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Publication Number
US-10980868-B2
Publication Date
2021-04-20
Expiration Date
Abstract
The present invention relates to an attenuated strain of Salmonella comprising at least one copy of a DNA molecule comprising an expression cassette encoding a VEGF receptor protein for use in cancer immunotherapy, wherein the cancer is characterized by VEGF receptor protein expressing cancer cells. The present invention further relates to an attenuated strain of Salmonella comprising at least one copy of a DNA molecule comprising an expression cassette encoding a VEGF receptor protein for use in cancer immunotherapy, wherein the cancer is characterized by VEGF receptor protein expressing cancer cells, and wherein the cancer is selected from the group consisting of glioblastoma, carcinoid cancer, kidney cancer, particularly renal cell carcinoma, thyroid cancer, lung cancer, particularly Non-Small Cell Lung Cancer (NSCLC), breast cancer, ovarian cancer, prostate cancer, gastrointestinal cancer, particularly colorectal cancer, more particularly colon cancer, and skin cancer, particularly melanoma. The present invention further relates to an attenuated strain of Salmonella comprising at least one copy of a DNA molecule comprising an expression cassette encoding a VEGF receptor protein for use in cancer immunotherapy in a patient comprising at least one VEGF receptor protein expressing cancer cell.
Core Innovation
The invention relates to a method of treating cancer in a human patient by determining that the patient has a cancer comprising VEGFR-2 expressing cancer cells or has at least one cancer cell expressing VEGFR-2. After this determination, the patient is orally administered a therapeutically effective dose of a live attenuated strain of Salmonella comprising at least one copy of a DNA molecule comprising a eukaryotic expression cassette encoding VEGFR-2.
The live attenuated strain of Salmonella is Salmonella typhi Ty21a. The VEGFR-2 encoded by the eukaryotic expression cassette comprises the amino acid sequence set forth in SEQ ID NO: 1 or an amino acid sequence that has at least 95% sequence identity to SEQ ID NO: 1. The described approach further includes individualized assessment of VEGFR-2 expression and/or pre-immune responses.
The document outlines assessment of VEGFR-2 (mRNA/protein; IHC/ISH/flow/RNA-seq) and pre-immune responses, and describes optional combination with chemotherapy/radiotherapy and additional Salmonella DNA vaccines encoding tumor/tumor-stroma antigens such as WT1, MSLN, CEA, CMV pp65, and FAP. A clinical example is described for operable recurrent glioblastoma assessing safety/tolerability, immune responses, and biomarker responses to VXM01.
Patient-specific MRI outcomes and immunohistochemistry showing VEGFR-2 expression changes and increased CD8+ T cells post-treatment are described in the document.
Claims Coverage
The document provides two independent claims that cover patient selection based on VEGFR-2 expression and oral administration of an attenuated Salmonella typhi Ty21a strain engineered with a DNA molecule encoding VEGFR-2 under a eukaryotic expression cassette, with sequence-identity constraints for VEGFR-2.
Patient selection by VEGFR-2 expression
Determining that the patient has a cancer comprising VEGFR-2 expressing cancer cells or has at least one cancer cell expressing VEGFR-2.
Oral live attenuated Salmonella delivery
Orally administering to the patient having the cancer comprising VEGFR-2 expressing cancer cells or the at least one cancer cell expressing VEGFR-2 a therapeutically effective dose of a live attenuated strain of Salmonella comprising at least one copy of a DNA molecule comprising a eukaryotic expression cassette encoding VEGFR-2.
Salmonella typhi Ty21a strain and VEGFR-2 sequence identity constraint
Wherein the live attenuated strain of Salmonella is Salmonella typhi Ty21a, and wherein the VEGFR-2 comprises the amino acid sequence set forth in SEQ ID NO: 1 or an amino acid sequence that has at least 95% sequence identity to SEQ ID NO: 1.
Across the independent claims, the core claim coverage is directed to orally treating human cancer patients by selecting based on VEGFR-2 expressing cancer cells and administering a therapeutically effective dose of Salmonella typhi Ty21a carrying a eukaryotic expression cassette encoding VEGFR-2 that matches SEQ ID NO: 1 or has at least 95% sequence identity.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treating operable recurrent glioblastoma with VXM01, including assessment of safety/tolerability, immune responses, and biomarker responses, and reporting patient-specific MRI outcomes and immunohistochemistry changes (including increased CD8+ T cells post-treatment).
Treatment of cancers characterized by tumor-cell VEGFR-2 expression, with cancer types listed including glioblastoma, carcinoid cancer, renal cell carcinoma, Non-Small Cell Lung Cancer (NSCLC), and melanoma.
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