Drug – bio-affecting and body treating compositions – Nonspecific immunoeffector – per se ; or nonspecific...
Reexamination Certificate
2001-06-11
2004-05-11
Saunders, David (Department: 1644)
Drug, bio-affecting and body treating compositions
Nonspecific immunoeffector, per se ; or nonspecific...
C424S085100, C424S085200, C424S130100, C424S277100, C514S034000, C514S152000, C514S154000, C514S731000, C514S733000, C514S734000
Reexamination Certificate
active
06733764
ABSTRACT:
FIELD OF THE INVENTION
The invention relates generally to novel anti-cancer compounds and their use as immunostimulators to enhance the activity of macrophages and lymphoid cells in attacking tumors and other neoplastic tissue. In particular, the invention relates to the use of immunostimulator compounds together with traditional anti-cancer therapeutic methods to achieve synergistic results.
BACKGROUND OF THE INVENTION
Cancer is the second-leading cause of death after cardiovascular disease in the United States. More than one million people were diagnosed with cancer last year and over 500,000 die of it each year. Surgery, radiation, and systemic drugs are the most common, traditional forms of cancer treatments. Localized cancer tumors are removed surgically or reduced through radiation. Tumors that have metastasized are treated with systemic therapies such as drugs, hormones, anti-hormones, and biological agents. Cytotoxic agents are the dominant therapy, however the problem with the use of these agents known as chemotherapy is that it can often cause cellular and organ damage to non-cancerous tissues, producing secondary problems including infections and death. Anti-cancer drugs are highly toxic causing serious and dose limiting side effects such as nausea, vomiting, neutropenia, and hair loss, organ damage, and death.
Basal cell carcinoma (BCC) is the most common malignant tumor of the skin, accounting for most of the approximately one million new cases of skin cancer diagnosed each year in the United States. See Miller, D. L., et al.,
Non
-
melanoma Skin Cancer in the United States: Incidence
. J. Am. Acad. Dermatol., 1994, Vol. 30, pp. 774-8. In selecting the most appropriate treatment, there are a number of variables that must be taken into account including histopathological type; size, location, and duration; and whether the lesion is primary or recurrent. The current treatment options of basal cell carcinoma is primarily surgical including Mohs micrographic surgery, simple excision, curettage and electro-dessication, or cryosurgery. See Drake, L. A., et al.,
Guidelines of Care for Basal Cell Carcinoma
. J. Am. Acad. Dermatol., 1992, Vol. 26, pp. 117-20.
Accumulating data has shown that therapy with immune response modifying agents may offer effective therapy for basal cell carcinoma. Patients with noduloulcerative and superficial basal cell carcinoma have been shown to be responsive to the intra-lesional, immunonomodulation with interferon alfa-2b. See Cornell, R. C., et al.,
Intra
-
lesional Therapy for Basal Cell Carcinoma
. J. Am. Acad. Dermatol., 1990, Vol. 23, pp. 694-700; and, Greenway, H. T., et al.,
Treatment of Basal Cell Carcinoma with Intra
-
lesional Interferon
. J. Am. Acad. Dermatol., 1986, Vol. 15, pp. 437-43. Interferon can increase cell surface antigenicity of neoplastic cells, improving cell-mediated cytotoxicity leading to cell destruction. Imiquimod 5% cream has recently been shown in a randomized, double-blind pilot trial to show clinical efficacy in the treatment of nodular or superficial BCCS. See Beutner, K. R., et al.,
Therapeutic Response of Basal Cell Carcinoma to the Immune Response Modifier Imiquimod
5%
Cream
. J. Am. Acad. Dermatol., 1999, Vol. 41, pp. 1002-7. Topically applied imiquimod has been shown to induce local proliferation of interferon and other cytokines that may be important mediators of tumor clearance. Fifteen of 15 patients who applied imiquimod cream either three times a week, once daily, or twice daily achieved complete clinical and histologic clearing of superficial BCCs. Beutner K R et al., supra.
