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Combination therapy for use in cancer therapy

a cancer therapy and combination therapy technology, applied in the direction of antibody medical ingredients, drug compositions, dsdna viruses, etc., can solve the problems of genital warts and the tendency to get anal cancer

Inactive Publication Date: 2016-08-11
THE TRUSTEES OF THE UNIV OF PENNSYLVANIA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention is related to a method of treating anal or vaginal tumors or cancer in humans by administering a combination therapy consisting of chemo-radiation therapy and a recombinant Listeria strain. The recombinant Listeria strain comprises a recombinant nucleic acid that contains a first open reading frame encoding a recombinant polypeptide that includes an N-terminal fragment of an LLO protein fused to a heterologous antigen or fragment thereof. The combined therapy results in effective treatment of the anal or vaginal tumor or cancer in humans, as well as eliciting an anti-tumor cytotoxic T cell response.

Problems solved by technology

Anal infection with human papillomavirus (HPV) resulting in genital warts is a major risk factor for the cancer, and immunocompromised patients, are prone to get anal cancer.

Method used

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  • Combination therapy for use in cancer therapy
  • Combination therapy for use in cancer therapy
  • Combination therapy for use in cancer therapy

Examples

Experimental program
Comparison scheme
Effect test

example 1

LLO-Antigen Fusions Induce Anti-Tumor Immunity

Materials and Experimental Methods (Examples 1-2)

Cell Lines

[0190]The C57BL / 6 syngeneic TC-1 tumor was immortalized with HPV-16 E6 and E7 and transformed with the c-Ha-ras oncogene. TC-1, provided by T. C. Wu (Johns Hopkins University School of Medicine, Baltimore, Md.) is a highly tumorigenic lung epithelial cell expressing low levels of with HPV-16 E6 and E7 and transformed with the c-Ha-ras oncogene. TC-1 was grown in RPMI 1640, 10% FCS, 2 mM L-glutamine, 100 U / ml penicillin, 100 μg / ml streptomycin, 100 μM nonessential amino acids, 1 mM sodium pyruvate, 50 micromolar (mcM) 2-ME, 400 microgram (mcg) / ml G418, and 10% National Collection Type Culture-109 medium at 37° with 10% CO2. C3 is a mouse embryo cell from C57BL / 6 mice immortalized with the complete genome of HPV 16 and transformed with pEJ-ras. EL-4 / E7 is the thymoma EL-4 retrovirally transduced with E7.

[0191]L. monocytogenes Strains and Propagation

[0192]Listeria strains used were ...

example 2

LM-LLO-E7 Treatment Elicits TC-1 Specific Splenocyte Proliferation

[0211]To measure induction of T cells by Lm-E7 with Lm-LLO-E7, TC-1-specific proliferative responses, a measure of antigen-specific immunocompetence, were measured in immunized mice. Splenocytes from Lm-LLO-E7-immunized mice proliferated when exposed to irradiated TC-1 cells as a source of E7, at splenocyte: TC-1 ratios of 20:1, 40:1, 80:1, and 160:1 (FIG. 4). Conversely, splenocytes from Lm-E7 and rLm control-immunized mice exhibited only background levels of proliferation.

example 3

Fusion of E7 to LLO, actA, or a Pest Amino Acid Sequence Enhances E7-Specific Immunity and Generates Tumor-Infiltrating E7-Specific CD8+ Cells

Materials and Experimental Methods

[0212]500 mcl (microliter) of MATRIGEL®, comprising 100 mcl of 2×105 TC-1 tumor cells in phosphate buffered saline (PBS) plus 400 mcl of MATRIGEL® (BD Biosciences, Franklin Lakes, N.J.) were implanted subcutaneously on the left flank of 12 C57BL / 6 mice (n=3). Mice were immunized intraperitoneally on day 7, 14 and 21, and spleens and tumors were harvested on day 28. Tumor MATRIGELs were removed from the mice and incubated at 4° C. overnight in tubes containing 2 milliliters (ml) of RP 10 medium on ice. Tumors were minced with forceps, cut into 2 mm blocks, and incubated at 37° C. for 1 hour with 3 ml of enzyme mixture (0.2 mg / ml collagenase-P, 1 mg / ml DNAse-1 in PBS). The tissue suspension was filtered through nylon mesh and washed with 5% fetal bovine serum+0.05% of NaN3 in PBS for tetramer and IFN-gamma stain...

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Abstract

The present invention provides methods of treating anal or vaginal tumors and cancers, comprising the step of administering to a subject a combination therapy comprising a chemo-radiation therapy and a recombinant Listeria strain.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of U.S. Provisional Application No. 62 / 063,828, filed on Oct. 14, 2014 and U.S. Provisional Application No. 62 / 065,973, filed on Oct. 20, 2014, both of which are incorporated by reference herein in their entirety.FIELD OF INVENTION[0002]The present invention provides methods of treating anal or vaginal tumors and anal or vaginal cancers, comprising the step of administering to a subject a combination therapy comprising a chemo-radiation therapy and a recombinant Listeria strain.BACKGROUND OF THE INVENTION[0003]Listeria monocytogenes (Lm) is a food-borne gram-positive bacterium that can occasionally cause disease in humans, in particular elderly individuals, newborns, pregnant women and immunocompromised individuals. In addition to strongly activating innate immunity and inducing a cytokine response that enhances antigen-presenting cell (APC) function, Lm has the ability to replicate in the cytosol of AP...

Claims

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Application Information

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IPC IPC(8): A61K39/12A61N5/10C12N7/00A61K31/407A61K31/513
CPCA61K31/407C12N7/00A61N5/10A61K2039/585C12N2710/20034C07K16/3046A61K2039/523A61K2039/522A61K39/12A61K31/513A61K2039/545C12Q1/68A61P35/00A61K39/0011A61K2039/54A61K2039/572A61K2039/6037A61K2300/00
Inventor PATERSON, YVONNE
Owner THE TRUSTEES OF THE UNIV OF PENNSYLVANIA
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