CD3 ⁺CD4 ^-CD8 ^- (Double-Negative) T Cells in Inflammation, Immune Disorders and Cancer

Older patients with acute myeloid leukemia (AML) respond poorly to standard induction therapy. B-cell lymphoma 2 (BCL-2) overexpression is implicated in survival of AML cells and treatment resistance. We report safety and efficacy of venetoclax with decitabine or azacitidine from a large, multicenter, phase 1b dose-escalation and expansion study. Patients (N = 145) were at least 65 years old with treatment-naive AML and were ineligible for intensive chemotherapy. During dose escalation, oral venetoclax was administered at 400, 800, or 1200 mg daily in combination with either decitabine (20 mg/m2, days 1-5, intravenously [IV]) or azacitidine (75 mg/m2, days 1-7, IV or subcutaneously). In the expansion, 400 or 800 mg venetoclax with either hypomethylating agent (HMA) was given. Median age was 74 years, with poor-risk cytogenetics in 49% of patients. Common adverse events (>30%) included nausea, diarrhea, constipation, febrile neutropenia, fatigue, hypokalemia, decreased appetite, and decreased white blood cell count. No tumor lysis syndrome was observed. With a median time on study of 8.9 months, 67% of patients (all doses) achieved complete remission (CR) + CR with incomplete count recovery (CRi), with a CR + CRi rate of 73% in the venetoclax 400 mg + HMA cohort. Patients with poor-risk cytogenetics and those at least 75 years old had CR + CRi rates of 60% and 65%, respectively. The median duration of CR + CRi (all patients) was 11.3 months, and median overall survival (mOS) was 17.5 months; mOS has not been reached for the 400-mg venetoclax cohort. The novel combination of venetoclax with decitabine or azacitidine was effective and well tolerated in elderly patients with AML (This trial was registered at www.clinicaltrials.gov as #NCT02203773).

γδ T cells are a unique and conserved population of lymphocytes that have been the subject of a recent explosion of interest owing to their essential contributions to many types of immune response and immunopathology. But what does the integration of recent and long-established studies really tell us about these cells and their place in immunology? The time is ripe to consider the evidence for their unique and crucial functions. We conclude that whereas B cells and αβ T cells are commonly thought to contribute primarily to the antigen-specific effector and memory phases of immunity, γδ T cells are distinct in that they combine conventional adaptive features (inherent in their T cell receptors and pleiotropic effector functions) with rapid, innate-like responses that can place them in the initiation phase of immune reactions. This underpins a revised perspective on lymphocyte biology and the regulation of immunogenicity.