Drug – bio-affecting and body treating compositions – Whole live micro-organism – cell – or virus containing – Animal or plant cell
Reexamination Certificate
1997-07-22
2001-06-26
Bansal, Geetha P. (Department: 1642)
Drug, bio-affecting and body treating compositions
Whole live micro-organism, cell, or virus containing
Animal or plant cell
C424S093100, C424S093200, C424S093710, C424S237100, C424S236100, C424S184100, C424S277100, C435S325000
Reexamination Certificate
active
06251385
ABSTRACT:
FIELD OF THE INVENTION
The invention generally relates to the treatment of cancer, and, more specifically, to the treatment of solid tumors, including their metastases, without radiation, surgery or standard chemotherapeutic agents.
BACKGROUND
Therapy for cancer has largely involved the use of radiation, surgery and chemotherapeutic agents. However, results with these measures, while beneficial in some tumors, has had only marginal or no effect in many others. Furthermore, these approaches have often unacceptable toxicity.
Both radiation and surgery suffer from the same theoretical drawback. It has been recognized that, given that a single clonogenic malignant cell can give rise to sufficient progeny to kill the host, the entire population of neoplastic cells must be eradicated. See generally, Goodman and Gilman
The Pharmacological Basis of Therapeutics
(Pergamon Press, 8th Edition) (pp. 1202-1204). This concept of “total cell kill” implies that total excision of a tumor is necessary for a surgical approach, and complete destruction of all cancer cells is needed in a radiation approach, if one is to achieve a cure. In practice this is rarely possible; indeed, where there are metastases, it is impossible.
The term “chemotherapy” simply means the treatment of disease with chemical substances. The father of chemotherapy, Paul Ehrlich, imagined the perfect chemotherapeutic as a “magic bullet;” such a compound would kill invading organisms without harming the host. This target specificity is sought in all types of chemotherapeutics, including anticancer agents.
However, specificity has been the major problem with anticancer agents. In the case of anticancer agents, the drug needs to distinguish between host cells that are cancerous and host cells that are not cancerous. The vast bulk of anticancer drugs are indiscriminate at this level. Typically anticancer agents have negative hematological effects (e.g., cessation of mitosis and disintegration of formed elements in marrow and lymphoid tissues), and immunosuppressive action (e.g., depressed cell counts), as well as a severe impact on epithelial tissues (e.g., intestinal mucosa), reproductive tissues (e.g., impairment of spermatogenesis), and the nervous system. P. Calabresi and B. A. Chabner, In: Goodman and Gilman
The Pharmacological Basis of Therapeutics
(Pergamon Press, 8th Edition) (pp. 1209-1216).
Success with chemotherapeutics as anticancer agents has also been hampered by the phenomenon of multiple drug resistance, resistance to a wide range of structurally unrelated cytotoxic anticancer compounds. J. H. Gerlach et al.,
Cancer Surveys,
5:25-46 (1986). The underlying cause of progressive drug resistance may be due to a small population of drug-resistant cells within the tumor (e.g., mutant cells) at the time of diagnosis. J. H. Goldie and Andrew J. Coldman,
Cancer Research,
44:3643-3653 (1984). Treating such a tumor with a single drug first results in a remission, where the tumor shrinks in size as a result of the killing of the predominant drug-sensitive cells. With the drug-sensitive cells gone, the remaining drug-resistant cells continue to multiply and eventually dominate the cell population of the tumor.
Treatment at the outset with a combination of drugs was proposed as a solution, given the small probability that two or more different drug resistances would arise spontaneously in the same cell. V. T. DeVita, Jr.,
Cancer,
51:1209-1220 (1983). However, it is now known that drug resistance is due to a membrane transport protein, “P-glycoprotein,” that can confer general drug resistance. M. M. Gottesman and I. Pastan,
Trends in Pharmacological Science,
9:54-58 (1988). Phenotypically, the tumor cells show, over time, a reduced cellular accumulation of all drugs. In short, combination chemotherapy appears not to be the answer.
What is needed is a specific anticancer approach that is reliably tumoricidal to a wide variety of tumor types. Importantly, the treatment must be effective with minimal host toxicity.
SUMMARY OF THE INVENTION
The invention generally relates to the treatment of cancer, and, more specifically, to the treatment of solid tumors, including their metastases, without radiation, surgery or standard chemotherapeutic agents. In one embodiment, the invention involves using superantigens, including SEA and SEB, to stimulate tumor draining lymph node cells ex vivo, allowing them to differentiate into tumor specific immune effector cells. The cells are then reintroduced into the same host to mediate anticancer therapeutic effects. In another embodiment, the stimulated cells are introduced into a different host. In still a third embodiment, the cells are established as a cell line for continuous anticancer use.
In one embodiment, lymphocytes are obtained early in life from cancer-free hosts. The cells are stored in appropriate containers under liquid nitrogen using conventional techniques (e.g., DMSO, culture media, fetal calf serum, etc.) until the onset of disease. At this point, the cells may be thawed, and cultured and stimulated in the manner of the present invention for reinfusion.
Alternatively, an established cell line may be made from cancer-free hosts. The cell line can be stored as above. On the other hand, they may be passed continuously in culture until use.
The ex vivo stimulation method has decided advantages over direct intravenous injection of superantigens, namely: 1) the superantigens are ensured of contacting their appropriate target cell, namely, T lymphocytes; in other words, stimulation is specific; 2) stimulation in culture allows for the removal of the stimulating antigens prior to reintroduction of the cells in the host, i.e., the host is exposed to only very small amounts of superantigens in vivo; and 3) lack of systemic exposure to the stimulating antigens precludes significant interference with naturally occurring or induced antibodies to superantigens.
The present invention demonstrates that superantigens can reliably produce tumoricidal reactions to a wide variety of tumor types. Moreover, success is achieved with minimal host toxicity using the in vitro sensitization technique.
In its simplest form, the present invention offers a method for inducing a tumoricidal reaction in vivo comprising contacting cells with superantigens ex vivo and infusing them into a tumor-bearing host. The cells are typically hematopoietic cells, such as peripheral blood lymphocytes, spleen cells, tumor-infiltrating lymphocytes or lymph node cells. Where they are lymph node cells, it is preferred that they are from a tumor-bearing host. The superantigens may comprise enterotoxins of
Staphylococcus aureus,
or synthetic polypeptides with substantial structural homology and statistically significant sequence homology to natural superantigens.
The present invention offers a method of human cancer treatment comprising: a) providing a human cancer patient; b) obtaining hematopoietic cells from said patient; c) contacting said cells ex vivo with one or more superantigens to generate stimulated cells; and d) re-introducing said stimulated cells into said patient so as to induce an in vivo therapeutic, tumoricidal reaction. Preferably the hematopoietic cells are cultured in culture media containing enterotoxins and the cultured cells are washed prior to re-introducing said stimulated cells into said patient so as to essentially avoid introducing enterotoxins in vivo.
The culture cells can be viewed as a reagent for treating cancer, comprising T cells sensitized to a growing tumor and stimulated with superantigens. Preferably, the T cells are suspended in media suitable for intravenous administration to a human cancer patient, such as a media comprising a physiological buffered saline solution.
While not limited to any mechanism, it is believed that culturing the cells in the manner proposed results in subset enrichment In this regard, the present invention provides a method of human cancer treatment comprising: a) providing a human cancer patient, having one or more growing tumors; b) obtaining V&bgr;-
Bansal Geetha P.
Livant Shmuel
Venable
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