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The Genomic Landscape of Antigenic Targets for T Cell-Based Leukemia Immunotherapy.

ABSTRACT: Intensive fundamental and clinical research in cancer immunotherapy has led to the emergence and evolution of two parallel universes with surprisingly little interactions: the realm of hematologic malignancies and that of solid tumors. Treatment of hematologic cancers using allogeneic hematopoietic cell transplantation (AHCT) serendipitously led to the discovery that T cells specific for minor histocompatibility antigens (MiHAs) could cure hematopoietic cancers. Besides, studies based on treatment of solid tumor with ex vivo-expanded tumor infiltrating lymphocytes or immune checkpoint therapy demonstrated that anti-tumor responses could be achieved by targeting tumor-specific antigens (TSAs). It is our contention that much insight can be gained by sharing the tremendous amount of data generated in the two-abovementioned universes. Our perspective article has two specific goals. First, to discuss the value of methods currently used for MiHA and TSA discovery and to explain the key role of mass spectrometry analyses in this process. Second, to demonstrate the importance of broadening the scope of TSA discovery efforts beyond classic annotated protein-coding genomic sequences.

SUBMITTER: Hardy MP

PROVIDER: S-EPMC6933603 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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The Genomic Landscape of Antigenic Targets for T Cell-Based Leukemia Immunotherapy.

Hardy Marie-Pierre MP Vincent Krystel K Perreault Claude C

Frontiers in immunology 20191220

Intensive fundamental and clinical research in cancer immunotherapy has led to the emergence and evolution of two parallel universes with surprisingly little interactions: the realm of hematologic malignancies and that of solid tumors. Treatment of hematologic cancers using allogeneic hematopoietic cell transplantation (AHCT) serendipitously led to the discovery that T cells specific for minor histocompatibility antigens (MiHAs) could cure hematopoietic cancers. Besides, studies based on treatme ...[more]

PMID: 31921187

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Project description:Mixed-phenotype leukemia (MPAL) is a type of acute leukemia in which the blast population shows mixed features of myeloid, T-lymphoid, and/or B-lymphoid differentiation. MPALs are rare and carry a poor prognosis, thus, often pose both a diagnostic and therapeutic challenge. Conventionally, the diagnosis of MPAL requires either a single blast population with a lineage-defining phenotypic expression of multiple lineages (myeloid, B-cell and/or T-cell) (biphenotypic) or two distinct blast populations that each independently satisfy criteria for designation as AML, B-ALL, and/or T-ALL (bilineage). Given the rarity of MPAL, minimal studies have been performed to describe the genomic landscape of these neoplasms. IRB approval was obtained. Central MCC database was searched for any patient with a diagnosis of acute undifferentiated leukemia (AUL), acute leukemia of ambiguous lineage (ALAL), and MPAL. All patient diagnoses were manually reviewed by a hematopathologist to confirm the diagnosis of MPAL. Genomic and molecular data were collated from the EMR and bioinformatically from MCC genomics repositories. Twenty-eight patients with MPAL were identified. Thirteen were female and 15 were male. Average age was 56 years old (range = 28-81). Ten cases were biclonal and 18 were biphenotypic. Diagnoses were as follows: B/myeloid (n = 18), T/myeloid (n = 9), and T/B (n = 1). Cytogenetic analysis (Karyotype +/- FISH) was available for 27 patients. The most frequent recurrent abnormalities were complex karyotype (n = 8), BCR/ABL1 translocation (n = 6), Del 5q/-5 (n = 4), Polysomy 21 (n = 4). Mutational analysis was available for 18 patients wherein mutations were detected in 45 unique genes. The most frequently mutated genes were TP53 (7), RUNX1 (6), WT1 (4), MLL2 (3), FLT3 (3), CBL (2), ASXL1 (2), TET2 (2), MAP3K6 (2), MLL (2), and MAP3K1 (2). Targetable or potentially targetable biomarkers were found in 56% of cases. Overall survival was 19.5 months (range = 0-70 m). Ten patients were treated with an allogeneic stem cell transplant and had superior outcome (p = 0.0013). In one the largest series of MPAL cases to date, we corroborate previous findings with enriched detection of RUNX1 and FLT3-ITD mutations along with discovery of unreported mutations (MAP3K) that may be amenable to therapeutic manipulation. We also report the frequent occurrence of AML with MDS-related changes (AML-MRC)-defining cytogenetic abnormalities (26%). Finally, we show that those patients that received stem cell transplant had a better overall survival. Our findings support the need to genomically profile MPAL cases to exploit opportunities for targeted therapies in this orphan disease with dismal prognosis.

Dataset Information

The Genomic Landscape of Antigenic Targets for T Cell-Based Leukemia Immunotherapy.

Publications

The Genomic Landscape of Antigenic Targets for T Cell-Based Leukemia Immunotherapy.

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