
- Infections of the prostate are commonly caused by the following bacterial species: Escherichia coli, Klebsiella spp., Enterobacter spp., Proteus mirabilis, enterococci spp., Pseudomonas spp., Corynebacterium spp., or Neisseria gonorrhoeae; or viral pathogens: herpes simplex.
- Infections of the testicle are commonly caused by the following bacterial species: Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Staphylococcus spp., Streptococcus spp., or Salmonella enteriditis; or viral pathogens: mumps, coxsackievirus, or lymphocytic choriomeningitis virus.
- Infections of the penis are commonly caused by the following bacterial species: Staphylococcus aureus, Streptococcus pyogenes, Neisseria gonorrhoeae, or Treponema pallidum; or viral pathogens: herpes simplex.
- Infections of the ovary/adnexae are commonly caused by the following bacterial species: Neisseria gonorrhoeae, Chlamydia trachomatis, Gardenerella vaginalis, Prevotella spp., Bacteroides spp., Peptococcus spp. Streptococcus spp., or Escherichia coli.
- Infections of the uterus are commonly caused by the following bacterial species: Neisseria gonorrhoeae, Chlamydia trachomatis, Gardenerella vaginalis, Prevotella spp., Bacteroides spp., Peptococcus spp., Streptococcus spp., or Escherichia coli.
- Infections of the cervix are commonly caused by the following bacterial species: Neisseria gonorrhoeae, Chlamydia trachomatis, or Treponema pallidum; or viral pathogens: herpes simplex.
- Infections of the vagina are commonly caused by the following bacterial species: Gardenerella vaginalis, Prevotella spp., Bacteroides spp., peptococci spp., Escherichia coli, Neisseria gonorrhoeae, Chlamydia Trachomatis, or Treponema pallidum; or viral pathogens: herpes simplex.
- Infections of the vulva are commonly caused by the following bacterial species: Staphylococcus aureus, Streptococcus pyogenes, or Treponema pallidum; or viral pathogens: herpes simplex.
- Bacterial Strains/Viral Subtypes It will be understood by a skilled person that bacterial species are classified operationally as collections of similar strains (which generally refers to groups of presumed common ancestry with identifiable physiological but usually not morphological distinctions, and which may be identified using serological techniques against bacterial surface antigens). Thus, each bacterial species (e.g., Streptococcus pneumoniae) has numerous strains (or serotypes), which differ in their ability to cause infection or differ in their ability to cause infection in a particular organ/site. For example, although there are at least 90 serotypes of Streptococcus pneumoniae, serotypes 1 , 3, 4, 7, 8, and 12 are most frequently responsible for pneumococcal disease in humans.
- ETEC enterotoxigenic E. coli
- EPEC enteropathogenic E. coli
- EHEC enterohemorrhagic E. coli
- STEC Shiga toxin-producing E. coli
- EAEC enteroaggregative E. coli
- EIEC enteroinvasive E. coli
- DAEC diffuse adhering E. coli
- ExPEC strains Even among the sub-category of ExPEC strains, specific virulence factors (e.g., production of type-1 fimbriae) enable certain strains to be more capable of causing infection of the bladder, while other virulence factors (e.g., production of P fimbriae) enable other strains to be more capable of causing infection in the kidneys.
- an ExPEC strain(s) that is more likely to cause infection in the bladder would be chosen for a formulation to target bladder cancer
- an ExPEC strain(s) that is more likely to cause infection in the kidney would be chosen for a formulation to target kidney cancer.
- ETEC ETEC
- EHEC EHEC
- STEC EAEC
- EIEC or DAEC strains of E. coli i.e, strains that cause colon infection
- influenza viruses there may be numerous subtypes of specific viruses.
- influenza A is more likely to be associated with viral lung infection
- influenza B is more likely to be associated with myositis (i.e., muscle infection).
- each of these three types of influenza virus have numerous subtypes, which also may differ in epidemiology, host range and clinical characteristics.
- one would choose an influenza A subtype most commonly associated with lung infection to target lung cancer whereas one would choose an influenza B strain most commonly associated with myositis to treat cancer of the muscle/soft tissues.
- compositions of the invention include antigens of pathogenic microbial (bacterial or viral) species that are pathogenic in a specific tissue or organ.
- the compositions may include whole bacterial species, or may include extracts or preparations of the pathogenic bacterial species of the invention, such as cell wall or cell membrane extracts or whole cell extracts.
- compositions may also include one or more isolated antigens from one or more of the pathogenic bacterial species of the invention; in some embodiments, such compositions may be useful in situations where it may be necessary to precisely administer a specific dose of a particular antigen, or may be useful if administering a whole bacterial species or components thereof (e.g., toxins) may be harmful.
- Pathogenic bacterial species may be available commercially (from, for example, ATCC (Manassas, VA, USA), or may be clinical isolates from subjects having a bacterial infection of a tissue or organ (e.g., pneumonia).
- compositions of the invention can be provided alone or in combination with other compounds (for example, nucleic acid molecules, small molecules, peptides, or peptide analogues), in the presence of a liposome, an adjuvant, or any pharmaceutically acceptable carrier, in a form suitable for administration to mammals, for example, humans.
- compounds for example, nucleic acid molecules, small molecules, peptides, or peptide analogues
- liposome for example, an adjuvant, or any pharmaceutically acceptable carrier
- 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 physiologically compatible.
- the carrier can be suitable for any appropriate form of administration, including subcutaneous, intradermal, intravenous, parenteral, intraperitoneal, intramuscular, sublingual, inhalational, intratumoral or oral administration.
- Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. The use of such media and agents for pharmaceutically active substances is well known in the art.
- compositions of the invention are incompatible with the active compound (i.e., the specific bacteria, bacterial antigens, or compositions thereof of the invention), use thereof in the pharmaceutical compositions of the invention is contemplated.
- Supplementary active compounds can also be incorporated into the compositions.
- treatment with bacterial antigens according to the invention may be combined with more traditional and existing therapies for cancer, such as chemotherapy, radiation therapy, surgery, etc., or with any other therapy intended to stimulate the immune system, reduce inflammation or otherwise benefit the subject, such as nutrients, vitamins and supplements.
- vitamin A, vitamin D, vitamin E, vitamin C, vitamin B complex, selenium, zinc, coenzyme Q10, beta carotene, fish oil, curcumin, green tea, bromelain, resveratrol, ground flaxseed, garlic, lycopene, milk thistle, melatonin, other antioxidants, cimetidine, indomethacin, or COX-2 Inhibitors e.g., Celebrex [celecoxib] or Vioxx [rofecoxib]
- COX-2 Inhibitors e.g., Celebrex [celecoxib] or Vioxx [rofecoxib]
- Suitable formulations or compositions may be employed to provide suitable formulations or compositions to administer the compounds to subjects suffering from a cancer.
- Any appropriate route of administration may be employed, for example, parenteral, intravenous, intradermal, subcutaneous, intramuscular, intracranial, intraorbital, ophthalmic, intraventricular, intracapsular, intraspinal, intrathecal, intracisternal, intraperitoneal, intranasal, inhalational, aerosol, topical, intratumoral, sublingual or oral administration.
- Therapeutic formulations may be in the form of liquid solutions or suspensions; for oral administration, formulations may be in the form of tablets or capsules; for intranasal formulations, in the form of powders, nasal drops, or aerosols; and for sublingual formulations, in the form of drops, aerosols or tablets.
- Formulations for parenteral administration may, for example, contain excipients, sterile water, or saline, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, or hydrogenated napthalenes.
- Biocompatible, biodegradable lactide polymer, lactide/glycolide copolymer, or polyoxyethylene-polyoxypropylene copolymers may be used to control the release of the compounds.
- parenteral delivery systems for include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes.
- Formulations for inhalation may contain excipients, for example, lactose, or may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or may be oily solutions for administration in the form of nasal drops, or as a gel.
- the pathogenic bacterial species are administered to an individual in an amount effective to stop or slow progression or metastasis of the cancer, or to increase survival of the subject (relative to for example prognoses derived from the SEER database) depending on the disorder.
- An "effective amount" of a pathogenic microbial species or antigen thereof according to the invention includes a therapeutically effective amount or a prophylactically effective amount.
- a “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result, such as reduction or elimination of the cancer cells or tumors, prevention of carcinogenic processes, slowing the growth of the tumour, or an increase in survival time beyond that which is expected using for example the SEER database.