Many cancer cells evade the immune system. They can then proliferate and spread throughout the body, eventually killing the host. Angiogenesis (capillary growth to the tumor) in melanoma and various carcinomas often correlates with the likelihood of the development of metastases and the prognosis in such patients. Immunostimulators that can also serve as a form of anti-angiogenic therapy would inhibit the growth of the cancer and its spread. Immunostimulators activate the immune system to search out and kill the spreading tumor cells. Immunostimulators can also help the body develop an immunological memory in the host and in this way can potentiate the immune system. Exemplary immunostimulators include cytokines, and lipopolysaccharides obtained from the cell walls of Gram-negative bacteria. Specific immunostimulators have been utilized in the treatment of ovarian or pancreatic tumors. Immunostimulators can also activate macrophages, but unfortunately, most immunostimulators developed to date have been less than 100% effective. Most will enhance the immune system but all of them lack the ability to stimulate an immunological memory to the tumor cells. Other suitable secondary immunostimulators include bacillus Calmette-Guérin, immunoglobulin, alpha-interferon, interleukin-2, synthetic agents such as levamisole and isoprinosine and mixtures thereof.
Urushiol is an immunostimulator which has been shown to invoke an inflammatory response, stimulating white blood cells and other components of the immune system to localize at a particular site. In the past several investigators have attempted to use urushiol as an anti-cancer agent to treat various cancer cell lines. In all cases, the treatment failed to kill the tumors or inhibit the growth of the tumors or tumor cell lines in comparison to adriamycin. What the investigators failed to realize is that urushiol is a weak anti-cancer agent, but a strong immunostimulator, which can be used in combination with other therapies. To date, no one has used or teaches the use of urushiol as an immunostimulator that enhances current therapies. The compound occurs naturally and is the main component of the irritant oil in the leaves of poison ivy,
Toxicodendron radicans
, poison oak
T. diversilobum
, and other plants of the genus Toxicodendron. See Hill, et al., J. Am. Chem. Soc., 1934, Vol. 56, p. 2736. It is a mixture of several compounds which are derivatives of catechol and unsaturated C
15
or C
17
side chains and which, upon hydrogenation, yield the same 3-pentadecylcatechol, q.v. or 3-heptadecylctechol. Intra-lesional therapy of urushiol into basal cell carcinoma will produce a local inflammatory response, stimulating immunologically-mediated cells to areas of malignant and premalignant cells. Urushiol in combination with tumor-associated antigens, would enhance the activity of the antigen.
The unequivocal demonstration that tumor-associated peptides are recognized by cytolytic T-lymphocytes (CTLs) has stimulated worldwide efforts to identify as many of such antigens as possible and their human leucocyte antigen (HLA) restricted presentation by various tumor types. A widely used strategy for the identification of T-cell epitopes is to predict HLA-restricted peptides out of the sequence of tumor-associated proteins by the use of appropriate algorithms. These peptides were used for the stimulation of T-cells, which were then tested for recognition of tumor cells. The main reason for the frequent failure of this approach is that the predicted peptides are not naturally processed and are therefore not relevant for tumor-cell recognition. Therefore, a biochemical strategy to obviate these failures has been developed. In a first step, the potential peptides are predicted, synthesized, and analyzed by HPLC-linked mass spectrometry. In a second step, the naturally produced peptides are eluted from the MHC class I molecules of solid tumors or of tumor cell lines. A mixture of predicted synthetic peptides is then checked against the great number of eluted peptides using a specially adapted computer software. Thus identified, naturally occurring tumor peptides are used for the activation of T-cells, and the T-cells are tested for tumor cell recognition.
Another promising strategy to improve the prediction of relevant cytotoxic T-cell epitopes comprises the combination of HLA-motif prediction and determination of the cleavage specificity of proteasomes. Proteasomal cleavage is essential
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