Drug – bio-affecting and body treating compositions – Whole live micro-organism – cell – or virus containing – Genetically modified micro-organism – cell – or virus
Reexamination Certificate
2001-12-26
2004-08-10
Guzo, David (Department: 1636)
Drug, bio-affecting and body treating compositions
Whole live micro-organism, cell, or virus containing
Genetically modified micro-organism, cell, or virus
C424S093100, C424S093200, C424S600000, C424S601000, C424S185100, C435S320100, C514S731000, C514S733000, C514S464000, C514S720000, C514S721000
Reexamination Certificate
active
06773702
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to new methods for treating tumor bearing animals including humans with a sufficient amount of Combretastatin A4 or its prodrugs to permit tumor regression but at doses that do not cause vascular shut-down.
BACKGROUND OF THE INVENTION
Cancer is a serious and pervasive disease worldwide. The National Cancer Institute has estimated that in the United States alone, 1 in 3 people will be struck with cancer during their lifetime. Moreover, approximately 50% to 60% of people contracting cancer will eventually succumb to the disease. The widespread occurrence of this disease underscores the need for improved anticancer regimens for the treatment of malignancy.
Although cancer is commonly considered to be a single disease, it actually comprises a family of diseases wherein normal cell differentiation is modified so that it becomes abnormal and uncontrolled. As a result, these malignant cells rapidly proliferate. Eventually, the cells spread or metastasize from their origin and colonize other organs, eventually killing their host.
In addition to alterations in cell growth regulation, cellular transformation during the development of malignant cancer involves multiple alterations in the normal pattern of cell morphology. Cancer cells are morphologically restructured to enhance their invasive properties. The accumulation of genetic modifications (mutation, gene amplification, chromosomal deletion or translocation) may lead to the expression of aberrant molecules or the altered expression of normal molecules. When these genetic modifications are manifested as alterations in the cell-to-cell associations within a tissue of origin, a malignant and metastatic cancer may develop. In the process of metastasizing, they may invade adjoining tissue before spreading to distant sites through the circulatory system. The metastatic cells can adhere to endothelial cells to aid their migration, but ultimately they escape from the circulation and begin growth in a foreign environment.
To invade a distant site, metastatic cells often produce elevated levels of both receptors for the basal lamina proteins and enzymes that digest collagen and other extracellular proteins, such as proteoglycans and glycosaminoglycans. As these proteins are disentegrated, the tumor cells penetrate the lamina and invade the foreign tissue. Once they have invaded a foreign tissue, tumor cells must be able to adhere to new types of cells and proliferate without a mass of surrounding identical cells. Therefore, the wide range of altered behaviors that underlie metastasis may have their basis in a new or variant surface protein made by the metastatic tumor cell.
Tumor Immune Surveillance
It might be expected that gross cell-surface alterations associated with malignancy would lead the immune system to recognize tumor cells as foreign. Indeed, there are a number of immune surveillance mechanisms by which abnormal cells are recognized early in the development of a tumor and destroyed. This antitumor effect can be demonstrated with a tumor transplantation test involving isograft rejection. When a tumor is grafted onto an animal previously immunized with inactivated cells of the same tumor, resistance to the graft is observed. This is because the tumor host is able to mount an immune reaction against tumor-specific transplantation antigens (TSTAs) on the surface of the tumor cells. Molecular cloning techniques have been used to identify TSTAs as mutant homologs containing slight variations from the sequence of a normal gene. In other instances, the TSTA gene is identical to the parental gene, but its expression is altered.
Histological studies of human tumors have shown that some contain a marked infiltrate of inflammatory immune cells, including lymphocytes, macrophages, dendritic cells, and granulocytes. Some of these cells can suppress tumor growth or metastasis by mounting a humoral immune response and producing antibodies against a tumor antigen. Some of these antibodies may interfere with tumor growth directly or they may mediate a tumor immune response by activating antibody-dependent cell-mediated toxicity (ADCC) or the complement system. While these mechanisms are important, an immune response generating cytotoxic effector cells is often much more effective. This type of immune response serves to lyse target cancer cells and, when sufficiently strong, results in tumor elimination.
