No abstract

BLyS, recently shown to be critical for survival of normal B cells, has been found to be elevated in a number of immune disease models. A role for BLyS in the survival of malignant B cells has also been revealed and we therefore sought to identify a role for BLyS and its receptors in non-Hodgkin lymphoma (NHL). We found that tumor cells from all NHL histologic subtypes expressed one or more of 3 known receptors (BCMA, TACI, and BAFF-R) for BLyS; however, the pattern of expression was variable. We provide evidence that BLyS is expressed in tumors from patients with NHL and that BLyS levels increase as tumors transform to a more aggressive phenotype. Additionally, we provide evidence that serum BLyS levels are elevated in a subgroup of patients with NHL. In patients with de novo large B-cell lymphoma, a high BLyS level correlated with a poorer median overall survival, the presence of constitutional symptoms, and elevated values of lactic dehydrogenase. When BLyS levels were correlated with response to therapy in all patients, responding patients had a significantly lower BLyS level than those with progressive disease. In summary, we found that BLyS and its receptors represent a potentially important therapeutic target in B-cell lymphoma.

IntroductionStandard gene-therapy approaches to cancer treatment, such as transfer of suicide genes that confer sensitivity to prodrugs, have limitations as cytoreductive strategies owing to insufficient bystander effects of the therapeutic gene combined with suboptimal transduction efficiency of currently available gene delivery vectors. A more compelling approach in this situation is the use of a vector or virus that is able to replicate within the tumor tissue, resulting in direct cell death through cytolysis or toxicity of viral proteins. Ideally, such an agent should also be capable of stimulating a potent immune response to the tumor within which it can replicate.Studies throughout the twentieth century have documented the lytic effects of various viruses on many types of human cancer, 1 and systematic study of candidate oncolytic viruses is intensifying. Viruses under investigation as oncolytic agents include human adenoviruses, ONYX-015, 2,3 reovirus, 4 herpes viruses 5,6 and vesicular stomatitis virus. 7 All of these viruses have shown promise in preclinical studies, and clinical studies of some of the agents are now in progress. 8 Viruses of the Paramyxoviridae family are also oncolytic. Almost 30 years ago, the human paramyxovirus, mumps, was administered to 90 patients with advanced malignancy, 9 resulting in significant (although mostly short-lived) responses. Toxicity was minimal. More recently, Newcastle disease virus, an avian paramyxovirus, has also shown promising results in preclinical studies, [10][11][12] and clinical trials in human subjects have begun.In this study, we have investigated another human paramyxovirus, measles, as a potential antitumor agent for lymphoid malignancies. Measles virus (MV) may be particularly promising as an oncolytic virus for the treatment of lymphoid malignancy for a number of reasons. First, a nonpathogenic strain of MV is available, well characterized, and safe. Live attenuated MV vaccines, derived from the Edmonston-B strain (MV-Ed), 13 have been used worldwide for more than 30 years, and in excess of 160 million doses have been administered in the United States alone with an excellent safety record. Second, although many human cell types are permissive for MV infection in vitro, in the presence of an intact immune system, virus replication after natural infection is limited to a few cell types in vivo. Lymphoid organs are prominent sites of MV replication; indeed, multinucleated giant cells develop during infection in lymph nodes as a result of gross cell-cell fusion. 14 Third, we have recently shown that expression of virally derived fusogenic membrane glycoproteins in tumor cells, including MV fusion (F) and hemagglutinin (H) glycoproteins, 15-17 results in a potent cytopathic effect mediated by massive cell-cell fusion. The considerable local bystander effect implies that transduction of all tumor cells would not be necessary to achieve significant tumor cell kill. However, the use of MV as a replicating vector with which to deliver the F and H glycopro...

To determine the biological and clinical relevance of programmed death 1 (PD-1) in follicular lymphoma (FL), we characterized PD-1+ T-cell subsets and assessed their biological function as well as potential clinical impact. We found that PD-1 is expressed on intratumoral CD4+ T cells with both bright and dim intensity, representing two different sub-populations of cells. By immunohistochemistry, we found that CD4+PD-1high T cells predominantly reside in the lymph node follicles, while PD-1low T cells are mainly located in an interfollicular pattern. Intratumoral CD4+PD-1high T cells have a TFH cell phenotype, express CXCR5, secrete IL-21 and are BCL-6 positive with no TIM-3 expression. In contrast, CD4+PD-1low T cells have an exhausted phenotype, express TIM-3 and do not express BCL-6 and CXCR5. Functionally, CD4+PD-1high T cells actively supported B-cell growth, while CD4+PD-1low T cells displayed a reduced cytokine production and cell-signal transduction. Clinically, we observed that the numbers of CD4+ or CD8+PD-1low T cells significantly correlate with a reduced overall survival in FL patients (P=0.007 and 0.04 respectively; n=32). In contrast, the number of CD4+PD-1high T cells was not associated with patient outcome. Taken together, these results indicated that PD-1 expression defines two sub-populations with distinct functions that differentially impact patient outcome in FL.