- a therapeutically effective amount of a pathogenic microbial (bacterial or viral) species or antigen(s) thereof may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the compound to elicit a desired response in the individual.
- Dosage regimens may be adjusted to provide the optimum therapeutic response.
- a therapeutically effective amount may also be one in which any toxic or detrimental effects of the pathogenic bacterial species or virus or antigen thereof are outweighed by the therapeutically beneficial effects.
- a “prophylactically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result, such as prevention of cancer, prevention of metastasis, slowing the growth of the tumour, reduction or elimination of the cancer cells, tissues, organs, or tumors, or an increase in survival time beyond that which is expected using for example the SEER database.
- a prophylactic dose is used in subjects prior to or at an earlier stage of cancer, so that a prophylactically effective amount may be less than a therapeutically effective amount.
- an exemplary range for therapeutically or prophylactically effective amounts of one or more pathogenic bacterial species may be about 1 million to 40,000 million organisms per ml, or may be 100 million to 7000 million organisms per ml, or may be 500 million to 6000 million organisms per ml, or may be 1000 million to 5000 million organisms per ml, or may be 2000 million to 4000 million organisms per ml, or any integer within these ranges.
- the total concentration of bacteria per ml may range from 10 million to 40,000 million organisms per ml, or may be 50 million to 7000 million organisms per ml, or may be 100 million to 6000 million organisms per ml, or may be 500 million to 5000 million organisms per ml, or may be 1000 million to 4000 million organisms per ml, or any integer within these ranges.
- the range for therapeutically or prophylactically effective amounts of antigens of a pathogenic bacterial species may be any integer from 0.1 nM- 0.1 M, 0.1 nM- 0.05M, 0.05 nM-15 ⁇ M or 0.01 nM-10 ⁇ M.
- dosage concentrations and ranges may vary with the severity of the condition to be alleviated, or may vary with the subject's immune response. In general, the goal is to achieve an adequate immune response.
- adequate immune response may be determined by, for example, by size of delayed local immune skin reaction at the site of injection (e.g, from 0.25 inch to 4 inch diameter).
- the dose required to achieve an appropriate immune response may vary depending on the individual (and their immune system) and the response desired. Standardized dosages may also be used.
- the total bacterial composition dose may, for example, range from 2 million bacteria (i.e., 0.001 ml of a vaccine with a concentration of 2,000 million organisms per ml) to more than 4,000 million bacteria (i.e., 2 ml of a vaccine with a concentration of 2,000 million organisms per ml).
- concentrations of individual bacterial species or antigens thereof within a composition may also be considered.
- the local immune skin reaction of an individual may be likely due to its response to this specific bacterial species.
- the immune system of an individual may respond more strongly to one bacterial species within a composition than another, depending for example on past history of exposure to infection by a particular species, so the dosage or composition may be adjusted accordingly for that individual.
- the timing and dose of treatments may be adjusted over time (e.g, timing may be daily, every other day, weekly, monthly) according to the individual need and the professional judgement of the person administering or supervising the administration of the compositions.
- the compositions may be administered every second day.
- An initial dose of approximately 0.05 ml may be administered subcutaneously, followed by increases from 0.01 -0.02 ml every second day until an adequate skin reaction is achieved at the injection site (for example, a 1 inch to 2 inch diameter delayed reaction of visible redness at the injection site). Once this adequate immune reaction is achieved, this dosing is continued as a maintenance dose.
- the maintenance dose may be adjusted from time to time to achieve the desired visible skin reaction (inflammation) at the injecition site.
- Dosing may be for a dosage duration, for example of at least 2 weeks, 2 months, 6 months, 1 , 2, 3, 4, or 5 years.
- Oral dosages may for example range from 10 million to 1 ,000,000 million organisms per dose, comprising antigenic determinants of one or more species. Oral dosages may be given, for example, from 4 times per day, daily or weekly. Dosing may be for a dosage duration, for example of at least 2 weeks, 2 months, 6 months, 1 , 2, 3, 4, or 5 years.
- the invention may include antigenic compositions administed sublingually or by inhilation, or administered to one or more epithelial tissues (i.e., skin by intradermal or subcutaneous injection; lung epithelium by inhalation; gastrointestinal mucosa by oral ingestion; mouth mucosa by sublingual administration) simultaneously or sequentially. Accordingly, in some embodiments the antigenic compositions of the invention are administered so as to provoke an immune response in an epithelial tissue. In some embodiments, one or more epithelial routes of administration may be combined with one or more additional routes of administration, such as intratumoral, intramuscular or intravenous administration.
- epithelial tissues i.e., skin by intradermal or subcutaneous injection; lung epithelium by inhalation; gastrointestinal mucosa by oral ingestion; mouth mucosa by sublingual administration
- the antigenic compositions of the invention are administered so as to provoke an immune response in an epithelial tissue.
- one or more epithelial routes of administration may be combined with
- the antigenic compositions that are administered to a patient may be characterized as having an antigenic signature, i.e. a combination of antigens or epitopes, that is sufficiently specific that the antigenic compsition is capable of eliciting an immune response that is specific to a particular pathogen, such as an adaptive immune response.
- an antigenic signature i.e. a combination of antigens or epitopes
- the non-adaptive or non-specific activation of the immune response that is mediated by these specific antigenic compositions is effective to treat cancers situated in the tissues in which the particular pathogen is pathogenic.
- Routes of administration and dosage ranges set forth herein are exemplary only and do not limit the route of administration and dosage ranges that may be selected by medical practitioners.
- the amount of active compound (e.g., pathogenic bacterial species or viruses or antigens thereof) in the composition may vary according to factors such as the disease state, age, sex, and weight of the individual. Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It may be advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage.
- an immunogenically effective amount of a compound of the invention can be provided, alone or in combination with other compounds, with an immunological adjuvant.
- the compound may also be linked with a carrier molecule, such as bovine serum albumin or keyhole limpet hemocyanin to enhance immunogenicity.
- An antigenic composition (“vaccine”) is a composition that includes materials that elicit a desired immune response.
- An antigenic composition may select, activate or expand memory B, T cells, neutrophils, monocytes or macrophages of the immune system to, for example, reduce or eliminate the growth or proliferation of cancerous cells or tissue.
- an antigenic composition includes a suitable carrier, such as an adjuvant, which is an agent that acts in a non-specific manner to increase the immune response to a specific antigen, or to a group of antigens, enabling the reduction of the quantity of antigen in any given vaccine dose, or the reduction of the frequency of dosage required to generate the desired immune response.
- a suitable carrier such as an adjuvant, which is an agent that acts in a non-specific manner to increase the immune response to a specific antigen, or to a group of antigens, enabling the reduction of the quantity of antigen in any given vaccine dose, or the reduction of the frequency of dosage required to generate the desired immune response.
- a bacterial antigenic composition may include live or dead bacteria capable of inducing an immune response against antigenic determinants associates with the disease or infection normally associated with the bacteria.
- an antigenic composition may include live bacteria that are of less virulent strains (attenuated), and therefore cause a less severe infection.
- the antigenic composition may include live, attenuated or dead viruses capable of inducing an immune response against antigenic determinants associates with the disease or infection normally associated with the virus.
- An antigenic composition comprising killed bacteria for administration by injection may be made as follows.
- the bacteria may be grown in suitable media, and washed with physiological salt solution.
- the bacteria may then be centrifuged, resuspended in salt solution, and killed with phenol.
- the suspensions may be standardized by direct microscopic count, mixed in required amounts, and stored in appropriate containers, which may be tested for safety, shelf life, and sterility in an approved manner.
- a killed bacterial vaccine suitable for administration to humans may include 0.4% phenol preservative and/or 0.9% sodium chloride.
- the bacterial vaccine may also include trace amounts of brain heart infusion (beef), peptones, yeast extract, agar, sheep blood, dextrose, and/or sodium phosphate.
- the bacterial vaccine may be used in tablet or capsule form or drops for oral ingestion, as an aerosol for inhalation, or as drops, aerosol or tablet form for sublingual administration.
- the concentrations of specific bacterial species in compositions for subcutaneous or intradermal injection may be about 1 million to 40,000 million organisms per ml, or may be 100 million to 7000 million organisms per ml, or may be 500 million to 6000 million organisms per ml, or may be 1000 million to 5000 million organisms per ml, or may be 2000 million to 4000 million organisms per ml, or any integer within these ranges.
