Whole-cell cancer vaccines and methods for selection thereof
Inventors
Lacher, Markus Daniel • Wagner, Joseph Paul • Wiseman, Charles Louis • Williams, William Valentine
Assignees
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Publication Number
US-11559574-B2
Publication Date
2023-01-24
Expiration Date
Abstract
The present invention provides a modified human cancer cell comprising a recombinant polynucleotide encoding an allele of a human leukocyte antigen gene. The present invention also provides methods for selecting a whole-cell cancer vaccine for a subject having cancer and methods of treating cancer using whole-cell cancer vaccines of the present invention. In addition, the present invention provides a method of determining the HER2 status of a cell. Compositions and kits are also provided herein.
Core Innovation
The invention relates to a modified human cancer cell engineered to include recombinant polynucleotides encoding defined human leukocyte antigen (HLA) class II alleles and defined HLA class I alleles. The HLA class II gene comprises an HLA-DRB3 gene, an HLA-DRB4 gene, an HLA-DRB5 gene, or a combination thereof, with the DRB3 allele comprising HLA-DRB3*02:02, HLA-DRB3*01:01, or HLA-DRB3*03:01. The HLA class I gene comprises specified alleles including HLA-A*11:01, HLA-A*01:01, HLA-A*02:01, HLA-A*03:01, HLA-A*26:01, HLA-A*29:02, HLA-A*32:01, HLA-A*24:02, HLA-A*33:03, HLA-A*68:01, HLA-A*31:01, and HLA-A*02:06, or combinations thereof.
The modified human cancer cell further comprises a recombinant polynucleotide encoding granulocyte-macrophage colony-stimulating factor (GM-CSF). In additional aspects, the engineered cancer cell includes expanded immune-related gene sets such as additional HLA genes and beta-2-microglobulin (B2M), and can further comprise recombinant polynucleotides encoding interferon alpha (IFN-α). The recombinant polynucleotides can be present on one or more vectors or integrated into the genome.
The summary describes whole-cell cancer vaccine concepts and therapy based on modified cancer cells. It also describes high-resolution HLA allele matching and identification of tumor-associated antigens, including PRAME, together with immune-related gene-expression profiling that includes HLA class I and class II components.
Claims Coverage
The independent claim set is directed to modified human cancer cells and compositions comprising modified human cancer cells. Across the claims, the inventive coverage centers on recombinant polynucleotides encoding specified HLA class I alleles, specified HLA class II alleles including HLA-DRB3/DRB4/DRB5 structures, and GM-CSF, with additional allele-constrained HLA combinations in separate independent-claim structures.
Engineered HLA class II and class I antigen presentation with GM-CSF
A modified human cancer cell comprising recombinant polynucleotides encoding an allele of an HLA class II gene comprising HLA-DRB3, HLA-DRB4, HLA-DRB5, or a combination thereof; recombinant polynucleotides encoding an allele of an HLA class I gene comprising HLA-A*11:01, HLA-A*01:01, HLA-A*02:01, HLA-A*03:01, HLA-A*26:01, HLA-A*29:02, HLA-A*32:01, HLA-A*24:02, HLA-A*33:03, HLA-A*68:01, HLA-A*31:01, HLA-A*02:06, or a combination thereof; and a recombinant polynucleotide encoding GM-CSF.
Composition of engineered modified human cancer cells with defined HLA alleles and GM-CSF
A composition comprising a modified human cancer cell comprising an HLA class II gene comprising HLA-DRB3, HLA-DRB4, HLA-DRB5, or a combination thereof; and an HLA class I gene comprising HLA-A*11:01, HLA-A*01:01, HLA-A*02:01, HLA-A*03:01, HLA-A*26:01, HLA-A*29:02, HLA-A*32:01, HLA-A*24:02, HLA-A*33:03, HLA-A*68:01, HLA-A*31:01, HLA-A*02:06, or a combination thereof; wherein the composition further comprises GM-CSF.
HLA class I fixed alleles with HLA class II allele repertoire
A modified human cancer cell comprising a recombinant polynucleotide encoding an allele of an HLA class I gene; and a recombinant polynucleotide encoding an allele of an HLA class II gene; wherein the allele of the HLA class I gene comprises an HLA-A*02:01 allele and an HLA-A*11:01 allele.
Fixed HLA-A alleles combined with HLA-DRB3 and HLA-DRB5 alleles
A modified human cancer cell comprising a recombinant polynucleotide encoding an allele of an HLA class I gene wherein the allele of the HLA class I gene comprises an HLA-A*03:01 allele; and a recombinant polynucleotide encoding an allele of an HLA class II gene wherein the allele of the HLA class II gene comprises an allele of an HLA-DRB3 gene and an allele of an HLA-DRB5 gene.
HLA-DRB3 allele-limited class II antigen presentation
A modified human cancer cell comprising a recombinant polynucleotide encoding an allele of an HLA class I gene; and a recombinant polynucleotide encoding an allele of an HLA class II gene, wherein the allele of the HLA class II gene comprises HLA-DRB3*02:02, HLA-DRB3*01:01, HLA-DRB3*03:01, or a combination thereof.
The claim coverage is directed to modified human cancer cells and a composition thereof engineered with recombinant polynucleotides encoding defined HLA class I alleles and defined HLA class II allele selections, together with GM-CSF in the claim structures that recite it, and further allele-constrained HLA combinations in additional independent-claim structures.
Stated Advantages
Whole-cell cancer vaccine/therapy for cancer treatment using modified cancer cells, including example GM-CSF-secreting allogeneic whole-cell vaccine concepts.
A relationship between an immune-stimulatory signature and tumor regression.
Documented Applications
Whole-cell cancer vaccine/therapy for cancer treatment using modified cancer cells, including example GM-CSF-secreting allogeneic whole-cell vaccine concepts.
Administration routes such as intradermal injection and intralymphatic injection.
Pharmaceutical dose forms including oral tablets/capsules, topical/transdermal, inhaled aerosols, parenteral sterile injectables, and lyophilized dosage forms (lyophilized syringes).
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