Activation of HIV transcription with short-course vorinostat in HIV-infected patients on suppressive antiretroviral therapy.

UNLABELLED: Human immunodeficiency virus (HIV) persistence in latently infected resting memory CD4+ T-cells is the major barrier to HIV cure. Cellular histone deacetylases (HDACs) are important in maintaining HIV latency and histone deacetylase inhibitors (HDACi) may reverse latency by activating HIV transcription from latently infected CD4+ T-cells. We performed a single arm, open label, proof-of-concept study in which vorinostat, a pan-HDACi, was administered 400 mg orally once daily for 14 days to 20 HIV-infected individuals on suppressive antiretroviral therapy (ART). The primary endpoint was change in cell associated unspliced (CA-US) HIV RNA in total CD4+ T-cells from blood at day 14. The study is registered at ClinicalTrials.gov (NCT01365065). Vorinostat was safe and well tolerated and there were no dose modifications or study drug discontinuations. CA-US HIV RNA in blood increased significantly in 18/20 patients (90%) with a median fold change from baseline to peak value of 7.4 (IQR 3.4, 9.1). CA-US RNA was significantly elevated 8 hours post drug and remained elevated 70 days after last dose. Significant early changes in expression of genes associated with chromatin remodeling and activation of HIV transcription correlated with the magnitude of increased CA-US HIV RNA. There were no statistically significant changes in plasma HIV RNA, concentration of HIV DNA, integrated DNA, inducible virus in CD4+ T-cells or markers of T-cell activation. Vorinostat induced a significant and sustained increase in HIV transcription from latency in the majority of HIV-infected patients. However, additional interventions will be needed to efficiently induce virus production and ultimately eliminate latently infected cells. TRIAL REGISTRATION: ClinicalTrials.gov NCT01365065.

Lenalidomide in combination with dexamethasone at first relapse in comparison with its use as later salvage therapy in relapsed or refractory multiple myeloma.

This subset analysis of data from two phase III studies in patients with relapsed or refractory multiple myeloma (MM) evaluated the benefit of initiating lenalidomide plus dexamethasone at first relapse. Multivariate analysis showed that fewer prior therapies, along with beta(2)-microglobulin (< or = 2.5 mg/L), predicted a better time to progression (TTP; study end-point) with lenalidomide plus dexamethasone treatment. Patients with one prior therapy showed a significant improvement in benefit after first relapse compared with those who received two or more therapies. Patients with one prior therapy had significantly prolonged median TTP (17.1 vs. 10.6 months; P = 0.026) and progression-free survival (14.1 vs. 9.5 months, P = 0.047) compared with patients treated in later lines. Overall response rates were higher (66.9% vs. 56.8%, P = 0.06), and the complete response plus very good partial response rate was significantly higher in first relapse (39.8% vs. 27.7%, P = 0.025). Importantly, overall survival was significantly prolonged for patients treated with lenalidomide plus dexamethasone with one prior therapy, compared with patients treated later in salvage (median of 42.0 vs. 35.8 months, P = 0.041), with no differences in toxicity, dose reductions, or discontinuations despite longer treatment. Therefore, lenalidomide plus dexamethasone is both effective and tolerable for second-line MM therapy and the data suggest that the greatest benefit occurs with earlier use.

A role for multiple chimeric antigen receptor-expressing leukocytes in antigen-specific responses to cancer.

While adoptive immunotherapy using chimeric antigen receptor (CAR)-modified T cells can induce remission of some tumors, the role of other CAR-modified leukocytes is not well characterized. In this study, we characterize the function of leukocytes including natural killer (NK) cells, macrophages and CAR T cells from transgenic mice expressing a CAR under the control of the pan-hematopoietic promoter, vav, and determine the ability of these mice to respond to ERB expressing tumors. We demonstrate the anti-tumor functions of leukocytes, including antigen specific cytotoxicity and cytokine secretion. The adoptive transfer of CAR T cells provided a greater survival advantage in the E0771ERB tumor model than their wildtype (WT) counterparts. In addition, CAR NK cells and CAR T cells also mediated increased survival in the RMAERB tumor model. When challenged with Her2 expressing tumors, F38 mice were shown to mount an effective immune response, resulting in tumor rejection and long-term survival. This was shown to be predominantly dependent on both CD8+ T cells and NK cells. However, macrophages and CD4+ T cells were also shown to contribute to this response. Overall, this study highlights the use of the vav-CAR mouse model as a unique tool to determine the anti-tumor function of various immune subsets, either alone or when acting alongside CAR T cells in adoptive immunotherapy.