Cyclin A1-targeted T-cell immunotherapy for cancer
Compositions and methods are provided for eliciting antigen-specific T-cell responses against human cyclin A1 (CCNA1), which is herein identified as a leukemia-associated antigen based on its overexpression in acute myeloid leukemia (AML) including leukemia stem cells (LSC) and in immunologically privileged testis cells, but not in other normal cell types. CCNA1-derived peptide epitopes that are immunogenic for T-cells including CTL are disclosed, as are immunotherapeutic approaches using such peptides for vaccines and generation of adoptive transfer therapeutic cells.
1. An isolated human cyclin A1 (CCNA1)-specific T cell comprising at least one recombinant expression vector encoding a T-cell receptor polypeptide that specifically binds in a human class I HLA-restricted manner to a CCNA1 polypeptide epitope of no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, or 9 amino acids comprising the amino acid sequence set forth in SEQ ID NO:1, 3, 4, 5, 6, or 8.
2. A method for treating a condition characterized by CCNA1 overexpression in cells of a subject, comprising adoptively transferring to the subject an effective amount of the CCNA1-specific T cell of claim 1 .
3. The isolated human CCNA1-specific T cell of claim 1 wherein the polypeptide epitope is a polypeptide of general formula:
N-X-C, [I]
wherein:
(a) N-X-C is a polypeptide of no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10 or 9 amino acids in which X is an amino acid sequence that is selected from:
[SEQ ID NO: 1]
CCNA1(120-131) VDTGTLKSDLHF,
[SEQ ID NO: 3]
CCNA1(227-235) FLDRFLSCM,
[SEQ ID NO: 4]
CCNA1(253-261) ASKYEEIYP,
[SEQ ID NO: 5]
CCNA1(118-127) YEVDTGTLKS,
[SEQ ID NO: 6]
CCNA1(167-175) YAEEIYQYL,
and
[SEQ IN NO: 8]
CCNA1(341-351) SLIAAAAFCLA,
(b) N is the amino terminus of the peptide and consists of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 amino acids that are independently selected from natural amino acids and non-natural amino acids, and
(c) C is the carboxy terminus of the peptide and consists of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 amino acids that are independently selected from natural amino acids and non-natural amino acids.