Clinical activity of single-dose systemic oncolytic VSV virotherapy in patients with relapsed refractory T-cell lymphoma

Abstract

Clinical success with intravenous (IV) oncolytic virotherapy (OV) has to-date been anecdotal. We conducted a phase 1 clinical trial of systemic OV and investigated the mechanisms of action in responding patients. A single IV dose of vesicular stomatitis virus (VSV) interferon-β (IFN-β) with sodium iodide symporter (NIS) was administered to patients with relapsed/refractory hematologic malignancies to determine safety and efficacy across 4 dose levels (DLs). Correlative studies were undertaken to evaluate viremia, virus shedding, virus replication, and immune responses. Fifteen patients received VSV-IFNβ-NIS. Three patients were treated at DL1 through DL3 (0.05, 0.17, and 0.5 × 1011 TCID50), and 6 were treated at DL4 (1.7 × 1011 TCID50) with no dose-limiting toxicities. Three of 7 patients with T-cell lymphoma (TCL) had responses: a 3-month partial response (PR) at DL2, a 6-month PR, and a complete response (CR) ongoing at 20 months at DL4. Viremia peaked at the end of infusion, g was detected. Plasma IFN-β, a biomarker of VSV-IFNβ-NIS replication, peaked between 4 hours and 48 hours after infusion. The patient with CR had robust viral replication with increased plasma cell-free DNA, high peak IFN-β 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. This trial is registered at www.clinicaltrials.gov as #NCT03017820.

© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.

Figures

Graphical abstract

Figure 1.

Clinical outcomes of treatment with 1 IV infusion of VSV-IFNβ-NIS. (A) Summary of patients treated in the study. (B) Maximum grade AEs by DL for each patient. (C) Levels of selected cytokines/chemokines before and after VSV infusion. (D) Swimmer plot (n = 15), in which each bar represents an individual patient as designated. Day 28 responses are indicated. Bars with solid arrows show patients with an ongoing response. ULOQ, upper limit of quantitation.

Figure 2.

A single dose of VSV-IFNβ-NIS monotherapy has clinical activity in patients with TCL. Photographs (A) and PET/CT scans (B) showing resolution of FDG-avid lesions of patient 4A.3 with TCL with cutaneous relapse of nodal PTCL who achieved a CR after receiving 1 dose of VSV-IFNβ-NIS at DL4. (C) FDG PET images of patient 4A.4 with nodal PTCL showing remarkable improvement in FDG-avid cervical, mediastinal, axillary, and abdominal lymph node disease (arrows) with decreased splenic size and FDG uptake (arrowheads) at 1 month. (D) Coronal fused FDG PET/CT images demonstrate improvement in splenic disease (arrowheads), with continued response in the spleen at the 6-month evaluation.

Figure 3.

Positive NIS imaging of virus-infected tumor corresponded with reduction in FDG avidity. (A) In patient 3A.1 with multiple myeloma, axial fused 99mTc-pertechnetate SPECT/CT images demonstrate increasing uptake within a lytic lesion in the anterior right ilium (arrows) on comparison at baseline before VSV, day 1 (24 hours), and day 5 images (arrows). (B) This same lesion demonstrated decreased FDG activity when comparing pre- and posttherapy PET/CT images (arrows). (C) In contrast, a left acetabular lesion in the same patient demonstrated no increased uptake on SPECT/CT at baseline, day 1, or day 5 scans, suggesting minimal VSV infection (arrows). The 6-month follow-up CT (D) and fused PET/CT images (E) showed progression of the acetabular lesion, with increased size, bone destruction, and FDG uptake (arrows).

Figure 4.

Pharmacokinetics and pharmacodynamics of VSV-IFNβ-NIS after IV infusion. (A) Profile of viremia (VSV-N RNA in blood) in each patient measured at baseline, end of infusion, 30 minutes, 60 minutes, 4 hours, 24 hours, and 3, 8, 15, and 28 days after VSV. (B) 24-hour viremia levels of each patient at all DLs. Corresponding plasma IFN-β profile (C) and peak IFN-β levels (D) per DL. (E) Cell-free DNA in plasma of patients. (F) IFN-γ ELISPOT assay for T cells reactive against select tumor antigens, VSV-N, or cytomegalovirus, Epstein-Barr virus, and Flu virus positive control. (G) Anti-VSV neutralizing antibody titers (average of patients per DL). Mean ± standard error of the mean shown where applicable.