- the total concentration of bacteria per ml may range from 10 million to 40,000 million organisms per ml, or may be 50 million to 7000 million organisms per ml, or may be 100 million to 6000 million organisms per ml, or may be 500 million to 5000 million organisms per ml, or may be 1000 million to 4000 million organisms per ml, or any integer within these ranges.
- a selected killed bacterial vaccine for cancer of the lung tissue would include the common bacterial lung pathogens, and may for example be: bacteria per ml Streptococcus pneumoniae 600 million
- a selected killed bacterial vaccine for cancer of the lung tissue would include only more common bacterial lung pathogens, and may for example be: bacteria per ml
- a selected killed bacterial vaccine for cancer of the lung tissue would include only the most common bacterial lung pathogen, and may be: bacteria per ml
- an antigenic microbial composition for treating cancer at a particular site may include pathogenic microbes that commonly, more commonly, or most commonly cause infection in that tissue or organ (e.g., infection in the lung tissue i.e., pneumonia).
- the pathogenic bacterial species and antigens thereof of the invention should be used without causing substantial toxicity.
- Toxicity of the compounds of the invention can be determined using standard techniques, for example, by testing in cell cultures or experimental animals and determining the therapeutic index, i.e., the ratio between the LD50 (the dose lethal to 50% of the population) and the LD100 (the dose lethal to 100% of the population).
- the invention involves the use of an antiinflammatory in conjunction with vaccinations.
- NSAIDs non-steroidal anti-inflammatory drugs
- NSAIDs non-steroidal anti-inflammatory drugs
- Cioxx a variety of herbs and natural health products may also be used to provide anti-inflammatory treatment, including but not limited to: green tea, fish oil, resveratrol, turmeric, bromelain, boswellia, feverfew, quercetin, ginger, rosemary, oregano, cayenne, clove, nutmeg, willowbark.
- Alternative anti-inflammatory modalities may also include lifestyle modifications, such as: exercise, weight loss, smoking cessation, stress reduction, seeking social support, treatment of depression, stress management, abdominal breath work and dietary change (such as adopting a mediterranean diet, a low glycemic diet, eating non-charred foods, including foods having omega-3 fatty acids).
- Staphylococcus aureus 1200 million viridans and non-hemolytic Streptococci 200 million Streptococcus pneumoniae 150 million
- This vaccine was produced for the following indications: rhinitis, infectious asthma, chronic sinusitis, nasal polyposis and chronic serous otitis media. Cancer treatment was not indicated as an intended use for this vaccine.
- the vaccine also included the following ingredients: 0.4% phenol, 0.9% NaCI, trace amounts of brain heart infusion (beef), peptones, yeast extract, agar, sheep blood, dextrose, and sodium phosphates.
- Stallergenes MRV Stallergenes MRV (Laboratories des Stallergenes, S.A., Fresnes, France), containing the following:
- This vaccine was produced for the same indications as the MRV vaccine i.e., recurrent respiratory tract infections, and listed cancer as a contraindication.
- Staphylococcus epidermidis 500 million Escherichia coli 200 million
- This vaccine was produced for chronic and recurrent inflammatory conditions of the upper and lower respiratory tract and genitourinary tract, including rhinopharyngitis, recurrent laryngitis, tracheitis, bronchitis, otitis media, chronic and recurrent neuralgia of trigeminal and occipital nerve, ischialgia, brachial plexitis, intercostals neuralgia, chronic cystoureteritis, vaginitis, adnexitis, and endometrium inflammation. Cancer treatment was not indicated as an intended use for this vaccine.
- PVF which contains E.
- coli a common pathogen of the colon, abdomen, kidney, ovaries, peritoneum, liver and pancreas, has been found to be effective in the treatment of cancers in the colon, abdominal lymph nodes, kidney, ovary, peritoneum, liver and pancreas.
- Staphage Lysate (Delmont Laboratories Inc., Swarthmore, PA, USA), containing the following:
- Staphage Lysate which contains Staphyloccocus aureus a common pathogen of the breast and bone, was found to be effective in the treatment of cancer in the breast and bone.
- the bacterial compositions were a suspension of killed bacterial cells and therefore, the suspensions were gently shaken prior to use to ensure uniform distribution prior to withdrawing dose from vial, and administered subcutaneously three times a week on Mondays, Wednesdays, and Fridays. Patients were advised to continue treatment for at least 6 months.
- the dose of vaccine required was determined by the adequacy of the immune reaction to the vaccine. Beginning with a very small dose (0.05cc), the dose was gradually increased (by 0.01 -0.02cc each time) until an adequate immune reaction was achieved. This delayed local reaction at the injection site occurred 6-24 hours after injection. The goal was to achieve a one to two inch diameter round patch of pinkness/redness at the injection site, indicating adequate immune stimulation.
- the dose was maintained at the level required to achieve this reaction. If the reaction was significantly less than two inches (e.g., half an inch) the dose was increased, if it was significantly more than two inches (e.g., three inches), the dose was decreased.
- This local immune reaction generally occurs within the first 24 hours after the injection. Patients were asked to check for this reaction and, if present, to measure or mark it.
- the maintenance dose required to achieve an adequate immune reaction varies considerably, depending on the individual's immune response - as little as 0.001 cc for some people, as much as 2cc for others.
- the vaccine must be stored in a refrigerator (2° to 8°C).
- the usual site for injection is the upper arms, the thighs or the abdomen. The exact site of each injection was varied so that it was not given in sites in which pinkness/redness was still present.
- a known contraindication to the vaccines is hypersensitivity to any component of the vaccine.
- a fifth vaccine a polymicrobial oral vaccine, was used in alternative aspects of the invention, as follows:
- Respivax produced by BB-NCIPD Ltd (Bulgaria). This oral vaccine contained the following freeze-dried killed bacterial species:
- Steptococcus pneumoniae 25 million
- Streptococcus pyogenes 25 million Haemophilus influenzae 25 million
- the Respivax oral vaccine was produced for the treatment for chronic respiratory infection, and contains many of the most common respiratory tract pathogens, including many of the most common causes of lung infection. Patients were treated with a dose of one 50 mg tablet per day, providing the equivalent of 1.25 x 109 cells of each species per dose. Patients were prescribed the above dose for a continuous period of at least 6 months.
- Respivax oral vaccine which contains many common lung pathogens, was found to be effective for the treatment of cancer of the lung.
- This section relates to primary cancer in the lung, or metastases to the lung, treated with microbial pathogens of the lung, such as endogenous respiratory bacteria flora, exogenous bacterial lung pathogens, or viral lung pathogens.
- microbial pathogens of the lung such as endogenous respiratory bacteria flora, exogenous bacterial lung pathogens, or viral lung pathogens.
- lung cancers may be classified as follows:
- T1 Tumour 3 cm or less in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (ie, not in the main bronchus)
- T2 Tumour with any of the following features of size or extent: More than 3 cm in greatest dimension Involves main bronchus, 2 cm or more distal to the carina Invades visceral pleura Associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung
- M1 Distant metastasis; includes separate tumour nodule(s) in the non- primary-tumour lobe (ipsilateral or contralateral)
- Charts with diagnostic codes 162.9 (lung cancer) and 197 (metastatic cancer) were collected manually and electronically. Information was collected on these patients, such as date of diagnosis, date of death, and cancer stage. Charts for patients were reviewed to confirm the date of diagnosis and cancer stage. Patients were excluded from the analysis for the following reasons: 1 ) wrong stage; 2) missing data; 3) no chart, or; 4) chart did not reach in time for the data analysis. 20 patients were excluded from the study because their charts have not arrived yet or there was insufficient information, of which 6 were MRV users. The study group includes 108 patients in total: 50 who took the MRV vaccine and 58 who did not take the MRV vaccine.
- SEER non-MRV MRV median survival 5 months 10.5 months 12.5 months survival at 1 year: 25% 45% 58% survival at 3 years: 5% 3% 20% survival at 5 years: 3% 0% 10%
- antigenic bacterial compositions used in repeated frequent injections (i.e., three times per week) for a prolonged period of time - such as at least 2, 3, 4, 5, 6 or 12 months, or 2, 3, 4 or 5 years (in the context of advanced cancer such as inoperable lung cancer, the longer periods may be most beneficial).
- Treatments of this kind may be carried out so as to provide sustained, prolonged immune stimulation.
- one-year survival of stage 3B or 4 lung cancer patients treated with MRV for at least two months was 70%, compared to just 48% for the non-MRV Lung 2 group and 23% for the SEER database group.
