Drug – bio-affecting and body treating compositions – Whole live micro-organism – cell – or virus containing – Genetically modified micro-organism – cell – or virus
Reexamination Certificate
1999-07-21
2004-02-03
Yucel, Remy (Department: 1636)
Drug, bio-affecting and body treating compositions
Whole live micro-organism, cell, or virus containing
Genetically modified micro-organism, cell, or virus
C424S282100, C435S004000, C435S243000, C536S023100
Reexamination Certificate
active
06685935
ABSTRACT:
1. FIELD OF THE INVENTION
The present invention is concerned with the isolation and use of super-infective, tumor-specific, attenuated strains of parasites including, but not limited to, bacteria, fungi and protists. In certain embodiments the parasites include the bacterium Salmonella spp., such as
Salmonella typhimurium
, the bacterium
Mycobacterium avium
, and the protozoan
Leishmania amazonensis
, for the diagnosis and treatment of sarcomas, carcinomas, and other solid tumor cancers. In other embodiments, the present invention is concerned with the isolation and use of super-infective, tumor-specific, suicide gene-containing strains of parasites.
2. BACKGROUND OF THE INVENTION
Citation or identification of any reference in Section 2 of this application shall not be construed as an admission that such reference is available as prior art to the present invention.
A major problem in the chemotherapy of solid tumor cancers is the delivery of therapeutic agents, such as drugs, in sufficient concentrations to eradicate tumor cells while at the same time minimizing damage to normal cells. Thus, studies in many laboratories are directed toward the design of biological delivery systems, such as antibodies, cytokines, and viruses for targeted delivery of drugs, pro-drug converting enzymes, and/or genes into tumor cells. Houghton and Colt, 1993, New Perspectives in Cancer Diagnosis and Management 1: 65-70; de Palazzo,et al., 1992a, Cell. Immunol. 142:338-347; de Palazzo et al., 1992b, Cancer Res. 52: 5713-5719; Weiner, et al., 1993a, J. Immunotherapy 13:110-116; Weiner et al., 1993b, J. Immunol. 151:2877-2886; Adams et al., 1993, Cancer Res. 53:4026-4034; Fanger et al., 1990, FASEB J. 4:2846-2849; Fanger et al., 1991, Immunol. Today 12:51-54; Segal, et al., 1991, Ann N.Y. Acad. Sci. 636:288-294; Segal et al., 1992, Immunobiology 185:390-402; Wunderlich et al., 1992; Intl. J. Clin. Lab. Res. 22:17-20; George et al., 1994, J. Immunol. 152:1802-1811; Huston et al., 1993, Intl. Rev. Immunol. 10:195-217; Stafford et al., 1993, Cancer Res. 53:4026-4034; Haber et al., 1992, Ann. N.Y. Acad. Sci. 667:365-381; Haber, 1992, Ann. N.Y. Acad. Sci. 667: 365-381; Feloner and Rhodes, 1991, Nature 349:351-352; Sarver and Rossi, 1993, AIDS Research & Human Retroviruses 9:483-487; Levine and Friedmann, 1993, Am. J. Dis. Child 147:1167-1176; Friedmann, 1993, Mol. Genetic Med. 3:1-32; Gilboa and Smith, 1994, Trends in Genetics 10:139-144; Saito et al., 1994, Cancer Res. 54:3516-3520; Li et al., 1994, Blood 83:3403-3408; Vieweg et al., 1994, Cancer Res. 54:1760-1765; Lin et al., 1994, Science 265:666-669; Lu et al., 1994, Human Gene Therapy 5:203-208; Gansbacher et al., 1992, Blood 80:2817-2825; Gastl et al., 1992, Cancer Res. 52:6229-6236.
Because of their biospecificity, such systems could in theory deliver therapeutic agents to tumors. However, it has become apparent that numerous barriers exist in the delivery of therapeutic agents to solid tumors that may compromise the effectiveness of antibodies, cytokines, and viruses as delivery systems. Jain, 1994, Scientific American 7:58-65 (Jain). For example, in order for chemotherapeutic agents to eradicate metastatic tumor cells, they must
a) travel to the tumors via the vasculature;
b) extravasate from the small blood vessels supplying the tumor;
c) traverse through the tumor matrix to reach those tumor cells distal to the blood supply; and
d) interact effectively with the target tumor cells (adherence, invasion, pro-drug activation, etc).
