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Publication Number
US-11400170-B2
Publication Date
2022-08-02
Expiration Date
Abstract
Compositions and methods for prevention of ovarian cancer recurrence and for the treatment of BRCA1/2-wild type ovarian cancer are disclosed herein. In some embodiments, the composition comprises an autologous tumor cell vaccine comprising cells genetically modified for furin knockdown and GM-CSF expression. In some embodiments, the method comprises administration of an autologous tumor cell vaccine prior to administration of a combination of the autologous tumor cell vaccine and atezolizumab. Also disclosed herein are methods for treating a cancer in an individual comprising a wild-type BRCA1 gene, a wild-type BRCA2 gene, or a combination thereof, and is identified as homologous recombination deficiency (HRD)-negative.
Core Innovation
The invention provides a method of treating a cancer in an individual in need thereof by administering an expression vector. The expression vector comprises a first insert encoding a Granulocyte Macrophage Colony Stimulating Factor (GM-CSF) sequence and a second insert comprising a sequence of SEQ ID NO:4. The individual is HRD-negative and/or has a wild-type BRCA1 gene, a wild-type BRCA2 gene, or a combination thereof.
For ovarian cancer, the invention further specifies treatment in an individual whose ovarian cancer has been eradicated, with the method preventing or delaying relapse of the eradicated ovarian cancer. The treatment again comprises administering an expression vector having a first insert encoding GM-CSF and a second insert comprising a sequence of SEQ ID NO:4, with the individual specified as HRD-negative and/or having wild-type BRCA1 and/or wild-type BRCA2.
In related aspects, the expression vector is administered as an autologous tumor cell transfected with the expression vector, and autologous tumor cell transfected material can be administered as an autologous tumor cell vaccine comprising the individual’s own tumor cells. The document also describes a promoter and/or CMV enhancer sequence and/or a CMV intron sequence, and use of a picornaviral 2A ribosomal skip peptide positioned between nucleic acid inserts.
Claims Coverage
The claim coverage includes three independent claims. The claims focus on administration of an expression vector containing a GM-CSF-encoding first insert and a second insert comprising SEQ ID NO:4, with HRD-negative and/or wild-type BRCA1/BRCA2 selection and ovarian-cancer-specific embodiments.
GM-CSF and SEQ ID NO:4 expression vector for HRD-negative and/or wild-type BRCA1/BRCA2 cancer treatment
A method of treating a cancer in an individual in need thereof by administering an expression vector comprising a first insert encoding a GM-CSF sequence and a second insert comprising a sequence of SEQ ID NO:4, wherein the individual is HRD-negative and/or has a wild-type BRCA1 gene, a wild-type BRCA2 gene, or a combination thereof.
Autologous tumor cell transfected with GM-CSF and SEQ ID NO:4 expression vector for BRCA1/2 wild type ovarian cancer
A method of treating BRCA1/2 wild type ovarian cancer in an individual in need thereof by administering an autologous tumor cell transfected with an expression vector comprising a first insert encoding a GM-CSF sequence and a second insert comprising a sequence of SEQ ID NO:4.
Relapse prevention or delay using eradicated ovarian cancer and GM-CSF and SEQ ID NO:4 expression vector in HRD-negative and/or wild-type BRCA1/BRCA2 individuals
A method of treating ovarian cancer in an individual in need thereof, wherein the individual has been eradicated of ovarian cancer and the method prevents or delays relapse of the eradicated ovarian cancer, comprising administering an expression vector with a first insert encoding a GM-CSF sequence and a second insert comprising a sequence of SEQ ID NO:4, wherein the individual is HRD-negative and/or has a wild-type BRCA1 gene, a wild-type BRCA2 gene, or a combination thereof.
Across the independent claims, the core coverage is administration of an expression vector defined by a GM-CSF-encoding first insert and a second insert defined as SEQ ID NO:4. The scope further includes HRD-negative and/or wild-type BRCA1/BRCA2 individuals, autologous tumor cell transfection, and relapse prevention or delay after eradication.
Stated Advantages
Enhancing neoantigen exposure for checkpoint synergy.
Reducing TGFβ-mediated immune suppression via downregulating TGFβ1/TGFβ2.
Improved OS in a BRCA1/2 wild-type subgroup.
Notably no Grade 3/4 related toxicities for Vigil® in certain analyses.
Improves prevention or delay of relapse of eradicated ovarian cancer.
Provides treatment for HRD-negative individuals and/or individuals with wild-type BRCA1 and/or wild-type BRCA2.
Documented Applications
Treatment of cancer in an individual in need thereof, including selection for HRD-negative and/or wild-type BRCA1/BRCA2 status.
Treatment of BRCA1/2 wild type ovarian cancer using an autologous tumor cell transfected with an expression vector comprising GM-CSF and SEQ ID NO:4.
Prevention or delay of relapse of eradicated ovarian cancer by administering an expression vector comprising GM-CSF and SEQ ID NO:4 in HRD-negative and/or wild-type BRCA1/BRCA2 individuals.
Clinical evaluation of Vigil® (gemogenovatucel-T) combined with or sequenced with atezolizumab, and a VITAL Phase 2b frontline maintenance trial of Vigil® versus placebo, including HRD/HRP stratification and subgroup analyses.
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