- 3-year survival of the MRV group was more than 4 times that of both the non-MRV patients and the SEER registry. None of the non-MRV group in the Lung 2 study survived for 5 years, whereas 15% of patients treated with MRV for a minimum two-month period were still alive 5 years after diagnosis.
- an illness such as inoperable lung cancer that is considered terminal and has a usual 5-year survival rate of only 3% (SEER registry)
- SEER registry 5-year survival rate of only 3%
- cancers such as advanced cancers, such as inoperable lung cancer
- a dosing duration of at least 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, 2 years, 3 years, 4 years, 5 years, or indefinitely.
- stage 3B lung cancer cancer is confined to the lungs, and thus, a targeted anti-cancer treatment response may be stimulated, in accordance with various aspects of the invention, by a vaccine, such as MRV, comprised of lung pathogens.
- a vaccine such as MRV
- stage 4 lung cancer the cancer has metastasized to distant organs not amenable to targeted stimulation by lung pathogens in accordance with methods of the invention.
- patients with stage 3B lung cancer may be selected for treatment with MRV vaccine, since all of the cancer is confined to the lungs and thus, will be targeted by the MRV vaccine.
- stage 3B lung cancer patients treated with MRV was 76%, compared to just 53% for the non-MRV Lung 2 group and 23% for the SEER database group.
- 3-year survival of the MRV group was 3 times that the non-MRV patients and more than 6 times the SEER registry. None of the non-MRV group survived for 5 years, whereas 14% of stage 3B patients treated with MRV were still alive 5 years after diagnosis.
- an illness such as inoperable stage 3B lung cancer that is considered terminal and has a usual 5-year survival rate of only 5% (SEER registry)
- SEER registry 5-year survival rate of only 5%
- stage 3B lung cancer patients not treated with MRV survived for 3 years
- 3-year survival of stage 3B patients treated with MRV was 33% and 5-year survival was14%, a remarkable and unexpected result.
- stage 3B lung cancer patients who had their first visit within 3 months of diagnosis died within 1 year of diagnosis
- 70% of stage 3B lung cancer patients treated with MRV within 3 months of diagnosis survived for 1 year
- 40% survived 3 years and 20% survived 5 years a truly remarkable survival benefit for early MRV treatment.
- One aspect of the invention involves the treatment of primary lung cancers or metastasis to the lung with antigenic compositions that comprise antigenic determinants of microbial pathogens that are known to be lung pathogens, such as exogenous lung pathogens or pathogens that are members of the endogenous flora of the respiratory system.
- antigenic determinants of the endogenous bacterial respiratory flora species that most commonly cause infection in the lung may be used to treat primary and metastatic cancers situated in the lung: Streptococcus pneumoniae, Moraxella catarrhalis, Mycoplasma pneumoniae, Klebsiella pneumoniae, Haemophilus influenza.
- common viral lung pathogens from Table 5 may be selected for use in some embodiments.
- a more exhaustive list of endogenous lung pathogens may be selected from Table 1 , based on the pathogenicity information provided in Table 2.
- viral lung pathogens listed in Table 4 may be used.
- exogenous bacterial lung pathogens from Table 3 may be used in formulating antigenic compositions of the invention, i.e.
- Achromobacter spp. Actinomadura spp., Alcaligenes spp., Anaplasma spp., Bacillus anthracis, other Bacillus spp., Balneatrix spp., Bartonella henselae, Bergeyella zoohelcum, Bordetella holmesii, Bordetella parapertussis, Bordetella pertussis, Borrelia burgdorferi, Borrelia recurrentis, Brucella spp., Burkholderia gladioli, Burkholderia mallei, Burkholderia pseudomallei, Campylobacter fetus, Capnoctyophaga canimorsus,
- one aspect of the invention involves the treatment of primary lung cancer and metastasis to the lung with antigenic compositions that comprise antigentic determinants of microbial pathogens that are known to be pathogenic in the lung, such as exogenous lung pathogens or pathogens that are members of the endogenous flora of the respiratory tract.
- antigenic determinants of the common lung pathogens may be used to treat primary and metastatic cancers situated in the lung, for example, antigenic determinants from one or more of the following bacterial species or viral types: Streptococcus pneumoniae, Moraxella catarrhalis, Mycoplasma pneumoniae, Klebsiella pneumoniae, Haemophilus influenza, influenza virus, adenovirus, respiratory syncytial virus, parainfluenza.
- antigenic determinants of Streptococcus pneumoniae, the most common cause of bacterial lung infection may be used alone or with other of the most common pathogens of the lung to treat cancer of the lung.
- Primary lung cancer may also arise from bronchial tissue and therefore, in some embodiments, antigenic compositions that comprise antigentic determinants of microbial pathogens that are known to cause bronchial infection may be used to treat patients with cancer situated in the bronchial tissue, including, for example, the following common causes of bronchial infection: Mycoplasma pneumoniae, Chlamydophila pneumoniae, Bordetella pertussis, Streptococcus pneumoniae, Haemophilus influenzae, influenza virus, adenovirus, rhinovirus, coronavirus, parainfluenza, respiratory syncytial virus, human metapneumovirus, or coxsackievirus.
- Mycoplasma pneumoniae Chlamydophila pneumoniae, Bordetella pertussis, Streptococcus pneumoniae, Haemophilus influenzae, influenza virus, adenovirus, rhinovirus, coronavirus, parainfluenza, respiratory syncytial virus, human metapneumovirus, or
- Lung cancer that is located in both lung and bronchial tissue may be treated with antigenic compositions that comprise antigentic determinants of microbial pathogens that are known to cause both lung and bronchial infection (for example, Streptococcus pneumoniae, Haemophilus influenza and Mycoplasma pneumoniae are all common lung and bronchial pathogens) or alternatively, with antigenic compositions that comprise antigentic determinants of microbial pathogens that are known to cause lung infection and antigentic determinants of microbial pathogens that are known to cause bronchial infection.
- antigenic compositions that comprise antigentic determinants of microbial pathogens that are known to cause both lung and bronchial infection (for example, Streptococcus pneumoniae, Haemophilus influenza and Mycoplasma pneumoniae are all common lung and bronchial pathogens) or alternatively, with antigenic compositions that comprise antigentic determinants of microbial pathogens that are known to cause lung infection and antigentic
- Example 1 B Breast Cancer with Metastasis to the Bone or Lung
- an antigenic composition comprising antigenic determinants of S. aureus may be used to treat breast cancer with metastases to the bone.
- PtR Patient R
- Staphylococcus aureus vaccine set out below in the Case Reports, illustrates the efficacy of this approach to treating breast cancer with bone metastases.
- one aspect of the invention involves the treatment of primary cancer in the breast or metastasis to the breast with antigenic compositions that comprise antigentic determinants of microbial pathogens that are known to be breast pathogens, and treatment of primary cancer of the bone or metastasis to the bone with antigenic compositions that comprise antigentic determinants of microbial pathogens that are known to be bone pathogens.
- a vaccine comprising antigenic determinants of Staphlyococcus aureus, the most common cause of both breast and bone infection, may be used alone or in combination with other of the most common pathogens of the breast to treat cancer in the breast, or alone or in combination with other of the most common pathogens of the bone to treat cancer in the bone.
- Example 1C Metastases to the Bone
- the MRV composition which contains antigenic determinants of S. aureus, the most common cause of bone infection, may be used for the treatment of metastases to the bone, for example in patients who have, or who have had, a primary prostate cancer.
- the graph of Figure 7 is a comparision of survival of a cumulative series of metastatic prostate cancer patients who had surgery or radiation to destroy their prostate gland (and thus, the primary tumour) and who had detectable cancer limited to bone metastases.
- one aspect of the invention involves the treatment of primary bone cancers or metastases to the bone with antigenic compositions that comprise antigentic determinants of microbial pathogens that are known to be bone pathogens, such as exogenous bone pathogens or pathogens that are members of the endogenous flora of the skin, mouth or colon.
- antigenic determinants of one or more of the following microbial species from the list of common bone pathogens may be used to treat primary and metastatic cancers situated in the bone: Staphylococcus aureus, coagulase-negative staphylococci, Streptococcus pyogenes, Streptococcus pneumoniae, Streptococcus agalactiae, other streptococci spp., Escherichia coli, Pseudomonas spp., Enterobacter spp., Proteus spp., Serratia spp., parvovirus B19, rubella, hepatitis B.
