Cyclin a1-targeted t-cell immunotherapy for cancer

Abstract

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.

Description

STATEMENT OF GOVERNMENT INTEREST[0001]This invention was made with government support under CA018029 awarded by the National Institutes of Health. The government has certain rights in this invention.STATEMENT REGARDING SEQUENCE LISTING[0002]The Sequence Listing associated with this application is provided in text format in lieu of a paper copy, and is hereby incorporated by reference into the specification. The name of the text file containing the Sequence Listing 360056_407D1_SEQUENCE_LISTING.txt. The text file is about 9.5 KB, was created on Dec. 19, 2018, and is being submitted electronically via EFS-Web.BACKGROUNDTechnical Field[0003]The present disclosure relates generally to methods for eliciting antigen-specific T-cell immune responses to a cancer-associated antigen. More specifically, the human cyclin A1 (CCNA1) isoform c polypeptide is herein identified as containing epitopes useful for the elicitation of specific T-cell responses against leukemic cells that overexpress CCN...

AI Technical Summary

Benefits of technology

The present invention provides an isolated peptide that can elicit an antigen-specific T-cell response to human cyclin A1 (CCNA1). The peptide is no more than 20 amino acids long and includes a sequence of at least 7 contiguous amino acids from the CCNA1 protein. The peptide can be used to develop a vaccine for the treatment of cancer, specifically acute myeloid leukemia (AML) or leukemic stem cells (LSC). The peptide is capable of being recognized by MHC class I or II human leukocyte antigens.

Problems solved by technology

However, allogeneic HSCT and unselected donor lymphocyte infusions are associated with significant toxicity due to both the conditioning regimen and the graft versus-host activity of donor lymphocytes.

In some AML patients, however, WT1 is not expressed, or is not detected at levels sufficiently distinct from those in HSC, or no anti-WT1 T-cell response can be elicited.

WT1 expression has also been detected in several non-hematopoietic organs such as spleen, ovary and kidney, at levels that can be as high or higher than in leukemic blasts, raising concerns that WT1-targeted immunotherapy would produce toxicities in these tissues as undesirable and potentially harmful side-effects.

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