Use of herpes vectors for tumor therapy

a technology of herpes and tumors, applied in the field of tumor specific immunity induction, can solve the problems of major difficulties in the therapeutic use of "cancer vaccines"

Inactive Publication Date: 2002-09-12
GEORGETOWN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0005] It is therefore an object of the present invention to provide a method of eliciting a systemic antitumor immune response in a patient who presents with or who is at risk of developing multiple metastatic tumors without manipulating the patient's autologous tumor cells or identifying or purifying specific antigens.

Problems solved by technology

The therapeutic use of "cancer vaccines" has presented major difficulties, however.

Method used

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  • Use of herpes vectors for tumor therapy
  • Use of herpes vectors for tumor therapy
  • Use of herpes vectors for tumor therapy

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0074] Antitumor Efficacy of G207 in CT26 Cell Line

[0075] The antitumor efficacy of G207 was evaluated in a bilateral, established subcutaneous tumor model with CT26 cells as described below.

[0076] Cell Line

[0077] The murine colorectal carcinoma CT26 cell line has been widely used as a syngeneic tumor model to study immunotherapy. Fearon et al. Cancer Res. 35: 2975-80 (1988); Wang, et al., J Immunol. 154: 4685-92 (1995); Huang et al., Proc. Natl. Acad. Sci. USA 93: 9730-35 (1996). CT26 is a transplantable colon epithelial tumor induced by intrarectal injections of N-nitroso-N-methylurethane in female BALB / c mice (H-2.sup.d). Corbett et al., Cancer Res. 35: 2434-39 (1975).

[0078] In normal mice, CT26 is poorly immunogenic: 10.sup.3-10.sup.4 cells can cause a lethal tumor and do not induce detectable tumor-specific CTL. Fearon et al., supra; Wang et al., supra. AH1, a nonmutated nonamer derived from the envelop protein (gp70) of an endogenous ecotropic murine leukemia provirus (MuLV), ...

example 2

[0097] Antitumor Efficacy of G207 in M3 Mouse Melanoma Cells

[0098] M3 mouse melanoma cells (3.times.10.sup.5) were inoculated bilaterally into the flanks of DBA / 2 mice. When the tumors were 5 mm in maximal diameter, the right flank tumor was inoculated one time with either 5.times.10.sup.7 pfu of G207 or an equivalent amount of mock Vero cell preparation (as a negative control).

[0099] Inoculation with G207 inhibited the growth of the inoculated tumor (p<0.0005), and also significantly inhibited the growth of the non-inoculated tumor (p<0.02). FIG. 2.

example 3

[0100] Antitumor Efficacy of G207 in Mouse N18 Neuroblastoma Cells

[0101] Bilateral Subcutaneous Tumors

[0102] Mouse N18 neuroblastoma cells were subcutaneously implanted bilaterally into syngeneic A / J mice. Eight days after tumor implantation, 10.sup.7 pfu of G207 or mock were injected into the left tumor. In six of eight animals, inoculation with G207 resulted in the disappearance of the tumors on both sides. FIG. 3.

[0103] Subcutaneous and Intracerebral Tumors

[0104] N18 neuroblastoma cells were subcutaneously implanted bilaterally into the left flank of A / J mice. Three days later, N18 neuroblastoma cells were intracerebrally implanted into the right frontal lobe of the mice. On days 10 and 13, the subcutaneous tumors only were injected with G207 (11 mice) or mock (11 mice). Within 35 days of cerebral implantation, all mock-treated mice died from or had intracerebral tumors. Four out of eleven mice treated with G207 had no intracerebral tumors, and one G207-treated mouse was a long-t...

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Abstract

Eliciting a systemic antitumor immune response, in a patient who presents with or who is at risk of developing multiple metastatic tumors of a given cell type, entails, in one embodiment, inoculating a tumor in the patient with a pharmaceutical composition consisting essentially of (A) a herpes simplex virus (HSV) that infects tumor cells but that does not spread in normal cells and (B) a pharmaceutically acceptable vehicle for the virus, such that an immune response is induced that is specific for the tumor cell type and that kills cells of the inoculated tumor and of a non-inoculated tumor. In another embodiment, the pharmaceutical composition also comprises a defective HSV vector which contains an expressible nucleotide sequence encoding at least one immune modulator. In another embodiment, the pharmaceutical composition contains a second HSV that infects tumor cells but that does not spread in normal cells. According to the latter approach, both the first HSV and the second HSV may have genomes that comprise, respectively, an expressible nucleotide sequence coding for at least one immune modulator. In another embodiment, the pharmaceutical composition comprises, in addition to a herpes simplex virus (HSV) that infects tumor cells but that does not spread in normal cells, a viral vector comprising at least one expressible nucleotide sequence coding for at least one immune modulator.

Description

BACKGROUND OF THE INVENTION[0001] Induction of tumor-specific immunity is an attractive approach for cancer therapy because of the prospect of harnessing the body's own defense mechanisms, rather than using standard toxic therapeutic agents, to provide long-term protection against tumor existence, growth and recurrence. This strategy is attractive for its potential to destroy small metastatic tumors which may escape detection, and to provide immunity against recurrent tumors.[0002] In principle, an immunotherapy would depend on the presence of tumor-specific antigens and on the ability to induce a cytotoxic immune response that recognizes tumor cells which present antigens. Cytotoxic T lymphocytes (CTL) recognize major histocompatibility complex (MHC) class I molecules complexed to peptides derived from cellular proteins presented on the cell surface, in combination with co-stimulatory molecules. Mueller et al., Annu. Rev. Immunol. 7: 445-80 (1989). In fact, tumor-specific antigens ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K35/763A61K38/19C12N15/09A61K38/20A61K48/00A61P35/00A61P37/04C12N7/00C12N7/01C12N7/04C12N15/869
CPCA01K2267/0331A61K39/245A61K48/00A61K48/005C12N15/86C12N2710/16632C12N2710/16643C12N2800/108C12N2840/203A61K38/208A61K38/1774A61K35/763A61K38/193A61K2300/00A61P35/00A61P35/04A61P37/04
Inventor RABKIN, SAMUEL D.TODA, MASAHIROMARTUZA, ROBERT L.
Owner GEORGETOWN UNIV
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