Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1995-06-06
2001-10-30
Martin, Jill D. (Department: 1632)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C435S320100, C435S455000, C435S456000, C435S069300, C435S069500, C435S069510, C435S069520, C435S325000
Reexamination Certificate
active
06310045
ABSTRACT:
TECHNICAL FIELD
The present invention relates generally to the field of cancer immunotherapeutics, and more specifically, to methods of inhibiting the growth of a selected tumor utilizing vector constructs.
BACKGROUND OF THE INVENTION
Cancer accounts for one-fifth of the total mortality in the United States, and is the second leading cause of death. Cancer is typically characterized by the uncontrolled division of a population of cells. This uncontrolled division typically leads to the formation of a tumor, which may subsequently metastasize to other sites.
Primary solid tumors can generally be treated by surgical resection. However, the majority of patients which have solid tumors also possess micrometastases beyond the primary tumor site. If treated with surgery alone, approximately 70% of these patients will experience recurrence of the cancer. In addition to surgery, many cancers are now also treated with a combination of therapies involving cytotoxic chemotherapeutic drugs (e.g., vincristine, vinblastine, cisplatin, methotrexate, 5-FU, etc.) and/or radiation therapy. One difficulty with this approach however, is that radiotherapeutic and chemotherapeutic agents are toxic to normal tissues, and often create life-threatening side effects. In addition, these approaches often have extremely high failure/remission rates (up to 90% depending upon the type of cancer).
In addition to chemo- and radiation therapies, many have attempted to bolster or augment an individual's own immune system in order to eliminate the cancer cells. Several immunotherapies have utilized bacterial or viral components as adjuvants, in order to stimulate the immune system to destroy the tumor cells. Examples of such components include BCG, endotoxin, mixed bacterial vaccines, interferons (, , and ), interferon inducers (e.g., Brucella abortus, and various viruses), and thymic factors (e.g., thymosin fraction 5, and thymosin alpha-1) (see generally “Principles of Cancer Biotherapy,” Oldham (ed.), Raven Press, New York, 1987). Such agents have generally been useful as adjuvants and as nonspecific stimulants in animal tumor models, but have not yet proved to be generally effective in humans.
Lymphokines have also been utilized in the treatment of cancer. Briefly, lymphokines are secreted by a variety of cells, and generally have an effect on specific cells in the generation of an immune response. Examples of lymphokines include Interleukins (IL)-1, -2, -3, and -4, as well as colony stimulating factors such as G-CSF, GM-CSF, and M-CSF. Recently, one group has utilized IL-2 to stimulate peripheral blood cells in order to expand and produce large quantities of cells which are cytotoxic to tumor cells (Rosenberg et al.,
N. Engl. J. Med.
313:1485-1492, 1985).
Others have suggested the use of antibody-mediated anti-cancer therapies. Briefly, antibodies may be developed which recognize certain cell surface antigens that are either unique, or more prevalent on cancer cells compared to normal cells. These antibodies, or “magic bullets,” may be utilized either alone or conjugated with a toxin in order to specifically target and kill tumor cells (Dillman, “Antibody Therapy,”
Principles of Cancer Biotherapy,
Oldham (ed.), Raven Press, Ltd., New York, 1987). For example, Ball et al. (Blood 62:1203-1210, 1983) treated several patients with acute myelogenous leukemia with one or more of several monoclonal antibodies specific for the leukemia, resulting in a marked decrease in circulating leukemia cells during treatment. Similarly, others have utilized toxin-conjugated antibodies therapeutically to treat a variety of tumors, including, for example, melanomas, colorectal carcinomas, prostate carcinomas, breast carcinomas, and lung carcinomas (see Dillman, supra). One difficulty however, is that most monoclonal antibodies are of murine origin, and thus hypersensitivity against the murine antibody may limit its efficacy, particularly after repeated therapies. Common side effects include fever, sweats and chills, skin rashes, arthritis, and nerve palsies.
Therefore, compositions and methods which augment natural host defenses against tumor induction or progression without the cytotoxic side effects of prior methods, may increase remission rates and enhance survival of patients with cancer. The present invention provides such compositions and methods, and further provides other related advantages.
SUMMARY OF THE INVENTION
Briefly stated, the present invention is directed towards methods for inhibiting the growth of a selected tumor. Within one aspect of the invention, a method is provided for inhibiting the growth of a selected tumor in a warm-blooded animal, comprising the step of directly administering to the tumor a vector construct which directs the expression of at least one anti-tumor agent, such that the growth of the tumor is inhibited. Within one embodiment of the invention, the vector construct is carried by a recombinant viral vector. Within a preferred embodiment, the recombinant viral vector is a recombinant retroviral vector.
Within one embodiment of the invention, the anti-tumor agent is selected from the group consisting of immune activators and tumor proliferation inhibitors. Immune activators include, for example, immune modulators and lymphokines. Representative examples of immune modulators include CD3, ICAM-1, ICAM-2, LFA-1, LFA-3, -2-microglobulin, chaperones, alpha interferon and gamma interferon, B7/BB1 and major histocompatibility complex (MHC). Representative examples of lymphokines include gamma interferon tumor necrosis factor, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, GM-CSF, CSF-1, and G-CSF. As noted above, within other embodiments of the invention, anti-tumor agents include tumor proliferation inhibitors such as, for example, toxins and antisense sequences. Representative examples of toxins include ricin, abrin, diphtheria toxin, cholera toxin, gelonin, pokeweed, antiviral protein, tritin, Shigella toxin, and Pseudomonas exotoxin A, herpes simplex virus thymidine kinase (HSVTK), and
E. coli
guanine phosphoribosyl transferase. Representative examples of antisense sequences include antisense thymidine kinase, antisense dihydrofolate reductase, antisense HER2, antisense ABL, antisense Myc, and antisense ras.
Within a particularly preferred embodiment of the invention, the anti-tumor agent is a membrane anchor-gamma interferon fusion protein. Within another embodiment, the anti-tumor agent is a gamma interferon-Interleukin-2 fusion protein.
Within additional aspects of the present invention, isolated DNA sequences are provided which encode membrane anchor-gamma interferon fusion proteins and membrane anchor-anti-tumor agent fusion proteins, as well as vector constructs which direct the expression of these sequences, and recombinant viral and retroviral vectors which carry the vector construct. Also provided are recombinant viral vectors and recombinant retroviral vectors carrying a vector construct which directs the expression of an Interleukin-2-gamma interferon fusion protein.
Also provided by the present invention are target cells infected with the recombinant retroviral vectors discussed above, as well as pharmaceutical compositions comprising the above described recombinant viral or retroviral vectors, in combination with a pharmaceutically acceptable carrier or diluent.
Within another aspect of the present invention, methods for inhibiting the growth of a selected tumor in a warm-blooded animal are provided, comprising the step of delivering to a warm-blooded animal a recombinant retroviral or viral vector as described above, such that the growth of the tumor is inhibited.
Within another aspect of the present invention, additional methods for inhibiting the growth of a selected tumor in a warm-blooded animal are provided, comprising the steps of (a) removing tumor cells associated with the selected tumor from a warm-blooded animal, (b) infecting the removed cells with a recombinant retroviral or viral vector as described above, and (c) delivering the infec
Barber Jack R.
Jolly Douglas J.
Respess James G.
Blackburn Robert
Chiron Corporation
Dollard Anne
Martin Jill D.
McMasters David
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