- Staphylococcus aureus the most common cause of bone infection, may be used alone or with other of the most common pathogens of the bone to treat cancer of the bone.
- Stage 4 colon cancer patients who were treated with PVF vaccine 1. Stage 4 colon cancer patients from the SEER (Surveillance, Epidemiology and End Results) database.
- the patient group included a total of 136 stage 4 colon cancer patients: 15 who took the PVF vaccine, 56 who took the MRV vaccine, and 65 who did not take a vaccine. Results are illustrated in Figure 8, as follows:
- SEER no vaccine MRV PVF median survival 8.4 mo. 15.1 mo. 15.0 mo. 33.6 mo. at 10 months 45 % 69 % 71 % 100 % at 20 months 24 % 42 % 36 % 67 % at 30 months 14 % 29 % 23 % 52 % at 5 years 5 % 6 % 7 % 10 %
- one aspect of the invention involves the treatment of colon cancers with antigenic compositions that comprise antigentic determinants of microbial pathogens that are known to be colon pathogens, such as pathogens that are members of the endogenous flora of the colon or exogenous colonic pathogens.
- antigenic determinants of the following microbial species may be used to treat primary and metastatic cancers situated in the colon: Escherichia coli, Clostridium difficile, Bacteroides fragilis, Bacteroides vulgatus, Bacteroides thetaiotaomicron, Clostridium perfringens, Salmonella enteriditis, Yersinia enterocolitica, Shigella flexneri; adenoviruses, astroviruses, caliciviruses, noroviruses, rotaviruses, or cytomegalovirus.
- cancers situated in the colon may be treated with the PVF composition, which contains E.
- antigenic determinants of E. coli may be used alone or with antigenic determinants of other common pathogens of the colon to treat cancer of the colon.
- Example 1 E Use of Respivax, an Oral Vaccine to Treat Lung Cancer
- Oral Respivax vaccine was administered as described above, with a dose of one 50 mg tablet per day, providing the equivalent of 1.25 x 109 cells of each species per dose. Patients were advised to continue the above dose for at least 6 months.
- one aspect of the invention involves the treatment of primary of the lung or metastases to the lung with oral administration of antigenic compositions that comprise antigentic determinants of microbial pathogens that commonly cause lung infection.
- Example 2 Case Reports [00180] These case reports are indicative of the patients that make up the patient populations reflected in the foregoing cumulative studies, as well as illustrating additional aspects of the invention.
- PtA continued treatment with this combination of MRV vaccine and adjuvant anti-inflammatory therapies for more than 4 years until the end of May, year 5 at which time there was no evidence of residual cancer, in spite of a diagnosis of terminal inoperable lung cancer more than 4 years previously. More than 12.5 years since diagnosis with terminal lung cancer, PtA continues to feel well with no evidence of residual cancer.
- one aspect of the invention involves the treatment of cancers in the lung with administration of antigenic compositions that comprise antigentic determinants of microbial pathogens that commonly cause lung infection.
- another aspect of the invention involves the administration of the immunogenic compositions repeatedly relatively frequently over a relatively long period of time.
- anti-inflammatory agents such as antioxidants, vitamin D and indomethicin
- MRV therapy was associated with substantially improved survival, which was greater than that of otherwise similar cases, in which these adjuvant anti-inflammatory modalities were not used in conjunction with the compositions of the invention.
- Patient B an otherwise similar case in which anti-inflammatories were not administered, was diagnosed with inoperable stage 3B non-small cell lung cancer, which was fatal within 3 months of diagnosis.
- one aspect of the invention involves the treatment of cancers with both the administration of antigenic compositions that comprise antigenic determinants of microbial pathogens that are pathogenic to the organ or tissue targeted, as well as adjuvant antiinflammatory treatments, for synergistic effect.
- Patient C In the spring of year 0, PtC began having pain in his right upper chest area. This pain persisted and on October 5, year 0 he had a chest x-ray that revealed a large 12 cm x 11 cm mass occupying virtually the entire right upper lobe. A fine needle aspiration was positive for poorly differentiated non-small cell lung cancer. Exploratory thoracotomy was performed on December 7, year 0, which revealed tumour invasion of the chest wall and superior vena cava and therefore, PtCs tumour was inoperable (i.e., stage 3B). PtC underwent a short course of palliative radiation and declined chemotherapy. He was told that he had terminal cancer with a 3 to 6 months life expectancy.
- PtC continued treatment with a combination of the MRV vaccine and adjuvant anti-inflammatory therapies (indomethicin, antioxidants and vitamin D) for more than 16 months until July 24, year 2, at which time indomethicin treatment was discontinued (as a result of decreased kidney function, a known potential side-effect of long-term indomethicin use). 6 months later, in December, year 2, after 22 months of targeted vaccine therapy, MRV treatment was discontinued (since MRV was no longer available past that date).
- adjuvant anti-inflammatory therapies indomethicin, antioxidants and vitamin D
- PtC continued to feel well until June, year 6, at which time he was diagnosed with a recurrence of cancer in both lungs, which lead to his death on May 26, year 7, more than 6.5 years after he was diagnosed with terminal lung cancer and told he had 3-6 months to live.
- adjuvant anti-inflammatory agents including antioxidants, vitamin D and indomethicin
- used in conjunction with targeted MRV therapy for more than 16 months was associated with substantially improved survival in the face of a diagnosis that is usually fatal within 1 year, which was greater than that of an otherwise similar case, Patient D, in which these adjuvant anti-inflammatory modalities were not used in conjunction with the compositions of the invention, and an inoperable lung cancer was fatal within 8 months of diagnosis.
- one aspect of the invention involves the treatment of cancers of the colon, liver and lung with administration of antigenic compositions that comprise antigentic determinants of microbial pathogens that are known to be pathogenic in the colon, liver and lung.
- PtG Patient G developed rectal bleeding in May, year 0, and was diagnosed with colon cancer. He underwent surgery, chemotherapy and radiation, but developed metastases to his lungs (stage 4 cancer) on 16 August, year 1 , a terminal diagnosis with a poor prognosis. He had begun a regime of antioxidant vitamins and vitamin D in June, year 0, and, on September 23, year 1 , he began taking the NSAID Celebrex 100 mg twice per day.
- the invention provides for the use of antiinflammatory modalities in conjunction with immunogenic compositions, such as PVF, for synergistic effect.
- PtI began a regime of antioxidant vitamins, vitamin D, large doses of turmeric (curcumin), fish oil (9 gm per day), resveratrol and green tea (equivalent of 36 cups per day) on September 27, year 2, all of which are antiinflammatory modalities, all of which he continues to take.
- curcumin curcumin
- fish oil 9 gm per day
- resveratrol and green tea (equivalent of 36 cups per day) on September 27, year 2, all of which are antiinflammatory modalities, all of which he continues to take.
- PtI began treatment with PVF three times per week in May year 4, which he has continued to use regularly for more than 2.5 years since then.
- PtI is alive more than 4 years after a diagnosis of terminal metastatic pancreatic cancer, a remarkably prolonged survival in the context of a diagnosis that has an extremely poor prognosis.
- one aspect of the invention involves the treatment of cancer of the pancreas, abdominal lymph nodes, liver and lung with administration of antigenic compositions that comprise antigentic determinants of microbial pathogens that are known to cause infection in the pancreas, abdominal lymph nodes, liver and lungs.
- PtJ Patient J
- PtJ had an essentially identical diagnoses to PtI (i.e., pancreatic cancer with metastases to abdominal lymph nodes, lungs and liver).
- PtJ who did not take any other anti-inflammatories along with the PVF vaccine except antioxidants, died within 4 months of diagnosis, whereas PtI, who took large doses of numerous other anti-inflammatories modalities (i.e., Celebrex, turmeric, fish oil, resveratrol and green tea) in conjunction with PVF vaccine, is still alive more than 4 years after diagnosis.
- PtI who took large doses of numerous other anti-inflammatories modalities (i.e., Celebrex, turmeric, fish oil, resveratrol and green tea) in conjunction with PVF vaccine, is still alive more than 4 years after diagnosis.
- one aspect of the invention involves the treatment of cancers of the breast and bone with administration of antigenic compositions that comprise antigentic determinants of microbial pathogens that are known to be pathogenic in the breast and bone infection.
