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Clinical Trial
. 2023 Oct 31:14:1279387.
doi: 10.3389/fimmu.2023.1279387. eCollection 2023.

A phase I oncolytic virus trial with vesicular stomatitis virus expressing human interferon beta and tyrosinase related protein 1 administered intratumorally and intravenously in uveal melanoma: safety, efficacy, and T cell responses

Katherine E R Smith  1 , Kah-Whye Peng  2 , Jose S Pulido  3 , Adam J Weisbrod  4 , Carrie A Strand  5 , Jacob B Allred  5 , Alysha N Newsom  2 , Lianwen Zhang  2 , Nandakumar Packiriswamy  2 , Timothy Kottke  2 , Jason M Tonne  2 , Madelyn Moore  2 , Heather N Montane  1 , Lisa A Kottschade  1 , Robert R McWilliams  1 , Arkadiusz Z Dudek  1 , Yiyi Yan  6 , Anastasios Dimou  1 , Svetomir N Markovic  1 , Mark J Federspiel  2 , Richard G Vile #  2 , Roxana S Dronca #  6 , Matthew S Block #  1
Affiliations
Clinical Trial

A phase I oncolytic virus trial with vesicular stomatitis virus expressing human interferon beta and tyrosinase related protein 1 administered intratumorally and intravenously in uveal melanoma: safety, efficacy, and T cell responses

Katherine E R Smith et al. Front Immunol. .

Abstract

Introduction: Metastatic uveal melanoma (MUM) has a poor prognosis and treatment options are limited. These patients do not typically experience durable responses to immune checkpoint inhibitors (ICIs). Oncolytic viruses (OV) represent a novel approach to immunotherapy for patients with MUM.

Methods: We developed an OV with a Vesicular Stomatitis Virus (VSV) vector modified to express interferon-beta (IFN-β) and Tyrosinase Related Protein 1 (TYRP1) (VSV-IFNβ-TYRP1), and conducted a Phase 1 clinical trial with a 3 + 3 design in patients with MUM. VSV-IFNβ-TYRP1 was injected into a liver metastasis, then administered on the same day as a single intravenous (IV) infusion. The primary objective was safety. Efficacy was a secondary objective.

Results: 12 patients with previously treated MUM were enrolled. Median follow up was 19.1 months. 4 dose levels (DLs) were evaluated. One patient at DL4 experienced dose limiting toxicities (DLTs), including decreased platelet count (grade 3), increased aspartate aminotransferase (AST), and cytokine release syndrome (CRS). 4 patients had stable disease (SD) and 8 patients had progressive disease (PD). Interferon gamma (IFNγ) ELIspot data showed that more patients developed a T cell response to virus encoded TYRP1 at higher DLs, and a subset of patients also had a response to other melanoma antigens, including gp100, suggesting epitope spreading. 3 of the patients who responded to additional melanoma antigens were next treated with ICIs, and 2 of these patients experienced durable responses.

Discussion: Our study found that VSV-IFNβ -TYRP1 can be safely administered via intratumoral (IT) and IV routes in a previously treated population of patients with MUM. Although there were no clear objective radiographic responses to VSV-IFNβ-TYRP1, dose-dependent immunogenicity to TYRP1 and other melanoma antigens was seen.

Keywords: epitope spreading; immunotherapy; oncolytic virus; phase 1; uveal melanoma.

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Conflict of interest statement

KP: Imanis Life Sciences stock; Vyriad stock. RM: Zentalis pharmaceuticals consulting. AD: Guardant health advisory board; TP therapeutics advisory board; Novartis clinical trial support; Sorrento therapeutics clinical trial support; Syntrix therapeutics clinical trial support; AnHeart Therapeutics clinical trial support; Merck clinical trial support; Intellisphere LLC honoraria. NP: Imanis life sciences LLCprincipal scientist. LK: Immunocore consulting; Novartis consulting. MS: Bristol-Myers Squibb grant/contract; Sorrento therapeutics grant/contract; other intellectual property. RV: Oncolytics Biotech, Canada scientific advisory board; Greenfire/MGFB scientific advisory board. RD: Bristol Myers Squibb funding; Elsai consulting; Elsevier advisory board; EMD Serono Inc consulting; Genzyme Corporation case series discussion; Immunovaccine Technologies consulting; Natera advisory board; Regeneron Pharmaceuticals consultant; Sanofi Genzyme advisory board. MB: Alkermes grant/contract; Bristol-Meyers Squibb grant/contract; Genentech grant/contract; Immune Design grant/contract; Marker Therapeutics grant/ contract; Merck grant/contract; nFerence grant/contract; Pharmacyclics grant/contract; TILT Biotherapeutics grant/contract; Transgene grant/contract; Viewpoint MolecularTargeting grant/contract. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission.

Figures

Figure 1
Figure 1
Heat Map of Maximum Adverse Events by Dose Level. Dose limiting toxicities (DLTs) occurred at DL4 for 1 patient (A4.3). These included: decreased platelets (grade 3), increased AST (grade 3), CRS (grade 3). CRS criteria met due to organ toxicity of grade 3 hepatitis. The DLTs resolved within 14 days. Non-DLT AEs did not significantly increase with dose escalation. * Infections and infestations is defined as a condition.
Figure 2
Figure 2
Overall Survival. Median Overall Survival (OS) was 18.9 months. There were no objective responses, but efficacy was a secondary endpoint. 4 patients had stable disease and 8 patients had progressive disease. The gray zone around the curve represents the 95% confidence interval (CI).
Figure 3
Figure 3
Viral Correlatives. (A, B) VSV-nucleocapsid (N) RNA was below level of detection (LOD) by day 3 (except for DL3, which was detected on day 8). VSV-N was detected only in mouth wash, no other body fluids (see supplementary data ). (C, D) IFN-β peak levels were lowest for DL1 and similar at DL2-4. (E) Neutralizing antibody titers were across all DLs.
Figure 4
Figure 4
ELIspot Data. CD8+ T cells and dendritic cells (DCs) were isolated from peripheral blood mononuclear cells (PBMCs). The DCs were then transfected with plasmids driving expression of OVA (positive control), TYRP1 (vaccine antigen), gp100 (another melanocyte differentiation antigen), or nothing (negative control); then cultured with purified CD8+ T cells (A–D). Alternatively, PBMCs were cultured with peptide pools from VSV, hTERT (melanoma antigen), Cyclin D1 (melanoma antigen), or the peptide SIINFEKL (irrelevant antigen) (E–H). T cell responses to VSV were seen in 10/11 patients across all DLs. Responses to TYRP-1 were seen more frequently in patients treated on DL3 and DL4 (5/6 patients versus 1/5 patients on DL1 and DL2). T cell responses were induced to other melanoma antigens, including hTERT (3 patients), gp100 (3 patients), and Cyclin D1 (5 patients).
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