Antibody-dependent cellular cytotoxicity (ADCC) is exerted by immune cells expressing surface Fcγ receptors (FcγRs) against cells coated with antibody, such as virus-infected or transformed cells. CD16, the FcγRIIIA, is essential for ADCC by NK cells, and is also expressed by a subset of human blood monocytes. We found that human CD16− expressing monocytes have a broad spectrum of ADCC capacities and can kill cancer cell lines, primary leukemic cells and hepatitis B virus-infected cells in the presence of specific antibodies. Engagement of CD16 on monocytes by antibody bound to target cells activated β2-integrins and induced TNFα secretion. In turn, this induced TNFR expression on the target cells, making them susceptible to TNFα-mediated cell death. Treatment with TLR agonists, DAMPs or cytokines, such as IFNγ, further enhanced ADCC. Monocytes lacking CD16 did not exert ADCC but acquired this property after CD16 expression was induced by either cytokine stimulation or transient transfection. Notably, CD16+ monocytes from patients with leukemia also exerted potent ADCC. Hence, CD16+ monocytes are important effectors of ADCC, suggesting further developments of this property in the context of cellular therapies for cancer and infectious diseases.
Top-Notch Young Talents Program of China, Special Support Program of Guangdong, Specialized Research Fund for the Doctoral Program of Higher Education (20110171120099), Program for New Century Excellent Talents in University (NCET-11-0529), National Medical Research Council of Singapore (TCR12DEC005), Tanoto Foundation Professorship in Medical Oncology, New Century Foundation Limited, Ling Foundation, Singapore National Cancer Centre Research Fund, and the US National Institutes of Health (1R01AR062886, 5U01GM092691-04, and 1R01AR063759-01A1).
Assessment of measurable residual disease (often referred to as “minimal residual disease”) has emerged as a highly sensitive indicator of disease burden during and at the end of treatment and has been correlated with time-to-event outcomes in chronic lymphocytic leukemia. Undetectable-measurable residual disease status at the end of treatment demonstrated independent prognostic significance in chronic lymphocytic leukemia, correlating with favorable progression-free and overall survival with chemoimmunotherapy. Given its utility in evaluating depth of response, determining measurable residual disease status is now a focus of outcomes in chronic lymphocytic leukemia clinical trials. Increased adoption of measurable residual disease assessment calls for standards for nomenclature and outcomes data reporting. In addition, many basic questions have not been systematically addressed. Here, we present the work of an international, multidisciplinary, 174-member panel convened to identify critical questions on key issues pertaining to measurable residual disease in chronic lymphocytic leukemia, review evaluable data, develop unified answers in conjunction with local expert input, and provide recommendations for future studies. Recommendations are presented regarding methodology for measurable residual disease determination, assay requirements and in which tissue to assess measurable residual disease, timing and frequency of assessment, use of measurable residual disease in clinical practice versus clinical trials, and the future usefulness of measurable residual disease assessment. Nomenclature is also proposed. Adoption of these recommendations will work toward standardizing data acquisition and interpretation in future studies with new treatments with the ultimate objective of improving outcomes and curing chronic lymphocytic leukemia.
Primary mediastinal large B‐cell lymphoma (PMBCL) is a distinct clinico‐pathological subtype of diffuse large B‐cell lymphoma with unclear prognostic factors and limited clinical data. Optimal treatment and role for radiotherapy is not fully defined. We performed a multicenter retrospective review of 124 patients with newly diagnosed PMBCL between 2001 and 2016. Treatment regimens were R‐CHOP (n = 41), R‐CHOP + RT (n = 37), and DA‐EPOCH‐R (n = 46). 6% (n = 3) in the DA‐EPOCH‐R group received RT. With a median follow up of 45 months, the overall 5‐year OS and PFS was 89.4% and 82.4%, respectively. The type of chemo‐radiotherapy regimen, B symptoms and Ann‐Arbor staging showed a significant association with OS on univariate analysis but only B symptoms remained prognostic (
P
= 0.012) after multivariate analysis. The chemo‐radiotherapy regimen, Japanese IPI and Ann‐Arbor stage was significantly associated with PFS in univariate analysis, but only chemo‐radiotherapy regimen remained significant (
P
= 0.02) after multivariate analysis. Patients who received R‐CHOP + RT or DA‐EPOCH‐R had better PFS than those receiving R‐CHOP alone, with 5‐year PFS of 90% vs 88.5% vs 56%, respectively (
P
= 0.02). In the subgroup analysis of patients with bulk (n = 71), R‐CHOP alone (n = 21) had inferior 5‐year PFS 56.6% compared to those who received R‐CHOP + RT (n = 23) 91.3% or DA‐EPOCH‐R (n = 27) 92.6% (
P
= 0.007). In contrast, in patients without bulk (n = 42), there was no impact of treatment regimen on PFS (
P
= 0.25). In conclusion, R‐CHOP + RT and DA‐EPOCH‐R provide excellent outcomes in patients with PMBCL. In patients with bulky disease, the use of DA‐EPOCH‐R may be preferable as it allows omission of RT without reduction in efficacy.
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