IntroductionNatural killer (NK) cells are CD56 ϩ CD3 Ϫ large granular lymphocytes that comprise a key cellular compartment of the innate immune system. NK cells have been shown to exert antitumor activity against the malignant plasma cell clone in multiple myeloma (MM). 1-4 However, through several established mechanisms, the NK-cell versus MM effect is attenuated as the disease inexorably progresses. 5-9 MM is increasing in incidence and remains incurable despite the advent of potent novel therapies such as lenalidomide and bortezomib. 10 In fact, both lenalidomide and bortezomib have been shown to confer anti-MM activity, in part, through recovery or enhancement of the NK-cell versus MM effect. 11,12 The NK-cell versus MM effect is subject to modulation through intracellular signal transduction cascades initiated by activating and inhibitory receptors at the NK-cell surface interacting with ligands expressed on MM tumor cells. Programmed death 1 (PD-1), a member of the B7 family of cosignaling molecules, and its associated ligands PD-L1 and PD-L2 have been shown to play a key role in down-regulating the T-cell immune response. 13 The constitutive or inducible expression of PD-1 has been characterized on several immune cell subsets, including T, B, and dendritic cells; however, to date, comparatively little is known regarding PD-1 expression on NK cells and whether or not the PD-1/PD-L1 axis is involved in the NK-cell versus MM effect. 14 CT-011 (CureTech, LTD; previously CT-AcTibody or BAT) is a novel immunoglobulin G1 (IgG1) humanized monoclonal antibody (mAb) that modulates the immune response through interaction with PD-1, with previously demonstrated antitumor efficacy in experimental models of both solid and liquid tumors. [15][16][17] Several human malignancies, including MM, express cognate ligands for PD-1 (eg, PD-L1) and play a key role in tumor immunoevasion. 18,19 In a phase 1 clinical trial of patients with advanced hematologic malignancies including MM, CT-011 was demonstrated to be safe and well tolerated with evidence of single-agent clinical beneficial responses in 33% of the patients. 20 Given the results of this phase 1 study and the potential complementary mechanisms of action between CT-011 and lenalidomide, we hypothesized these agents in combination may represent a promising novel therapy for MM.Lenalidomide (Revlimid; Celgene) exerts efficacy in part through enhancement of the NK-cell versus MM effect, 11 an effect likely mediated through T-cell production of interleukin-2 (IL-2) in response to this agent. 21 The numbers of both T cells and NK cells are increased in patients receiving lenalidomide therapy 22 ; however, NK-cell killing is also enhanced, including antibodydependent cellular cytotoxicity and natural cytotoxicity. 23,24 Moreover, these events correlate with clinical responses to lenalidomide therapy in patients with MM. 22 In this report, we show that the PD-1/PD-L1 signaling axis mediates NK-cell activation and cytotoxicity against MM. We show that freshly isolated NK cells...

Head and neck cancers positive for human papillomavirus (HPV) have a more favorable clinical outcome than HPV-negative cancers, but it is unknown why this is the case. We hypothesized that prognosis was affected by intrinsic features of HPV-infected tumor cells or differences in host immune response. In this study, we focused on a comparison of regulatory