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Oncolytic virotherapy may be a means of improving the dismal prognosis of malignant brain tumors. The rat H-1 parvovirus (H-1PV) suppresses tumors in preclinical glioma models, through both direct oncolysis and stimulation of anticancer immune responses. This was the basis of ParvOryx01, the first phase I/IIa clinical trial of an oncolytic parvovirus in recurrent glioblastoma patients. H-1PV (escalating dose) was administered via intratumoral or intravenous injection. Tumors were resected 9 days after treatment, and virus was re-administered around the resection cavity. Primary endpoints were safety and tolerability, virus distribution, and maximum tolerated dose (MTD). Progression-free and overall survival and levels of viral and immunological markers in the tumor and peripheral blood were also investigated. H-1PV treatment was safe and well tolerated, and no MTD was reached. The virus could cross the blood-brain/tumor barrier and spread widely through the tumor. It showed favorable pharmacokinetics, induced antibody formation in a dose-dependent manner, and triggered specific T cell responses. Markers of virus replication, microglia/macrophage activation, and cytotoxic T cell infiltration were detected in infected tumors, suggesting that H-1PV may trigger an immunogenic stimulus. Median survival was extended in comparison with recent meta-analyses. Altogether, ParvOryx01 results provide an impetus for further H-1PV clinical development.

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BACKGROUND.: Despite the importance of non-Hodgkin lymphoma (NHL) as a posttransplant complication, the relationship between NHL and recipient seropositivity for Epstein-Barr virus (EBV) or cytomegalovirus (CMV) is incompletely understood. METHODS.: Kidney, heart, and liver transplant recipients reported to the Collaborative Transplant Study with known pretransplant EBV and CMV serostatus were analyzed in terms of clinically manifest NHL. Cox multivariate regression analysis was performed to account for a wide range of possible confounders. RESULTS.: In total, 18,682 kidney, 2042 heart, and 2616 liver transplant recipients were analyzed. Regardless of age, pretransplant EBV serostatus was significantly associated with risk of NHL in kidney transplant recipients (P<0.001). There was no significant difference in lymphoma rates according to CMV and CMV serostatus among EBV and EBV recipients (log-rank P=0.55 and P=0.57, respectively), but hospitalization for CMV disease during year 1 posttransplant was associated with subsequent NHL (hazard ratio [HR] 6.1; 95% confidence interval [CI] 2.0-18.4; P=0.001). EBV serostatus was also associated with increased risk of NHL in heart transplant patients (HR 3.6; 95% CI 1.1-11.3; P=0.031) but, contrary to expectation, not in liver recipients (HR 0.6; 95% CI 0.1-1.7; P=0.32). CONCLUSIONS.: In view of the striking increase in risk of NHL in EBV kidney transplant recipients of all ages, EBV serostatus should be determined pretransplant in all age groups. CMV serostatus was not independently associated with risk of NHL after kidney transplantation. Surprisingly, in liver transplantation, the risk of NHL was virtually unaffected by EBV serostatus.

Summary The proteasome constitutes the central proteolytic component of the highly conserved ubiquitin–proteasome system, which is required for the maintenance and regulation of basic cellular processes, including differentiation, proliferation, cell cycling, gene transcription and apoptosis. Here we show that inhibition of proteasomal proteolytic activity by the proteasome inhibitors bortezomib and lactacystin suppresses essential immune functions of human CD4+ T cells activated by allogeneic dendritic cells (DCs). In activated CD4+ T cells, proteasome inhibition induces apoptosis accompanied by rapid accumulation and stabilization of the tumour suppressor protein p53. Activated CD4+ T cells surviving proteasome inhibition undergo inhibition of proliferation by induction of G1 phase cell‐cycle arrest. Induction of G1 arrest is accompanied by the accumulation of cyclin‐dependent kinase inhibitors p21WAF1/CIP1 and p27KIP1 and the disappearance of cyclin A, cyclin D2 and proliferating cell nuclear antigen, proteins known to regulate G1 to S phase cell‐cycle transitions. Expression of the activation‐associated cell surface receptors CD25, CD28, CD120b and CD134 as well as production of interferon‐γ (IFN‐γ), tumour necrosis factor‐α (TNF‐α), interleukin‐4 (IL‐4) and IL‐5 is suppressed in response to proteasome inhibition in CD4+ T cells activated by DCs. Expression of CD25, IFN‐γ, TNF‐α, IL‐4 and IL‐5 is known to be mediated by the transcriptional activity of nuclear factor of activated T cells (NFAT), and we show here that proteasome inhibition suppresses activation and nuclear translocation of NFATc2 in activated CD4+ T cells. Thus, the proteasome is required for essential immune functions of activated CD4+ T cells and can be defined as a molecular target for the suppression of deregulated and unwanted T‐cell‐mediated immune responses.

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