Composition of NY-ESO-1-specific t cell receptors restricted on multiple major histocompatibility complex molecules
Tumor-specific T cell receptor (TCR) gene transfer enables specific and potent immune targeting of tumor antigens. The canonical cancer-testis antigen, NY-ESO-1, is not expressed in normal tissues but is aberrantly expressed across a broad array of cancer types. It has also been targeted with A2-restricted TCR gene therapy without adverse events or notable side effects. To enable the targeting of NY-ESO-1 in a broader array of HLA haplotypes, we isolated TCRs specific for NY-ESO-1 epitopes presented by four MHC molecules: HLA-A2, -B07, -B18, and -C03. Using these TCRs, we have developed an approach to extend TCR gene therapies targeting NY-ESO-1 to patient populations beyond those expressing HLA-A2.
1 . A polynucleotide disposed in a vector, wherein:
the polynucleotide encodes a Vα T cell receptor polypeptide and a Vβ T cell receptor polypeptide; and
when a Vα/Vβ T cell receptor comprising the Vα T cell receptor polypeptide and/or the Vβ T cell receptor polypeptide is expressed in a CD 8 + T cell, the Vα/Vβ T cell receptor recognizes a NY-ESO-1 peptide associated with:
human leukocyte antigen A2; and
the vector comprises:
(a) a polynucleotide encoding a 3A1 Vα polypeptide (SEQ ID NO: 3); and
(b) a polynucleotide encoding a 3A1 Vβ polypeptide (SEQ ID NO: 4);
wherein the vector comprises a polynucleotide sequence that modulates expression of the polypeptide within CD 8 + T cells.
2 . The polynucleotide of claim 1 , wherein the vector is a Sendai viral vector, an adenoviral vector, an adeno-associated virus vector, a retroviral vector, or a lentiviral vector.
3 . A composition of matter comprising a host cell transduced with a vector comprising a polynucleotide, wherein:
the polynucleotide encodes a Vα T cell receptor polypeptide and a Vβ T cell receptor polypeptide; and
when a Vα/Vβ T cell receptor comprising the Vα T cell receptor polypeptide and/or the Vβ T cell receptor polypeptide is expressed in a CD 8 + T cell, the Vα/Vβ T cell receptor recognizes a NY-ESO-1 peptide associated with:
human leukocyte antigen A2; and
the vector comprises:
(a) a polynucleotide encoding a 3A1 Vα polypeptide (SEQ ID NO: 3); and
(b) a polynucleotide encoding a 3A1 Vβ polypeptide (SEQ ID NO: 4).
4 . The composition of claim 3 , wherein the host cell is a human CD 8 + T cell.
5 . The composition of claim 4 , wherein the composition is a pharmaceutical composition comprising one more pharmaceutically acceptable excipients selected from the group consisting of buffering agents, antimicrobial agents, tonicity adjusting agents, wetting agents, detergents and pH adjusting agents.
6 . The composition of claim 5 , wherein:
the CD8 + T cell is obtained from an individual diagnosed with a cancer that expresses a NY-ESO-1 antigen; and
the CD8 + T cell is transduced with a vector comprising a polynucleotide encoding a TCR Vα polypeptide in combination with a polynucleotide encoding a TCR Vβ polypeptide such that a heterologous TCR is expressed on a surface of the CD8 + T cell, wherein the heterologous TCR recognizes a NY-ESO-1 peptide associated with a human leukocyte antigen expressed on the surface of cells of the cancer.
7 . The composition of claim 6 , wherein the vector is a retroviral vector.