LMTK3 expression in breast cancer: association with tumor phenotype and clinical outcome

Interactions between kinases and the estrogen receptor α (ERα) are thought to be a critical signaling pathway in the majority of human breast cancers. We have recently identified a previously uncharacterized molecule, lemur tyrosine kinase-3 (LMTK3) as a prognostic and predictive oncogenic ERα regulator with a central role in endocrine resistance. Unusually this protein has undergone Darwinian positive selection between Chimpanzees and humans suggesting it may contribute to human susceptibility to ERα-positive tumors. Using over 600 European primary breast cancer cases, we wished to establish tumor characteristics associated with both cytoplasmic and nuclear LMTK3 expression, and then externally validate our observed European clinical outcomes with samples from Asian individuals receiving chemotherapy. Both nuclear and cytoplasmic expression correlated with tumor grade (P < 0.001) and in the Asian cohort, independent blinded analyses demonstrated that high basal LMTK3 expression was associated with advanced stage of primary breast cancers as well as decreased overall (P = 0.03) and disease-free survival (P = 0.006). In summary, higher LMTK3 expression is associated with more aggressive cancers. These data support our previous findings and suggest LMTK3 expression may be a reliable new biomarker in breast cancer

Anti-CCR9 Chimeric Antigen Receptor T cells for T Cell Acute Lymphoblastic Leukemia

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy of immature T lymphocytes, associated with higher rates of induction failure in comparison to B-ALL. The potent immunotherapeutic approaches applied in B-ALL, which have revolutionized the treatment paradigm, have proven more challenging in T-ALL, largely due to a lack of target antigens expressed on malignant but not healthy T cells. Unlike B cell depletion, T cell aplasia is highly toxic. Here, we demonstrate that the chemokine receptor CCR9 is expressed in >70% of cases of T-ALL, including >85% or relapsed/ refractory disease, and only on a small fraction (<5%) of normal T cells. Using cell line models and patient-derived xenografts, we show chimeric antigen receptor (CAR)-T cells targeting CCR9 are resistant to fratricide and have potent anti-leukemic activity both in vitro and in vivo, even at low target antigen density. We propose anti-CCR9 CAR-T cells could be a highly effective treatment strategy for T-ALL, avoiding T cell aplasia and the need for genome engineering that complicate other approaches

Molecular, clinical and therapeutic determinants of outcome in NPM1 mutated AML

Although NPM1-mutated acute myeloid leukemia (AML) carries a generally favorable prognosis, many patients still relapse and die. Previous studies identified several molecular and clinical features associated with poor outcome, however only FLT3-ITD mutation and adverse karyotype are currently used for risk stratification due to inconsistent results and uncertainty around how other factors should influence treatment, particularly given the strong prognostic impact of post-induction measurable residual disease (MRD). Here we analyzed a large group of patients with NPM1mut AML enrolled in prospective trials (NCRI AML17 and AML19, n=1357) to delineate the impact of baseline molecular and clinical features, post induction MRD status and treatment intensity on outcome. FLT3-ITD (HR 1.28, 95%CI 1.01-1.63), DNMT3A (HR 1.65, 95%CI 1.32-2.05), WT1 (HR 1.74, 95%CI 1272-2.38) and non-ABD NPM1 mutations (HR 1.64, 95%CI 1.22-2.21) were independently associated with poorer overall survival (OS). These factors were also strongly associated with MRD positivity. For patients achieving MRD negativity, these mutations (except FLT3-ITD) were associated with an increased cumulative incidence of relapse (CIR) and poorer OS. However, apart from the few patients with adverse cytogenetics, we could not identify any group of MRD negative patients with a CIR >40% or with benefit from allograft in first remission. Intensified chemotherapy with the FLAG-Ida regimen was associated with improved outcomes in all subgroups, with greater benefits observed in the highest risk molecular subgroups