Although antibodies and viruses can express specific recognition sites for tumor cells, they are dependent solely upon the forces of diffusion and convection in order to reach these sites. According to Jain:
An agent that destroys cancers cells in a culture dish should, in theory, be able to kill such cells in the body. . . . Sadly, however, the existing pharmacopoeia has not markedly reduced the number of deaths caused by the most common solid tumors in adults, among them cancers of the lung, breast, colon, rectum, prostate, and brain. . . . Before a blood-borne drug can begin to attack malignant cells in a tumor, it must accomplish three critical tasks. It has to make its way into a microscopic blood vessel lying near malignant cells in the tumor, exit from the vessel into the surrounding matrix (the interstitium), and finally, migrate through the matrix to the cells. Unfortunately, tumors often develop in ways that hinder each of these steps.
Jain points out that blood vessels supplying tumors are irregular and convoluted in shape so that blood flow is frequently restricted compared to that in normally vascularized tissue. In addition, there is an unusually high interstitial pressure in many tumors that counteracts the blood flow. Jain further points out that the two chief forces governing the transport of agents to tumor cells via the circulatory system are convection (the transport of molecules by a stream of flowing fluid), and diffusion (the movement of molecules from an area of high concentration to an area of low concentration). Since tumors are often non-uniformly vascularized, many cells in the tumors receive nutrients through the process of diffusion through the matrix. Jain and coworkers obtained data suggesting that “a continuously supplied monoclonal antibody having a molecular weight of 150,000 daltons could take several months to reach a uniform concentration in a tumor that measured one centimeter in radius and had no blood supply in its center.”
2.1. Bacterial Infections and Cancer
Regarding bacteria and cancer, an historical review reveals a number of clinical observations in which cancers were reported to regress in patients with bacterial infections. Nauts et al., 1953, Acta Medica. Scandinavica 145:1-102, (Suppl. 276) state:
The treatment of cancer by injections of bacterial products is based on the fact that for over two hundred years neoplasms have been observed to regress following acute infections, principally streptococcal. If these cases were not too far advanced and the infections were of sufficient severity or duration, the tumors completely disappeared and the patients remained free from recurrence.
Shear, 1950, J. A.M.A. 142:383-390 (Shear), observed that 75% of the spontaneous remissions in untreated leukemia in the Children's Hospital in Boston occurred following an acute episode of bacterial infection. Shear stated:
Are pathogenic and non-pathogenic organisms one of Nature's controls of microscopic foci of malignant disease, and in making progress in the control of infectious diseases, are we removing one of Nature's controls of cancer?
Subsequent evidence from a number of research laboratories indicated that at least some of the anti-cancer effects are mediated through stimulation of the host immune system, resulting in enhanced immuno-rejection of the cancer cells. For example, release of the lipopolysaccharide (LPS) endotoxin by Gram negative bacteria such as Salmonella triggers release of tumor necrosis factor, TNF, by cells of the host immune system, such as macrophages, Christ et al., 1995, Science 268:80-83. Elevated TNF levels in turn initiate a cascade of cytokine-mediated reactions which culminate in the death of tumor cells. In this regard, Carswell et al., 1975, Proc. Natl. Acad. Sci. USA 72:3666-3669, demonstrated that mice injected with bacillus Calmette-Guerin (BCG) have increased serum levels of TNF and that TNF-positive serum caused necrosis of the sarcoma Meth A and other transplanted tumors in mice. Further, Klimpel et al., 1990, J. Immunol. 145:711-717, showed that fibroblasts infected in vitro with Shigella or Salmonella had increased susceptibility to TNF.
As a result of such observations as described above, immunization of cancer patients with BCG injections is currently utilized in some cancer therapy protocols. See Sosnowski, 1994, Compr. Ther. 20:695-701; Barth and Morton, 1995, Cancer 75 (Suppl. 2) :726-734; Friberg, 1993, Med. Oncol. Tumor. Pharmacother. 10:31-36 for reviews of BCG therapy.
2.2. Parasites and Cancer Cells
Although th
Bermudes David
Low Kenneth Brooks
Pawelek John M.
Pennie & Edmonds LLP
Sandals William
Yale University
Yucel Remy
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