Combined physical and immunotherapy for cancer

Details Combined physical and immunotherapy for cancer Combined physical and immunotherapy for cancer

1998-03-19

2001-11-13

Bansal, Geetha P. (Department: 1642)

Drug, bio-affecting and body treating compositions

Antigen, epitope, or other immunospecific immunoeffector

Cancer cell or component thereof

C424S184100, C424S278100

Reexamination Certificate

active

06316007

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Technical Field
The present invention relates generally to methods for treating neoplasms and products derived therefrom and, more specifically, to treatment methods combining direct physical tumor therapy and immunotherapy in order to induce immediate neoplastic cellular destruction and simultaneously stimulate the self-immunological defense system against residual neoplastic cells.
2. Background
A neoplasm is an abnormal tissue that grows by cellular proliferation more rapidly than normal. It continues to grow even after the stimulus that initiated its growth dissipates. Neoplasms show a partial or complete lack of structural organization and functional coordination with the normal tissue and usually form a distinct mass which may be either benign or malignant.
Cancer is a general term frequently used to indicate any of the various types of malignant neoplasms, most of which invade surrounding tissues, may metastasize to several sites, and are likely to recur after attempted removal and to cause death of the patient unless adequately treated. Cancer can develop in any tissue of any organ at any age.
Once an unequivocal diagnosis of cancer is made, treatment decisions become paramount. Though no single treatment approach is applicable to all cancers, successful therapy must be focused on the primary tumor and its metastases, whether clinically apparent or microscopic.
Conventional Treatments
Historically, local and regional therapy, such as surgery or radiation, have been used in cancer treatment, along with systemic therapy, e.g., drugs.
Surgery is the oldest effective form of cancer therapy. In 1988, about 1,500,000 persons developed cancer; of those, about 515,000 had cancer of either the skin or cervix. About 985,000 had other systemic forms; 64% had operable lesions, with an estimated cure rate of 62%. Cancers that may be positively influenced with surgery alone, if detected in early stages, include those of the cervix, breast, bladder, colon, prostate, larynx, endometrium, ovary, oral cavity, kidney, testis (nonsemino-matous) and lung (non-small cell). It must be noted, however, that the percentage rate of treatment success varies greatly between the cancer sites.
Radiation plays a key role in the remediation of Hodgkin's disease, nodular and diffuse non-Hodgkin's lymphomas, squamous cell carcinoma of the head and neck, mediastinal germ-cell tumors, seminoma, prostate cancer, early stage breast cancer, early stage non-small cell lung cancer, and medulloblastoma. Radiation can be used as palliative therapy in prostate cancer and breast cancer when bone metastases are present, in multiple myeloma, advanced stage lung and esophagopharyngeal cancer, gastric cancer, and sarcomas, and in brain metastases. Cancers that may be curable with radiation alone include Hodgkin's disease, early-stage non-Hodgkin's lymphomas, cancers of the testis (seminomal), prostate, larynx, cervix, and, to a lesser extent, cancers of the nasopharynx, nasal sinuses, breast, esophagus, and lung.
Antineoplastic drugs are those that prevent cell division (mitosis), development, maturation, or spread of neoplastic cells. The ideal antineoplastic drug would destroy cancer cells without adverse effects or toxicities on normal cells, but no such drug exists. Despite the narrow therapeutic index of many drugs, however, treatment and even cure are possible in some patients. Certain stages of choriocarcinoma, Hodgkin's disease, diffuse large cell lymphoma, Burkitt's lymphoma and leukemia have been found to be susceptible to antineoplastics, as have been cancers of the testis (nonseminomatous) and lung (small cell). Common classes of antineoplastic drugs include alkylating agents, antimetabolites, plant alkaloids, antibiotics, nitrosoureas, inorganic ions, enzymes, and hormones.
Despite some success, the above treatments are not effective to the degree desired, and the search has continued for more efficacious therapies.
Recent Advances
Two of the more recent oncological treatment modalities investigated by the medical community are photodynamic therapy and tumor immunotherapy.
I. Photodynamic Therapy
It has been known for many years that photosensitizing compounds show a photochemical reaction when exposed to light. Photodynamic therapy (PDT) uses such photosensitizing compounds and lasers to produce tumor necrosis. Treatment of solid tumors by PDT usually involves the systemic administration of tumor localizing photosensitizing compounds and their subsequent activation by laser. Upon absorbing light of the appropriate wavelength the sensitizer is converted from a stable atomic structure to an excited state. Cytotoxicity and eventual tumor destruction are mediated by the interaction between the sensitizer and molecular oxygen within the treated tissue to generate cytotoxic singlet oxygen.
Two good general references pertaining to PDT, biomedical lasers and photosensitizing compounds, including light delivery and dosage parameters, are
Photosensitizing Compounds: Their Chemistry, Biology and Clinical Use
, published in 1989 by John Wiley and Sons Ltd., Chichester, U.K., ISBN 0 471 92308 7, and
Photodynamic Therapy and Biomedical Lasers: Proceedings of the International Conference on Photodynamic Therapy and Medical Laser Applications, Milan,
Jun. 24-27 1992, published by Elsevier Science Publishers B.V., Amsterdam, The Netherlands, ISBN 0 444 81430 2, both incorporated herein by reference.
United States patents related to PDT include U.S. Pat. Nos. 5,095,030 and 5,283,225 to Levy et al.; U.S. Pat. No. 5,314,905 to Pandey et al.; U.S. Pat. No. 5,214,036 to Allison et al; and U.S. Pat. No. 5,258,453 to Kopecek et al., all of which are incorporated herein by reference. The Levy patents disclose the use of photosensitizers affected by a wavelength of between 670-780 nm conjugated to tumor specific antibodies, such as receptor-specific ligands, immunoglobulins or immunospecific portions of immunoglobulins. The Pandey patents are directed to pyropheophorbide compounds for use in standard photodynamic therapy. Pandey also discloses conjugating his compositions with ligands and antibodies. The Allison patent is similar to the Levy patents in that green porphyrins are conjugated to lipocomplexes to increase the specificity of the porphyrin compounds for the targeted tumor cells. The Kopecek patent also discloses compositions for treating cancerous tissues. These compositions consist of two drugs, an anti-cancer drug and a photoactivatable drug, attached to a copolymeric carrier. The compositions enter targeted cells by pinocytosis. The anti-cancer drug acts after the targeted cell has been invaded. After a period of time, a light source is used to activate the photosensitized substituent.
II. Tumor Immunotherapy
The major functions of the immune system are to develop the concept of “self” and eliminate what is “nonself”. Although microorganisms are the principal nonself entities encountered every day, the immune system also works to eliminate neoplasms and transplants. See Chapters 18 and 103 of
The Merck Manual of Diagnosis and Therapy
, Sixteenth Edition, published in 1992 by Merck Research Laboratories of Rahway, N.J., ISBN 0911910-16-6 and 0076-6526; the same being incorporated herein by reference.
There are several distinct types of immunity. Nonspecific, or innate, immunity refers to the inherent resistance manifested by a species that has not been immunized (sensitized or allergized) by previous infection or vaccination. Its major cellular component is the phagocytic system, whose finction is to ingest and digest invading microorganisms. Phagocytes include neutrophils and monocytes in the blood and macrophages in the tissues. Complement proteins are the major soluble component of nonspecific immunity. Acute phase reactants and cytokines, such as interferon, are also part of innate immunity.
Specific immunity is an immune status in which there is an altered reactivity directed solely against the antigenic determinants (infectious agent or other) th

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