Villasboas, Jose Caetano

Clinical success with intravenous (IV) oncolytic virotherapy (OV) has to date been anecdotal. Here, we conducted a phase 1 clinical trial of systemic OV therapy and investigated the mechanisms of action in responding T-cell lymphoma (TCL) patients. A single IV dose of VSV-IFNβ-NIS was administered to patients with relapsed refractory hematologic malignancies to determine safety and efficacy across 4 dose levels (DL). Correlative studies were undertaken to evaluate viremia, virus shedding, virus replication and immune responses. Fifteen patients received VSV-IFNβ-NIS (7 multiple myeloma, 7 TCL, 1 acute myeloid leukemia); 3 patients were treated at each DL1 through DL3 (0.05, 0.17, and 0.5 x 1011 TCID50), and 6 at DL4 (1.7 x 1011 TCID50). There were no dose limiting toxicities. 3 of 7 patients with TCL had RECIST responses: a 3-month PR at DL2, a 6-month PR and a durable CR ongoing at 20 months at DL4. Viremia peaked at the end of infusion and no infectious virus shedding was detected. Plasma interferon-β levels, a biomarker of VSV-IFNβ-NIS replication, peaked between 4h and 48h post infusion. The patient with CR had robust viral replication with increased ell free DNA in her plasma, a very high peak IFNβ level of 18,213 pg/ml, a strong anti-VSV neutralizing antibody response, and increased numbers of tumor reactive T-cells. VSV-IFNβ-NIS as a single agent was effective in patients with TCL resulting in durable disease remissions in heavily pretreated patients. Correlative analyses suggest that responses may be due to a combination of direct oncolytic tumor destruction and immune-mediated tumor control. Further clinical testing is warranted. (This trial is registered at www.clinicaltrials.gov as NCT03017820).

In 2013, the American Society of Hematology (ASH) published recommendations with Choosing Wisely to limit surveillance imaging in aggressive lymphoma. We studied surveillance imaging practice patterns for diffuse large B-cell lymphoma (DLBCL) before and after the ASH Choosing Wisely campaign. We used OptumLabs Data Warehouse, a national insurance claims database, to retrospectively study imaging frequency in survivors of DLBCL from 2008 to 2016. Three time periods were defined: Period 1 (2008 to 2010), Period 2 (2011 to 2013), and Period 3 (2014 to 2016). One thousand four hundred seventy-two patients were included. Median follow up was approximately 2 years. During the first and second years of surveillance, imaging remained stable between Period 1 (years 1 and 2: 199 [91%] and 137 [83%], respectively) and Period 2 (years 1 and 2: 257 [88%] and 172 [77%], respectively; P = .38), but decreased in Period 3 (years 1 and 2: 315 [78%] and 83 [61%], respectively; P < .01). In a multivariable logistic regression, year after 2012 was a significant predictor of decreased overuse (more than two scans per year in the first year of surveillance; [odds ratio, 0.49 for 2013 v 2008; P = .02]). Our study demonstrated the rate of surveillance scans—both computed tomography and positron emission tomography imaging—in DLBCL decreased after the ASH Choosing Wisely campaign. Multiple factors, such as changes in recommendations, reimbursement, and provider knowledge base, may have all contributed and should be studied further.