Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cancer testis antigen (CTA) preferentially expressed antigen of melanoma (PRAME) is overexpressed in many hematologic malignancies, including chronic myeloid leukemia (CML). The sensitivity of CML to donor lymphocyte infusion after allogeneic stem cell transplantation suggests this tumor can be highly susceptible to cellular immunotherapy targeted to tumor associated antigens. We therefore tested whether functional PRAME-specific cytotoxic T lymphocytes (PRAME CTLs) could be generated and expanded from healthy donors and CML patients, or whether the limited immunogenicity of this CTA coupled with tumor-associated anergy would preclude this approach. Using optimized culture conditions and HLA-A*02-restricted PRAME-peptides, we have consistently generated PRAME CTLs from 8/9 healthy donors and 5/6 CML patients. These CTLs released IFNgamma in response to PRAME peptides (between 113 +/- 8 and 795 +/- 23 spot forming cells/10(5) T cells) and lysed PRAME peptide-loaded cells (45 +/- 19% at an effector:target [E:T] ratio of 20:1) in a MHC-restricted fashion. Importantly, these CTLs recognized and had cytotoxic activity against HLA-A*02(+)/PRAME(+) tumor cell lines, and could recognize and respond to primary CML cells. PRAME CTLs were generated almost exclusively from the naive T-cell compartment, and clonal analysis showed these cells could have high alphabetaTCR-peptide avidity. PRAME CTLs or vaccines may thus be of value for patients with CML.
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PMID:Cytotoxic T lymphocytes directed to the preferentially expressed antigen of melanoma (PRAME) target chronic myeloid leukemia. 1859 81

A number of different human leukocyte antigen (HLA) allele associations with chronic myelogenous leukemia (CML) have been previously reported. The specific associations reported in one population, however, are rarely replicated in other populations. We attempted to explore these associations by performing a meta-analysis of published studies. Following a Medline search, we identified four studies which presented raw data on all allele associations with CML (significant and non-significant). Meta-analysis of these revealed a significant risk association with the HLA-A*02 (pooled odds ratio 1.33, 95% confidence interval 1.10-1.61) allele and a significant protective effect with the HLA-B*35 allele (pooled odds ratio 0.64, 95% confidence interval 0.48-0.86). To our knowledge this is the first study to demonstrate the epidemiologic association between HLA-A*02 and the risk of CML, and we discuss this in the context of recent immunological studies reporting data on BCR-ABL fusion peptide presentation and subsequent immune response. Our findings suggest that individual epidemiological studies may lack statistical power, or may have other interfering factors which prevent the unmasking of overall associations. Meta-analyses of published studies may overcome these limitations and may prove useful in uncovering allele-disease associations.
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PMID:Human leukocyte antigen class I alleles and the risk of chronic myelogenous leukemia: a meta-analysis. 2038 56

Acute and chronic leukemias, including CD34(+) CML cells, demonstrate increased expression of the Wilms tumor gene 1 product (WT1), making WT1 an attractive therapeutic target. However, WT1 is a currently undruggable, intracellular protein. ESKM is a human IgG1 T-cell receptor mimic monoclonal antibody directed to a 9-amino acid sequence of WT1 in the context of cell surface HLA-A*02. ESKM was therapeutically effective, alone and in combination with tyrosine kinase inhibitors (TKIs), against Philadelphia chromosome-positive acute leukemia in murine models, including a leukemia with the most common, pan-TKI, gatekeeper resistance mutation, T315I. ESKM was superior to the first-generation TKI, imatinib. Combination therapy with ESKM and TKIs was superior to either drug alone, capable of curing mice. ESKM showed no toxicity to human HLA-A*02:01(+) stem cells under the conditions of this murine model. These features of ESKM make it a promising nontoxic therapeutic agent for sensitive and resistant Ph(+) leukemias.
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PMID:A TCR-mimic antibody to WT1 bypasses tyrosine kinase inhibitor resistance in human BCR-ABL+ leukemias. 2472 81

Treatment-free remission (TFR) is one of the therapeutic goals for patients with chronic phase chronic myeloid leukemia (CML-CP). Although previous reports indicated that anti-tumor immunity contributes to TFR, its determinants are still unclear. We previously reported that allelic polymorphisms of killer immunoglobulin-like receptors (KIRs) and human leukocyte antigens (HLAs) are associated with achievement of deep molecular response (DMR) in patients with CML-CP. Here, we examined the association between TFR and polymorphisms of KIRs and HLAs in patients who discontinued tyrosine kinase inhibitors (TKIs). Seventy-six patients were enrolled and their KIR and HLA polymorphisms and natural killer cell (NK cell) activation status were investigated as previously described. Overall, 33 patients discontinued TKIs, and 21 of 33 achieved TFR [63.6%; 95% confidence interval (CI), 44.9-77.5%] at one year. Multivariate analysis revealed that male sex [HR, 0.157; 95% CI, 0.031-0.804; P=0.003] and HLA-A*02:01, *11:01, or *24:02 [HR, 6.386; 95% CI, 1.701-23.980; P=0.006] were associated with TFR. Patients who achieved DMR and discontinued TKIs exhibited higher NK cell activation status than those who did not. By contrast, there were no significant differences in NK cell activation status between the patients who achieved TFR and those who experienced molecular relapse. These results suggest NK cell activation status contributes to achievement of DMR, whereas T cell-mediated immunity contributes to TFR in patients with CML-CP.
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PMID:HLA polymorphisms are associated with treatment-free remission following discontinuation of tyrosine kinase inhibitors in chronic myeloid leukemia. 3308 74