Clinical pharmacology and therapeutics
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Clin. Pharmacol. Ther. · Sep 2016
CD19-Targeted chimeric antigen receptor-modified T-cell immunotherapy for B-cell malignancies.
Chimeric antigen receptors (CARs) comprise a tumor-targeting moiety, often in the form of a single chain variable fragment derived from a monoclonal antibody, fused to one or more intracellular T-cell signaling sequences. Lymphodepletion chemotherapy followed by infusion of T cells that are genetically modified to express a CD19-specific CAR is a promising therapy for patients with refractory CD19(+) B-cell malignancies, producing rates of complete remission that are remarkably high in acute lymphoblastic leukemia and encouraging in non-Hodgkin lymphoma and chronic lymphocytic leukemia. ⋯ CAR-modified T-cell immunotherapy can be complicated by cytokine release syndrome and neurologic toxicity, which in most cases are manageable and reversible. Here we review recent clinical trial data and discuss issues for the field.
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Clin. Pharmacol. Ther. · Sep 2016
Implications of Programmed Cell Death 1 Ligand 1 Heterogeneity in the Selection of Patients With Non-Small Cell Lung Cancer to Receive Immunotherapy.
The use of programmed cell death 1 ligand 1 (PD-L1) as a predictive biomarker to select patients to receive programmed cell death 1 (PD-1) or PD-L1 inhibitors in non-small cell lung cancer (NSCLC) is limited by the definitions of positivity, interassay agreement, and intra- and intertumoral heterogeneity of expression. Although PD-L1 expression enriches for responses, the lack of expression does not exclude clinical benefit.
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Clin. Pharmacol. Ther. · Sep 2016
The clinical utility of PD-L1 testing in selecting non-small cell lung cancer patients for PD1/PD-L1-directed therapy.
Lung cancer is the leading cause of cancer mortality in the United States and worldwide. Long thought to be nonimmunogenic, immunotherapy in lung cancer has historically been met with disappointing results. Programmed death-1 (PD-1), and the PD-1 ligand, PD-L1, are immune checkpoint proteins that fine-tune the antigen-specific T-cell response after stimulation of the T-cell receptor and are crucial for self-tolerance. ⋯ In 2015, the US Food and Drug Administration (FDA) approved two immuno-oncology agents, the PD-1 inhibitors nivolumab and pembrolizumab, for the treatment of previously treated advanced non-small cell lung cancer (NSCLC). Coincident with the clinical trials that led to these regulatory approvals has been the development of several immunohistochemistry (IHC) tests of PD-L1 expression, which may serve to select patients who will derive the most benefit from PD1- or PD-L1-directed therapy. The PD-L1 IHC assays are distinct in their methods and interpretation, which poses a challenge to clinicians selecting patients for these therapies.