- Patient L PtL
- PtL was diagnosed with breast cancer with metastases to bone on October 11 , year 0. She was not prescribed an NSAID or other anti-inflammatories. PtL began treatment with MRV on February 27, year 1. She died 9 months later on November 4, year 1 , just over one year after diagnosis with stage 4 breast cancer with metastases to bone.
- the contrast between the othewise similar cases of PtK and PtL illustrates the potential for synergistic treatment with anti-inflammatories and the antigenic compositions of the invention.
- Patient M PtM was diagnosed with stage 4 breast cancer with metastases to bone on June 15, year 0. She began on the NSAID Naprosyn 250 mg twice per day on an ongoing basis for pain relief and, in October, year 3, she began doses of antioxidants and vitamin D. Three months later, on January 15, year 4, she began treatment with MRV vaccine (which contains Staphylococcus aureus, the most common breast and bone pathogen) in combination with these anti-inflammatory therapies (i.e., Naprosyn, antioxidants and vitamin D). PtM lived for more than 9 years after being first diagnosed with stage 4 metastatic breast cancer with metastases to bone, an unusually long survival considering the usual poor prognosis associated with this diagnosis.
- MRV vaccine which contains Staphylococcus aureus, the most common breast and bone pathogen
- one aspect of the invention involves the treatment of cancers of the breast and bone with administration of antigenic compositions that comprise antigentic determinants of microbial pathogens that are known to be common causes of breast and bone infection.
- Patient O was diagnosed in June, year 0 with kidney cancer with metastases to the lungs bilaterally and to the bone (left femur). This is generally considered to be an incurable terminal diagnosis with a poor prognosis. He began treatment with the MRV on August 10, year 0 and continued regular treatment (three times per week) for 16 months (after which MRV was no longer available). In September, year 0, he began 7 months of treatment with an experimental drug, pegylated interferon alpha-2a. His left femur was 'pinned' due to the risk of fracture as a result of the metastasis but, due to surgical complications, amputation of the left leg below the mid-thigh was required.
- one aspect of the invention involves the treatment of metastases to the lung with administration of antigenic compositions that comprise antigentic determinants of microbial pathogens that are known to be lung pathogens.
- one aspect of the invention involves the treatment of metastases to the lung and bone with administration of antigenic compositions that comprise antigentic determinants of microbial pathogens that are common causes of lung and bone infection.
- Patient R In May, year 0, PtR was diagnosed with breast cancer with metastases to her sternum, femur and cervical spine, an incurable cancer with a poor prognosis. She was treated with radiation and Tamoxefen. In May, year 4, she developed an additional area of metastasis in her lumbar spine and she began on treatment with Megace. In November, year 4, she began treatment with a vaccine (Staphage Lystate vaccine) containing only
- Staphylococcus aureus the most common cause of infection of both the breast and bone and thus, a selected formulation for the treatment of breast and bone cancer. She continued regular therapy with this vaccine for 5 years. In spite of a diagnosis of metastatic breast cancer with multiple bone metastases, PtR survived for more than 17 years, a remarkable survival in the context of incurable metastatic breast cancer and a testament to the promise of targeted vaccine therapy for the treatment of breast cancer.
- one aspect of the invention involves the treatment of cancers of the breast and bone with administration of antigenic compositions that comprise antigentic determinants of microbial pathogens that are known to be the most common cause of the breast and bone infection.
- This embodiment illustates that a formulation that includes antigenic determinants of only the most frequently pathogenic organisms for a tissue may provide particular advantages.
- one aspect of the invention involves formulating the antigenic compositions such that antigentic determinants of microbial pathogens that are known to be the common causes of infection are given preferential priority in the proportions of the formulation, with the most common cause of infection receiving the greatest preferential priority.
- the proportion of antigenic determinants that are derived from pathogens that are known to be a common cause of infection may be 20, 30, 40, 50, 60, 70, 80, 90, 95 or 99%.
- the invention provides antigenic compositions in which a threshold proportion of antigenic determinants selected in accordance with the invention are used, relative to any other antigenic determinants in the composition.
- antigenic compositions may have greater than X% of the antigenic determinants therein derived from pathogenic (or commonly pathogenic, or most commonly pathogenic) species, where X may for example be 20, 30, 40, 50, 60, 70, 80, 90, 95 or 99 (or any integer value between 20 and 100).
- at least X% of the antigenic determinants in the antigenic composition may be specific for microbial pathogens that are pathogenic (or commonly pathogenic, or most commonly pathogenic) in the specific organ or tissue of the patient within which the cancer is situated.
- the antigenic composition may accordingly consist essentially of antigenic determinants of one or more microbial pathogens that are each pathogenic in the specific organ or tissue of the patient within which the cancer is situated.
- the antigenic composition may consist essentially or entirely of antigenic determinants of microbial pathogens that are commonly pathogenic in the specific organ or tissue of the patients with which the cancer is situated.
- the antigenic antigenic composition may consist essentially or entirely of antigenic determinants of microbial pathogens that are most commonly pathogenic in the specific organ or tissue of the patients with which the cancer is situated.
- MRV Magnetic MRV for Multiple Myeloma
- Patient S was diagnosed with multiple myeloma (stage 3A) in the fall of year 0, with multiple lesions on bone scan, including skull, humeri and pelvis. He was treated with standard chemotherapy (melphalan and prednisone) for 6 months. However, in December year 3, he developed a pathological fracture of his right femur as a result of his disease, which required pinning and local radiation. On April 28, year 4, PtS began treatment with MRV, which contains Staphylococcus aureus a common cause of septicemia, which he continued for more than 13 years until this vaccine was no longer available in December year 17. Remarkably, PtS was still alive 23 years after being diagnosed with multiple myeloma, a truly extraordinary outcome considering his 'terminal' diagnosis.
- one aspect of the invention involves the treatment of hematological cancers with administration of antigenic compositions that comprise antigentic determinants of microbial pathogens that are known to cause septicemia.
- another aspect of the invention involves the administration of the immunogenic compositions repeatedly relatively frequently over a relatively long period of time, as described elsewhere herein.
- one aspect of the invention involves the treatment of cancer in abdominal lymph nodes with administration of antigenic compositions that comprise antigentic determinants of microbial pathogens that are known to cause infection in abdominal lymph nodes.
- one aspect of the invention involves the treatment of cancer of the skin and perineum with administration of antigenic compositions that comprise antigentic determinants of microbial pathogens that are known to be common causes infection in the skin and perineum.
- Patient V was diagnosed with breast cancer in May, year 0, at which time she had a masectomy with adjuvant chemotherapy. In January, year 12, she developed abdominal pain and ascites and was diagnosed with peritoneal metastases, a diagnosis with a poor prognosis. On August 5, year 12, PtV began treatment with PVF, which contains E. colia common cause of peritoneal infection, which she continued regularly for 1 year. Her tumour markers and ascites decreased and, in August year 13, after one year of PVF treatment, she had abdominal surgery for an unrelated medical condition, at which time the surgeon could not find any evidence of the previous peritoneal cancer. PtV discontinued use of the vaccine. PtV is alive, 3 years and 9 months after being diagnosed with terminal peritoneal metastases.
- one aspect of the invention involves the treatment of peritoneal metastases with administration of antigenic compositions that comprise antigentic determinants of microbial pathogens that are known to cause peritoneal infection.
- Patient W was diagnosed with stage 3B poorly differentiated ovarian cancer in the fall of year 0. She had surgery in November year 0, with removal of the left ovary, but the cancer could not be completely excised and thus, she was at extreme risk for recurrence. She had a full course of post-operative chemotherapy. However, in year 2 her tumour markers began to rise and in
- one aspect of the invention involves the treatment of ovarian and pelvic cancer with administration of antigenic compositions that comprise antigentic determinants of microbial pathogens that are known to cause infection in the ovary and pelvic areas.
- Patient Y was diagnosed with stage 4A Follicular Non- Hodgkin's lymphoma, with extensive marked lymphadenopathy (i.e., enlarged lymph glands). He declined all conventional treatment. PtY began treatment with the MRV composition, which contains many of the pathogens which commonly cause infection of the lymph nodes of the head and neck, axillae, mediastinum and inguinal areas. In addition, he began treatment with a multiple vitamin/supplement regime, healthful diet and other immune enhancement treatments. He continued regular use of this vaccine for more than 3 years, at which time his lymph glands had begun to greatly reduce in size and he was feeling well.
- one aspect of the invention involves the treatment of lymphoma with administration of antigenic compositions that comprise antigentic determinants of microbial pathogens that are known to be common causes of lymph node infection in the region the lymphoma is located.
