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Proteins created from recurrent fusion genes like CBFB-MYH11 are prevalent in acute myeloid leukemia (AML), often necessary for leukemogenesis, persistent throughout the disease course, and highly leukemia specific, making them attractive neoantigen targets for immunotherapy. A nonameric peptide derived from a prevalent CBFB-MYH11 fusion protein was found to be immunogenic in HLA-B*40:0T donors. High-avidity [CD8.sup.+] T cell clones isolated from healthy donors killed CBFB-[MYH11.sup.+] HLA-B*40:[01.sup.+] AML cell lines and primary human AML samples in vitro. CBFB-MYH11-specific T cells also controlled CBFB-[MYH11.sup.+] HLA-B*40:[01.sup.+] AML in vivo in a patient-derived murine xenograft model. High-avidity CBFB-MYH11 epitope-specific T cell receptors (TCRs) transduced into [CD8.sup.+] T cells conferred antileukemic activity in vitro. Our data indicate that the CBFB-MYH11 fusion neoantigen is naturally presented on AML blasts and enables T cell recognition and killing of AML. We provide proof of principle for immunologically targeting AML-initiating fusions and demonstrate that targeting neoantigens has clinical relevance even in low-mutational frequency cancers like fusion-driven AML. This work also represents a first critical step toward the development of TCR T cell immunotherapy targeting fusion gene-driven AML., Introduction Fusion genes represent essential early events in leukemic transformation in acute myeloid leukemia (AML), particularly in younger patients (1). The core-binding factor (CBF) leukemias are a prevalent subgroup of [...]

BACKGROUND: Myxoid/round cell liposarcoma (MRCL) is the second most common liposarcoma subtype, accounting for >33% of liposarcomas and approximately 10% of all soft tissue sarcomas. Although MRCL is a chemosensitive subtype, patients with metastatic disease have a poor outcome. NY-ESO-1 is a cancer-testis antigen (also known as cancer germ cell antigen) that has been successfully targeted in vaccine trials and in adoptive T-cell therapy trials for the treatment of several solid tumors. METHODS: The authors investigated the feasibility of targeting NY-ESO-1 in patients with MRCL by evaluating the prevalence of NY-ESO-1 expression in tumors using immunohistochemistry and quantitative reverse transcriptase-polymerase chain reaction analysis. NY-ESO-1-specific tumor recognition by NY-ESO-1-specific T-cells also was analyzed using a chromium release assay. RESULTS: A search of the University of Washington Sarcoma Tissue Bank identified paraffin-embedded tumor samples from 25 patients with MRCL. NY-ESO-1 expression was observed in every MRCL tumor assessed (100%); in 18 tumors (72%), staining was homogenous. In all but 2 tumors, staining was sufficiently robust (2+) that such patients would be eligible for clinical trials of NY-ESO-1-directed therapy. By using NY-ESO-1 specific, CD8-positive T-cells, the in vitro sensitivity of myxoid liposarcoma cell lines to antigen-specific lysis was demonstrated. CONCLUSIONS: The current results establish NY-ESO-1 as an important target antigen for the treatment of patients with MRCL. Cancer 2012. © 2012 American Cancer Society. [ABSTRACT FROM AUTHOR]

Minor histocompatibility (H) antigens are major targets of a graft-versus-leukemia (GVL) effect mediated by donor CD8+ and CD4+ T cells following allogeneic hematopoietic cell transplantation (HCT) between human leukocyte antigen identical individuals. In the 15 years since the first molecular characterization of human minor H antigens, significant strides in minor H antigen discovery have been made as a consequence of advances in cellular, genetic and molecular techniques. Much has been learned about the mechanisms of minor H antigen immunogenicity, their expression on normal and malignant cells, and their role in GVL responses. T cells specific for minor H antigens expressed on leukemic cells, including leukemic stem cells, can be isolated and expanded in vitro and infused into allogeneic HCT recipients to augment the GVL effect to prevent and treat relapse. The first report of the adoptive transfer of minor H antigen-specific T-cell clones to patients with leukemic relapse in 2010 illustrates the potential for the manipulation of alloreactivity for therapeutic benefit. This review describes the recent developments in T-cell recognition of human minor H antigens, and efforts to translate these discoveries to reduce leukemia relapse after allogeneic HCT. [ABSTRACT FROM AUTHOR]

Abstract: Animal models and human studies of allogeneic hematopoietic cell transplantation (HCT) demonstrate that immunologic nonidentity between donor and recipient is responsible for a graft versus leukemia (GVL) effect that contributes to complete tumor eradication. A variety of immune cells have been implicated in the GVL effect including NK cells, B cells, and CD4+ and CD8+ T cells that recognize minor histocompatibility (H) or leukemia-associated antigens. Here we discuss strategies for employing T cells specific for minor H antigens to augment the GVL effect. [Copyright &y& Elsevier]

Targeted T-cell therapy is a potentially less toxic strategy than allogeneic stem cell transplantation for providing a cytotoxic antileukemic response to eliminate leukemic stem cells (LSCs) in acute myeloid leukemia (AML). However, this strategy requires identification of leukemia-associated antigens that are immunogenic and exhibit selective high expression in AML LSCs. Using microarray expression analysis of LSCs, hematopoietic cell subpopulations, and peripheral tissues to screen for candidate antigens, cyclin-A1 was identified as a candidate gene. Cyclin-A1 promotes cell proliferation and survival, has been shown to be leukemogenic in mice, is detected in LSCs of more than 50% of AML patients, and is minimally expressed in normal tissues with exception of testis. Using dendritic cells pulsed with a cyclin-A1 peptide library, we generated T cells against several cyclin-A1 oligopeptides. Two HLA A*0201 -restricted epitopes were further characterized, and specific CD8 T-cell clones recognized both peptide-pulsed target cells and the HLA A*0201 -positive AML line THP-1, which expresses cyclin-A1. Furthermore, cyclin-A1 -specific CD8 T cells lysed primary AML cells. Thus, cyclin-A1 is the first prototypic leukemia-testis-antigen to be expressed in AML LSCs. The pro-oncogenic activity, high expression levels, and multitude of immunogenic epitopes make it a viable target for pursuing T cell-based therapy approaches. [ABSTRACT FROM AUTHOR]