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Publication Number
US-10293037-B2
Publication Date
2019-05-21
Expiration Date
Abstract
The present invention relates to an attenuated mutant strain of Salmonella comprising a recombinant DNA molecule encoding a VEGF receptor protein. In particular, the present invention relate to the use of said attenuated mutant strain of Salmonella in cancer immunotherapy.
Core Innovation
The invention relates to an oral cancer vaccine (VXM01) that provides cancer immunotherapy by administering to a patient an attenuated mutant Salmonella typhi Ty21a carrier strain transformed with a plasmid (pVAX10.VR2-1) comprising an expression cassette encoding human VEGFR-2 having the amino acid sequence of SEQ ID NO 1 under a CMV promoter. The approach targets tumor vasculature and/or endothelial cells through VEGFR-2 expression.
A key aspect is the use of a DNA vaccine concept based on an attenuated mutant Salmonella typhi Ty21a carrier, with a single dose of 10^9 CFU or less. The description also includes low-dose efficacy concepts down to approximately 10^5 to 10^7 CFU and frames the vaccine as an oral, patient-independent concept, with possible individualized concepts based on antigen and immune response.
The disclosed clinical context focuses on anti-angiogenic cancer immunotherapy, including pancreatic cancer in stage IV and locally advanced settings, including patients with metastases. The vaccine is described for use as monotherapy and in combination with gemcitabine, chemotherapy cycles and/or radiotherapy and other therapies, with monitoring of VEGFR-2-specific immune responses and angiogenesis-related biomarkers as clinical readouts.
Claims Coverage
Two independent claims are identified. Across the independent claims, the inventive subject matter centers on administering an attenuated mutant Salmonella typhi Ty21a-based DNA vaccine encoding human VEGFR-2 (SEQ ID NO 1), specifically designated as VXM01/pVAX10.VR2-1, together with a restricted single-dose level of 10^9 CFU or less.
Attenuated mutant Salmonella typhi Ty21a DNA vaccine encoding human VEGFR-2 under CMV promoter
Administering to a cancer patient a DNA vaccine comprising an attenuated mutant strain of Salmonella typhi Ty21a comprising an expression cassette encoding a human VEGFR-2 having the amino acid sequence of SEQ ID NO 1.
Single-dose restriction for the VEGFR-2 DNA vaccine
Administering the DNA vaccine wherein a single dose of the vaccine is 10^9 colony forming units (CFU) or less than 10^9 CFU.
VXM01 defined as Ty21a transformed by plasmid pVAX10.VR2-1 expressing VEGFR-2 under CMV control
Administering a DNA vaccine VXM01 comprising the attenuated Salmonella typhi strain Ty21a transformed by a 7580 bp plasmid, the plasmid comprising a DNA encoding the VEGFR-2 protein of SEQ ID NO 1 under the control of a CMV promoter, with the plasmid being designated as pVAX10.VR2-1.
Plasmid component specification for VXM01/pVAX10.VR2-1
The plasmid includes the kanamycin resistance gene and the pMB1 ori as part of VXM01/pVAX10.VR2-1.
Claim coverage focuses on cancer immunotherapy using an attenuated mutant Salmonella typhi Ty21a-based DNA vaccine that encodes human VEGFR-2 (SEQ ID NO 1) under a CMV promoter, including a defined VXM01/pVAX10.VR2-1 plasmid configuration, and limits immunotherapy to a single dose of 10^9 CFU or less.
Stated Advantages
Oral, patient-independent concept.
Possible individualized concepts based on antigen and immune response.
Documented Applications
Anti-angiogenic cancer immunotherapy, including pancreatic cancer (stage IV and locally advanced pancreatic cancer with metastases) as monotherapy.
Anti-angiogenic cancer immunotherapy, including pancreatic cancer (stage IV and locally advanced pancreatic cancer with metastases) in combination with gemcitabine and/or radiotherapy and other therapies.
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