- PVF for Colon Cancer with Metastases to the Liver and Kidneys
- Patient Z was diagnosed with metastatic spread of previously treated colon cancer, with a metastasis to the liver and probable other metastases to both kidneys. The liver metastasis was excised. The prognosis for this stage (i.e., stage 4) of colon cancer is poor and the benefit of further conventional treatment (i.e., chemotherapy) is limited. PtZ declined chemotherapy initially.
- PtZ began treatment with Polyvaccinum Forte (PVF), which contains E. coli, a common cause of infection of the colon, liver and kidneys.
- PtZ began treatment with a multiple vitamin/supplement regime and healthful diet.
- one aspect of the invention involves the treatment of cancer of the colon, liver and kidneys with administration of antigenic compositions that comprise antigentic determinants of microbial pathogens that are known to be pathogenic in the colon, liver and kidneys.
- PVF for Colon Cancer with Metastases to the Liver. Porta Hepatic Lymph Nodes and Lung
- Patient AA was diagnosed with metastatic colon cancer with metastases to the liver, portahepatic lymph nodes and lungs.
- the prognosis for this stage (i.e., stage 4) of colon cancer is very poor (i.e., 'terminal' cancer) and the benefit of conventional treatment (i.e., chemotherapy) is limited.
- PtAA began chemotherapy, but discontinued treatment approximately 5 months after his diagnosis due to side effects, at which time he began treatment with Polyvaccinum Forte (containing bacterial species which cause infection in the colon, liver, abdominal lymph nodes and lungs) every second day as well as a multiple vitamin/supplement regime and a healthy diet.
- one aspect of the invention involves the treatment of cancer of the colon, liver, abdominal lymph nodes and lungs with administration of antigenic compositions that comprise antigentic determinants of microbial pathogens that are known to be pathogenic in the colon, liver, abdominal lymph nodes and lungs.
- the invention utilizes microbial antigens, such as bacterial or viral antigens, to formulate antigenic compositions, where the microbial species is selected on the basis of the tissue or organ within which the microbe is known to cause infections.
- Bacterial resident flora are the most common pathogens, accounting for the vast majority of infectious episodes of most animals, including humans. Resident flora can for example infect through primary attachment, or attachment and invasion following mucosa damage, resulting for example from vascular, trauma, chemical insult, or damage resulting from primary infection.
- virulence and infection potential is a combination of the ability of the microbe to adhere, to produce enzymes, to survive immunoproducts (complement, antibody) and to survive the microbiocidal activity of macrophage and neutrophils.
- Some bacteria, including endogenous bacteria, may be sufficiently virulent as to cause monomicrobial infections, while others are more effective with the synergy of polymicrobial infection.
- Bacteria successful at intracellular survival within macrophages are more commonly associated with chronic infection, as are bacteria with slow growth cycles.
- acute infection may, in some cases, provide more optimal immune stimulation, accordingly, in some embodiments, the invention utilizes microbial species that are involved in acute infection.
- bacteria that are members of the endogenous flora of a particular region may be used to formulate antigenic compositions of the invention.
- the rows of Table 1 list a number of bacterial species, together with the biological regions in which each species may form a part of the endogenous flora.
- Abiotrophia spp. are typically members of the endogenous flora of the respiratory tract and the mouth.
- Endogenous microbial flora such as bacteria
- Endogenous microbial flora have access to tissues for pathogenesis either through contiguous spread or bacteremic spread. Under favorable conditions, all endogenous organisms can become pathogenic and invade locally and spread by contiguous spead to adjacent tissues and organs.
- Endogenous bacterial flora of the skin, mouth and colon are the species that are understood to be amenable to bacteremic spread. Bacteria that are members of a particular endogenous flora domain may therefore cause infection in tissues or organs to which these bacteria may spread.
- one aspect of the invention involves the use of endogenous microbial pathogens to treat a cancer of a tissue or organ to which the endogenous bacteria may spread to cause infection.
- the columns of Table 2 list 9 domains for endogenous flora, the: skin, respiratory system, genitals, GU system, mouth, stomach, duodenum/jejunum, ileum and colon.
- the rows of Table 2 list organs or tissues within which cancers may be situated. Accordingly, one aspect of the invention involves the use of endogenous microbial pathogens to formulate antigenic compositions, or the selection of existing formulations having the pathogens, for treating cancers situated in tissues or organs to which the pathogen may spread to cause an infection.
- tumors situated in the tissues or organs listed in the first column of Table 2 may be treated with antigenic compositions comprising antigenic determinants that are specific for microbial pathogens that are members of the endogenous flora of one or more of the endogenous flora domains listed in the first row of Table 2 and indicated with an X or a check mark in the appropriate row.
- tumors situated in the prostate may be treated with an antigenic composition having antigenic determinants specific for a microbial pathogen or pathogens endogenous to the GU system and/or genital system.
- one aspect of the invention involves the treatment of a cancer situated in a tissue listed in Table 2 with an antigenic composition comprising antigenic determinants of the bacterial species that are listed in Table 1 , where the regions of endogenous flora linked to the tumor in Table 2 match the regions of endogenous flora linked to the bacterial species in Table 1.
- cancers located in the tissues or organs set out in column 1 of Table 2 may be treated with antigenic compositions comprising antigenic determinants of the corresponding bacterial species of Table 1 , so that the column headings in Table 2 are in effect replaced with the bacterial species of Table 1.
- microbial pathogens for use in the invention may be exongenous bacterial pathogens.
- the organisms listed in Table 3 may be used as microbial pathogens to formulate antigenic compositions, or antigenic compositions having those pathogens may selected, for use to treat cancers situated in the tissues or organs listed with the relevant organism in Table 3.
- antigenic determinants of both endogenous and exogenous bacterial species targeted to a specific tissue or organ may be used in combination.
- microbial pathogens for use in the invention may be viral pathogens.
- Table 4 provides an exemplary list of viral pathogens together with the tissue and organ sites for which each viral species is reportedly a pathogen.
- one aspect of the invention involves utilizing immunogenic compositions that are specific for the named viruses to treat a cancer situated in the organs or tissues that are identified adjacent to the name of the virus in Table 4.
- an antigenic composition derived from, or specific for, a vaccinia virus may be used to treat a cancer situated in the skin, hematological tissues, lymph nodes, brain, spinal cord, eye or heart.
- Table 4 Viral Human Pathogens and Their Sites of Infection
- Tables 1 through 4 provides an extensive identification of microbial pathogens that may be used in the formulation of antigenic compositions of the invention, together with an identication of the tissues or organs in which these organisms are pathogenic, and accordingly the tissues or organs in which a cancer is situated that may be treated with the antigenic formulation.
- the microbial pathogen selected for use in antigenic compositions of the invention may be one that is a common cause of acute infection in the tissue or organ in which the cancer to be treated is situated.
- Table 5 identifies bacterial and viral pathogens of this kind, together with the tissues and organs in which they commonly cause infection. Accordingly, in selected embodiments, a cancer residing in a tissue identified in the first column of Table 5 may be treated with an antigenic composition that comprises antigenic determinants for one or more of the pathogenic organisms listed in the second column of Table 5.
- a cancer residing in the skin may be treated with an antigenic composition comprising antigenic determinants of one or more of the following organisms: Staphylococcus aureus, Beta hemolytic streptococci group A, B, C and G, Corynebacterium diptheriae, Corynebacterium ulcerans, Pseudomonas aeruginosa, rubeola, rubella, varicella-zoster, echoviruses, coxsackieviruses, adenovirus, vaccinia, herpes simplex, or parvo B19.
- particular microbial pathogens may be suited for treatment of particular cancers, examples of selected embodiments are set out in Table 5. These are exemplary embodiments, and not an exhaustive list of the alternative formulations for use in accordance with the invention.
- the specific microbes which commonly cause infection in a specific tissue or organ may vary by geographical location.
- Mycobacterium tuberculosis is a more common cause of lung infection in some geographical locations and populations than in others and therefore, while M. tuberculosis may not be a common lung pathogen in some geographic and population groups it may be a common lung pathogen in others.
- Table 5 is thus not an exhaustive list of common pathogens for all geographic locations and population groups. It is understood that a clinical microbiologist skilled in the art could determine the common pathogenic species in a particular geographic area or population group for a specific tissue or organ site in accordance with the invention.
