The intratumoral injection of talimogene laherparepvec, an oncolytic virus engineered to enhance immune recognition of cancer, resulted in a high response rate in combination with anti−PD-1 therapy. SUMMARYHere we report a phase 1b clinical trial testing the impact of oncolytic virotherapy with talimogene laherparepvec on cytotoxic T-cell infiltration and therapeutic efficacy of the anti−PD-1 antibody pembrolizumab. Twenty-one patients with advanced melanoma were treated with talimogene laherparepvec followed by combination therapy with pembrolizumab. Therapy was generally well-tolerated, with fatigue, fevers, and chills as the most common adverse events.

No abstract

To better understand the requirements for telomerase-mediated telomere addition in vivo, we developed an assay in S. cerevisiae that creates a chromosome end immediately adjacent to a short telomeric DNA tract. The de novo end acts as a telomere: it is protected from degradation in a CDC13-dependent manner, telomeric sequences are added efficiently, and addition occurs at a faster rate in mutant strains that have long telomeres. Telomere addition was detected in M phase arrested cells, which permitted us to determine that the essential DNA polymerases alpha and delta and DNA primase were required. This indicates that telomeric DNA synthesis by telomerase is tightly coregulated with the production of the opposite strand. Such coordination prevents telomerase from generating excessively long single-stranded tails, which may be deleterious to chromosome stability in S. cerevisiae.

Purpose Pembrolizumab provides durable antitumor activity in metastatic melanoma, including complete response (CR) in about 15% of patients. Data are limited on potential predictors of CR and patient disposition after pembrolizumab discontinuation after CR. We describe baseline characteristics and long-term follow-up in patients who experienced CR with pembrolizumab in the KEYNOTE-001 study ( ClinicalTrials.gov identifier: NCT01295827). Patients and Methods Patients with ipilimumab-naive or -treated advanced/metastatic melanoma received one of three dose regimens of pembrolizumab. Eligible patients who received pembrolizumab for ≥ 6 months and at least two treatments beyond confirmed CR could discontinue therapy. Response was assessed every 12 weeks by central Response Evaluation Criteria in Solid Tumors version 1.1. For this analysis, CR was defined per investigator assessment, immune-related response criteria, and potential predictors of CR were evaluated using univariate and multivariate analyses. Results Of 655 treated patients, 105 (16.0%) achieved CR after median follow-up of 43 months. At data cutoff, 92 patients (87.6%) had CR, with median follow-up of 30 months from first CR. Fourteen (13.3%) patients continued to receive treatment for a median of ≥ 40 months. Pembrolizumab was discontinued by 91 patients (86.7%), including 67 (63.8%) who proceeded to observation without additional anticancer therapy. The 24-month disease-free survival rate from time of CR was 90.9% in all 105 patients with CR and 89.9% in the 67 patients who discontinued pembrolizumab after CR for observation. Tumor size and programmed death-ligand 1 status were among the baseline factors independently associated with CR by univariate analysis. Conclusion Patients with metastatic melanoma can have durable complete remission after discontinuation of pembrolizumab, and the low incidence of relapse after median follow-up of approximately 2 years from discontinuation provides hope for a cure for some patients. The mechanisms underlying durable CR require further investigation.