Compositions and methods for enhanced tumor cell immunity in viv

Drug – bio-affecting and body treating compositions – Whole live micro-organism – cell – or virus containing – Genetically modified micro-organism – cell – or virus

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4353201, 435 691, 435325, 435 723, 435 911, 435 914, A01N 6300

Patent

active

061207632

ABSTRACT:
The invention provides a method of preventing or reducing the severity of a cancer in a subject by stimulating the subject's immune response against the cancer. The invention provides, for example, a method of stimulating an immune response in a subject by administering to the subject tumor cells that are substantially similar to the subject's cancer cells and that are genetically modified to reduce or inhibit the expression of one or more immunosuppressive agents. The invention also provides a method of preventing or reducing the severity of cancer in a subject by stimulating the subject's immune response against the cancer by administering to the subject tumor cells that are substantially similar to the subject's cancer cells and that are genetically modified to prevent the expression of an immunosuppressive agents and, in combination with the genetically modified tumor cells, an immunostimulatory agent. The invention further provides compositions useful for practicing the claimed methods.

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Brabletz et al., "Transforming Growth Factor .beta. and Cyclosporin A Inhibit the Inducible Activity of the Interleukin-2 Gene in T Cells Through a Noncanonical Octamer-Binding Site," Mol. Cell. Biol. 13:115-162 (1993).
Gridley et al., "Effects of Anti-Transforming Growth Factor .beta. Antibody and Interleukin-2 in Tumor-bearing Mice," Cancer Biother. 8:159-170 (1993).
Hanks et al., "Amino Acids Sequence of the BSC-1 Cell Growth Inhibitor (Polyergin) Deduced from the Nucleotide Sequence of the cDNA," Proc. Natl. Acad. Sci. USA. 85:79-82 (1988).
Hirte et al., "Reversal of Suppression of Lymphokine-Activated Killer Cells by Transforming Growth Factor-.beta. in Ovarian Carcinoma Ascitic Fluid Requires Interleukin-2 Combined with Anti-CD3 Antibody," Cell. Immunol. 142:207-216 (1992).
Hirte and Clarke, "Generation of Lymphokine-Activated Killer Cells in Human Ovarian Carcinoma Ascitic Fluid: Identification of Transforming Growth Factor-.beta. as a Suppressive Factor," Cancer Immunol. Immunother. 32:296-302 (1991).
Inge et al., "Inhibition of Tumor-Specific Cytotoxic T-Lymphocyte Responses by Transforming Growth Factor .beta..sub.1," Cancer Res. 52:1386-1392 (1992).
Jachimczak et al., "The Effect of Transforming Growth Factor-.beta.-Specific Phosphorothioate-Anti Sense Oligodeoxynucleotides in Reversing Cellular Immunosuppression in Malignant Glioma," J. Neurosurg. 78:944-951 (1993).
Kuppner et al., "Inhibition of Lymphocyte Function by Glioblastoma-Derived Transforming Growth Factor .beta.2," J. Neurosurg. 71:211-217 (1989).
Lord et al., "Transfection of TGF-.beta. Producing Tumors with IL-2 Elicits Tumor Rejection," Annals of the New York Academy of Sciences 690:346-348 (1993).
Rosenberg et al., "Gene Transfer into Human-Immunotherapy of Patients with Advanced Melanoma, Using Tumor-Infiltrating Lymphocytes Modified by Retroviral Gene Trasduction," New Engl. J. Med. 323:570-578 (1990).
Ruffini et al., "Factors, Including Transforming Growth Factor .beta., Released in the Glioblastoma Residual Cavity, Impair Activity of Adherent Lymphokine-Activated Killer Cells," Cancer Immunol. 36:409-416 (1993).
Sulitzeanu, Dov, "Immunosupressive Factors in Human Cancer," Adv. Cancer Res. 60:247-267 (1993).
Tepper and Mule, "Experimental and Clinical Studies of Cytokine Gene-Modified Tumor Cells," Human Gene Therapy 5:153-164 (1994).
Weiskirch et al., "Transforming Growth Factor-.beta.-Mediated Down-Regulation of Antitumor Cytotoxicity of Spleen Cells form MOPC-315 Tumor-Rearing Mice Engaged in Tumor Eradication Following Low-Dose Melphalan Therapy," Cancer Immun. 38:215-224 (1994).
Wu et al., "Repression of Autocrine Transforming Growth Factor .beta..sub.1 and .beta..sub.2 in Quiescent CBS Colon Carcinoma Cells Leads to Progression of Tumorigenic Properties," J. Cell Biology 116: 187-196 (1992).
Yamamoto et al., "TGF-.beta. Mediates Natural Suppressor Activity of IL-2-Activated Lymphocytes," J. Immunol. 3842-3847 (1994).

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