- the microbial pathogen selected for use in antigenic compositions of the invention may be one that is the most common cause of acute infection in the tissue or organ in which the cancer to be treated is situated, which may provide particular benefit as illustrated by the case of Patient R.
- Staphylococcus aureus would be the bacterial species selected
- cancer in lung tissue Streptococcus pneumoniae would be selected
- breast cancer Staphylococcus aureus would be selected
- kidney or bladder cancer Escherichia coli would be selected
- colon cancer Escherichia coli would be the bacterial species selected.
- a clinical microbiologist skilled in the art could determine the most frequently pathogenic species, bacterial or viral, for each specific tissue or organ in accordance with the invention.
- only antigenic determinants of the most common pathogen for the particular tissue or organ could be used to treat cancers of that tissue or organ.
- antigenic determinants of the most common pathogen for the particular tissue or organ could be used in combination with antigenic determinants of other pathogens that are known to be pathogenic in the of that particular tissue or organ, preferentially selecting from the more common pathogens.
- the invention provides antigenic compositions in which a threshold proportion of antigenic determinants selected in accordance with the invention are used, relative to any other antigenic determinants in the composition.
- antigenic compositions may have greater than X% of the antigenic determinants therein derived from pathogenic (or commonly pathogenic, or most commonly pathogenic) species, where X may for example be 20, 30, 40, 50, 60, 70, 80, 90, 95 or 99 (or any integer value between 20 and 100).
- at least X% of the antigenic determinants in the antigenic composition may be specific for microbial pathogens that are pathogenic (or commonly pathogenic or most commonly pathogenic) in the specific organ or tissue of the patient within which the cancer is situated.
- At least X% may be selected to be microbial pathogens that are pathogenic (or commonly pathogenic or most commonly pathogenic) in the specific organ or tissue of the patient within which the cancer is situated.
- the antigenic composition may accordingly consist essentially of antigenic determinants of one or more microbial pathogens that are each pathogenic (or commonly pathogenic or most commonly pathogenic) in the specific organ or tissue of the patient within which the cancer is situated.
- the one patient (Patient R) who was treated with a vaccine specifically targeted for breast cancer and bone cancer i.e., containing only Staphylococcus aureus, by far the most common cause of both breast and bone infection
- a vaccine specifically targeted for breast cancer and bone cancer i.e., containing only Staphylococcus aureus, by far the most common cause of both breast and bone infection
- the inclusion, in MRV, of other bacterial species that do not (or far less commonly) cause bone infection and commonly cause infection elsewhere (i.e., respiratory tract) appears to substantially reduce the benefit of this vaccine for the treatment of cancer of the breast and bone.
- stage 3B lung cancer patients treated with Respivax i.e., median survival of 38 months and 40% 5-year survival
- MRV median survival of 18 months and 14% 5-year survival
- Respivax contains substantially greater relative concentrations of the bacterial species that commonly cause lung infection than MRV does. 67% of the bacterial cell count of Respivax is comprised of bacterial species that are the common causes of lung infection, whereas only 30% of the bacterial cell count of MRV is comprised of bacterial species that are the common causes of lung infection.
- the composition having the greater proportion of bacteria that most commonly cause lung infections, Respivax is shown to be more effective for the treatment of lung cancer than the MRV formulation.
- stage 4 colon cancer patients treated with MRV which does not contain any colon pathogens
- MRV which does not contain any colon pathogens
- the invention comprises the use of bacterial or viral vaccines that are approved for other purposes (e.g., poliomyelitis vaccine, H. influenza vaccine, meningococcal vaccine, pneumococcal vaccine, influenza vaccine, hepatitis B vaccine, hepatitis A vaccine, diphtheria vaccine, tetanus vaccine, pertussis vaccine, measles vaccine, mumps vaccine, rubella vaccine, varicella vaccine, BCG vaccine, cholera vaccine, Japanese encephalitis vaccine, rabies vaccine, typhoid vaccine, yellow fever vaccine, small pox vaccine, etc.) for use as cancer treatments by selecting a vaccine containing a pathogen (or antigenic constituent of a pathogen) that is pathogenic in the specific organ or tissue of the patient within which the cancer is situated by consulting Tables 1 -5.
- poliomyelitis vaccine e.g., H. influenza vaccine, meningococcal vaccine, pneumococcal vaccine, influenza vaccine, hepatitis B vaccine,
- a S. pneumoniae vaccine either a whole cell vaccine or a vaccine comprised of one or more antigenic components of S. pneumoniae (e.g., pneumococcal polysaccharide-23-valent) could be used to treat cancer at any of the following sites in which S. pneumoniae is listed as a common pathogen in Table 5: pulmonary hilar lymph nodes, hematological cancers, bone, meninges, spinal cord, eye/orbit, sinus, thyroid, bronchi, lungs, pleura or peritoneum.
- S. pneumoniae vaccine either a whole cell vaccine or a vaccine comprised of one or more antigenic components of S. pneumoniae (e.g., pneumococcal polysaccharide-23-valent) could be used to treat cancer at any of the following sites in which S. pneumoniae is listed as a common pathogen in Table 5: pulmonary hilar lymph nodes, hematological cancers, bone, meninges, spinal cord, eye/orbit, sinus, thyroid,
- a hepatitis B vaccine could be used to treat cancer at any of the following sites in which hepatitis B virus is listed as a pathogen in Table 4, as follows: liver, pancreas, or hematological cancers.
- compositions and methods are specifically excluded from the scope of the invention.
- the use of the following microbial pathogens in the treatment of the following cancers is excluded from some embodiments, so that the claimed invention may extend to particular embodiments with the exception of one or more of the following: a) BCG (Mycobacterium bovis) for the treatment of stomach cancer and colon cancer, for example by injection; b) Mycobacterium wfor the treatment of lung cancer, for example by injection; c) Mycobacterium vaccae for the treatment of non-small-cell lung cancer, for example by injection; d) Corynebacterium parvum for the treatment of melanoma, for example by injection; e) Streptococcus pyogenes for the treatment of stomach cancer, for example by injection; f) Nocardia rubra for the treatment of lung cancer or acute myelogenous leukemia, for example by injection; g) Lactobacillus casei for the treatment of cervical cancer, for
- Staphylococcus aureus Klebsiella pneumoniae.
Abstract
Description
Claims
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PCT/CA2007/001915 WO2008049231A1 (en) | 2006-10-27 | 2007-10-25 | Tissue targeted antigenic activation of the immune response to treat cancers |
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US8501198B2 (en) | 2004-06-07 | 2013-08-06 | Qu Biologics Inc. | Tissue targeted antigenic activation of the immune response to treat cancers |
US9107864B2 (en) | 2004-06-07 | 2015-08-18 | Qu Biologics Inc. | Tissue targeted antigenic activation of the immune response to treat cancers |
RU2517719C2 (en) * | 2008-05-29 | 2014-05-27 | Трансжене Са | Biomarker for selecting patients and respective questions |
NZ606490A (en) | 2010-07-26 | 2015-04-24 | Qu Biolog Inc | Immunogenic anti-inflammatory compositions |
US8980279B2 (en) | 2010-07-26 | 2015-03-17 | Qu Biologics | Personalized site-specific immunomodulation |
CN105816863A (en) * | 2010-07-26 | 2016-08-03 | Qu生物制药公司 | Immunogenic anti-inflammatory compositions |
RU2724895C2 (en) | 2014-05-02 | 2020-06-26 | Кью Байолоджикс Инк. | Antimicrobial immunomodulation |
CN106011007A (en) * | 2016-06-06 | 2016-10-12 | 余国华 | Combined drug-resistant bacterium immunoreactive protein, and preparation method and application thereof |
CN112074283A (en) * | 2018-02-06 | 2020-12-11 | 伊夫罗生物科学公司 | Compositions and methods for treating cancer and immune disorders using bacteria of the genus veillonella |
CN110872632A (en) * | 2018-08-30 | 2020-03-10 | 深圳华大生命科学研究院 | Specific gene sequence of streptococcus pharyngolaris, detection primer and application thereof |
CN111560330B (en) * | 2020-05-12 | 2022-04-26 | 天津科技大学 | Lactobacillus casei with immunoregulation, anti-inflammatory and anti-cervical cancer effects and application thereof |
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CA2997459A1 (en) | 2008-04-27 |
CA2997459C (en) | 2020-09-22 |
EP3338797A1 (en) | 2018-06-27 |
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CN107412759A (en) | 2017-12-01 |
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