There are three main types of cytotoxic effector cells that are capable of recognizing and destroying tumor cells:
1) Cytotoxic T lymphocytes (CTL). Activation of CTL can occur by recognition of tumor antigen on the MHC class I either of an antigen presenting cell (e.g. a dendritic cell or a macrophage) that has engulfed tumor cell fragments and which are also providing necessary costimulatory signals, e.g. by the B7 molecule, or alternatively of a tumor cell provided that T-cell produced cytokines are present to give costimulation. When activated, these cells kill tumors in an antigen-specific and MHC class I-restricted manner by releasing an arsenal of cytotoxic compounds including perforin, granzymes, IFN-&ggr;, and TNF-&agr;.
2) Macrophage cells. These cells are primarily activated by the IFN-gamma and kill tumor cells in a nonspecific, MHC-unrestricted fashion by the same mechanisms they use to kill microorganisms (TNF-&agr;, lysozyme, reactive oxygen intermediates, nitric oxide).
3) Natural Killer (NK) cells. NK cells kill tumor cells in an MHC-unrestricted way by recognizing various membrane molecules including adherence molecules in the absence of inhibitory signals provided by membrane MHC class I of tumor cells. Effector mechanisms include perforin, granzymes, IFN-&ggr;, and Fas-L mediated apoptosis.
Tumor Escape Mechanisms
Despite the elaborate defense mechanisms of the host immune system, tumor cells find ways to elude immune detection and kill the host. A variety of mechanisms have been proposed to explain evasion:
1) Lack of co-stimulatory molecules—Many tumors are only weakly immunogenic. This is not necessarily because the antigens are lacking, but because the antigens are presented without the necessary costimulation. Activation of CTL requires co-stimuli, which may be cell-surface molecules or cytokines secreted by APCs or T cells. The B7 molecule, present on specialized APCs, is now known to be a key co-stimulus acting via its counter-receptor CD28 on the T-cell surface. Interaction of T cells with tumors that lack the co-stimulatory B7 molecule renders the T cells anergic and unable to respond to the tumor if alternative costimulation is not provided by T cell produced cytokines.
Equally important is that tumors may also show a reduction or a complete loss of MHC Class I molecules on their cell surface.
These antigens are required for the presentation of tumor antigen peptides, and in their absence a cytotoxic T cell is incapable of even binding the tumor cell. Furthermore, some tumor cells may lack receptor molecules required for lymphocyte adhesion (e.g., LFA-1 or ICAM-1) or they may express anti-adhesive molecules (e.g., Mucin).
2) Blocking antibodies—Many tumors are capable of shedding tumor antigens. Complexes composed of antibodies and shed tumor antigens can saturate the Fc receptors on effector cells, preventing them from interacting with tumor cells.
3) Antigenic Modulation—Binding of a TSTA by antibody can induce internalization of the antigen by endocytosis. Degradation of the antigen eliminates a potential target of cell-mediated immune response.
4) Secretion of Immunosuppressive Factors—Tumors can secrete immunosuppressive cytokines such as Transforming Growth Factor (TGF-&bgr;), Prostaglandin E2 (PGE2), or IL-10. These factors inhibit the development and proliferation of cytolytic T cells.
Cancer Immunotherapy
Due to the wide variety of cancers presently observed, numerous strategies have been developed to destroy cancer within the body. Currently the top three methods of treating cancer in the United States include surgery, chemotherapy, and radiation therapy. While t
Edvardsen Klaus
Lee Francis Y. F.
Pero Ronald W.
Sjögren Hans Olov
Biswas, Esq. Naomi S.
Elrifi, Esq. Ivor R.
Guzo David
Mintz Levin Cohn Ferris Glovsky and Popeo P.C.
OXiGENE, Inc.
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