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Publication Number
US-9415098-B2
Publication Date
2016-08-16
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 disclosure describes an oral live attenuated Salmonella typhi Ty21a DNA vaccine (VXM01) encoding a VEGF receptor protein having the amino acid sequence as found in SEQ ID NO 1. The vaccine includes at least one copy of a recombinant DNA molecule comprising an expression cassette that drives eukaryotic, CMV-controlled expression of the VEGF receptor protein. The formulation is administered to treat pancreatic cancer, including stage IV or locally advanced pancreatic cancer, with administration as a single dose of 1×10^9 CFU or less.
The problem addressed is the treatment of pancreatic cancer by targeting tumor neovasculature/VEGFR-2. The disclosure provides a rationale for immune targeting through VEGFR-2 and reports immune readouts consistent with VEGFR-2-specific T cells, including IFN-γ ELISpot responses. The document further reports tumor perfusion and angiogenesis-related biomarker monitoring, including DCE-MRI Ktrans and angiogenesis biomarkers, to assess treatment activity.
The disclosure also addresses clinical context and safety-related observations, including monitoring safety/tolerability endpoints and observations related to excretion/shedding for environmental risk and vector containment. A single-dose administration concept is presented with related CFU dose constraints, and patient context includes use in locally advanced/stage IV pancreatic cancer. The document additionally describes the use of the vaccine in combination with chemotherapy in a chemotherapy treatment cycle context, including mention of gemcitabine.
Claims Coverage
The independent claim defines a treating method for pancreatic cancer using a vaccine made from an attenuated Salmonella typhi Ty21a mutant strain carrying a recombinant DNA expression cassette encoding a VEGF receptor protein with the amino acid sequence of SEQ ID NO 1, administered as a single dose of 1×10^9 CFU or less. Dependent claims further refine route, CFU dose constraints, cancer stage, and timing relative to chemotherapy cycles.
Single-dose VEGFR-2 (SEQ ID NO 1) Salmonella typhi Ty21a DNA vaccine for pancreatic cancer
Administering to a patient in need thereof a vaccine comprising an attenuated mutant strain of Salmonella typhi Ty21a comprising at least one copy of a recombinant DNA molecule comprising an expression cassette encoding a VEGF receptor protein having the amino acid sequence as found in SEQ ID NO 1, wherein the vaccine is administered in a single dose of 1×10^9 CFU or less.
Oral administration of the Ty21a VEGFR-2 vaccine
Administering the vaccine of the method to the patient orally.
Single-dose CFU constrained to 1×10^8 to 1×10^9 CFU
Administering the vaccine in a single dose of 1×10^8 to 1×10^9 CFU.
Stage IV or locally advanced pancreatic cancer treatment
The method wherein the pancreatic cancer is stage IV or locally advanced pancreatic cancer.
VEGFR-2 DNA vaccine VXM01 using pVAX10.VR2-1 and SEQ ID NO 3
The method wherein the vaccine comprises the plasmid pVAX10.VR2-1 with the DNA sequence of SEQ ID NO 3 to create a DNA vaccine designated VXM01.
Immunotherapeutic vaccine timing during chemotherapy treatment cycle
The method wherein the immunotherapeutic vaccine treatment is administered during the chemotherapy treatment cycle.
Overall claim coverage centers on treating pancreatic cancer with an oral live attenuated Salmonella typhi Ty21a mutant strain vaccine encoding VEGFR-2 (SEQ ID NO 1) from a recombinant DNA expression cassette, with a key limitation to a single dose of 1×10^9 CFU or less and additional refinements concerning oral route, cancer stage, a specific named DNA vaccine/plasmid configuration, and timing relative to chemotherapy cycles.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treating pancreatic cancer, including stage IV or locally advanced pancreatic cancer, in patients using the described oral live attenuated Salmonella typhi Ty21a DNA vaccine (VXM01).
Combination therapy context in a chemotherapy treatment cycle, including mention of gemcitabine add-on.
Monitoring immune responses (VEGFR-2-specific IFN-γ ELISpot T cells), tumor perfusion effects (DCE-MRI Ktrans), and angiogenesis biomarkers (e.g., VEGF-A and collagen IV), with safety/tolerability and excretion/shedding observations for environmental risk and vector containment.
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