505 Relationship of infusion duration and dose to safety, efficacy and pharmacodynamics: second part of a phase 1–2 study using VSV-IFNβ-NIS (VV1) oncolytic virus in patients with refractory solid tumors

BackgroundOncolytic viruses (OVs) show significant potential for treating tumors alongside immunotherapies.1 VV1 is an OV derived from the innocuous vesicular stomatitis virus (VSV). VV1 has been engineered to expresses human interferon (IFN) β and thyroidal sodium iodide symporter (NIS).2 VV1-infected cells produce IFNβ, which protects non-cancer cells from VV1 and allows VV1 to spread more efficiently in cancerous tissue.3 4 NIS expression on cells imports 99mTc pertechnetate, which facilitates in vivo imaging of virus infection.2 This three-part, phase 1–2 study was designed to determine the safety and tolerability of VV1 in patients with advanced unresectable and metastatic solid tumors. Here we report on the second part of this study: selection of recommended phase 2 regimen (RP2D), comprising further assessment of both duration and dose.MethodsPatients (n=29) were enrolled to receive a single IV infusion of VVI monotherapy. 23 patients received IV VV1 1.7 x1010 TCID50 over 15, 30, 60 or 180 min. Six patients received 1.0 x1011 TCID50 over 30 min with aggressive premedication and fluid support overnight. Patients were monitored for dose limiting toxicities over 21 days with efficacy assessments after 6 weeks and then every 3 months for survival. The primary objective was to establish the safety and tolerability of IV VV1. Secondary objectives included preliminary efficacy, pharmacokinetics and pharmacodynamics.ResultsIn this study VV1, demonstrated an acceptable safety profile. No deaths or Grade 4 infusion-related reactions (IRR) were reported. VV1 shedding by buccal swabs was negative at all study visits. Peak IFNβ serum levels and preliminary efficacy signals (2 PRs) were associated with 30 min infusion duration and higher dose, with RECIST data pending for 1 x 1011(table 1).Abstract 505 Table 1ConclusionsIn this study, the absence of viral shedding demonstrates that VV1 is safe for patient and caregiver with little/no environmental impact. There was no difference in safety between the lower and the higher dose infusions. In this patient population acceptable tolerability was observed at the higher dose with 30 min duration, thus the RP2D is 1x 1011 over 30 mins.Trial RegistrationNCT02923466ReferencesHemminki O, Dos Santos JM, Hemminki A. Oncolytic viruses for cancer immunotherapy. J Hematol Oncol 2020;13(1):84.Naik S, Nace R, Federspiel MJ, Barber GN, Peng KW, Russell SJ. Curative one-shot systemic virotherapy in murine myeloma. Leukemia 2012;26(8):1870–1878.Barber GN. Vesicular stomatitis virus as an oncolytic vector. Viral Immunol 2004;17(4):516–527.Lichty BD, Power AT, Stojdl DF, Bell JC. Vesicular stomatitis virus: re-inventing the bullet. Trends Mol Med 2004;10(5):210–216.Ethics ApprovalEthics approval was granted by WCG IRB. IRB tracking number: 20163005. Voluntary written informed consent was obtained from every patient prior to participation.

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Phase II trial of Voyager-V1 (vesicular stomatitis virus expressing human IFNβ and NIS, VV1), in combination with cemiplimab (C) in patients with NSCLC, melanoma, HCC or endometrial carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.tps3161 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. TPS3161-TPS3161

Author(s):

Mario Sznol ◽

Jose Lutzky ◽

Alex A. Adjei ◽

Steven Francis Powell ◽

Aiwu Ruth He ◽

...

Keyword(s):

Endometrial Cancer ◽

Solid Tumors ◽

Vesicular Stomatitis Virus ◽

Checkpoint Inhibitors ◽

Oncolytic Viruses ◽

Type I ◽

Sodium Iodide Symporter ◽

Term Survival ◽

Vesicular Stomatitis ◽

Anti Tumor Activity

TPS3161 Background: VV1 is an oncolytic vesicular stomatitis virus engineered to express human IFNβ to enhance cellular anti-tumor immune responses and tumor selectivity, and the human sodium iodide symporter (NIS) for virus tracking by SPECT imaging. Cancer cells are often hyporesponsive to IFNβ, enabling the efficient spread of VV1 and resulting in increased oncolysis. Differently from other oncolytic viruses, VV1 is suitable for both intra-tumoral (IT) and/or intra-venous (IV) administration. Despite considerable anti-tumor activity with checkpoint inhibitors (CPI) among some malignancies, long term survival and overall cures remain elusive. Prior Ph 1 studies have shown significant anti-tumor activity among several malignancies when VV1 was administered either as monotherapy or in combination with a CPI, despite progression on prior CPI monotherapy. Furthermore, pre- and post-treatment biopsy evaluations after VV1 treatment have demonstrated T cell infiltration and inflammation in both IT injected and non-injected lesions. Among IV treated patients (pts), IFNβ was detectable in the serum correlating with viral replication, making it an effective biomarker. C is a high-affinity potent human IgG4 anti-PD-1 monoclonal antibody. Though approved for use in cutaneous squamous cell carcinoma, C has shown anti-tumor activity, similar to other CPI, in several other indications. Therefore, VV1 and C could be an attractive combination for the immunotherapy for several solid tumors. This study represents the first clinical evaluation of VV1 in combination with C in pts with advanced solid tumors. Methods: The Ph 2 Simon 2 stage five-arm study of IV administration VV1 in combination with IV C will enroll pts with advanced NSCLC, HCC, melanoma & endometrial cancer. Enrolled pts with NSCLC & melanoma will be recent CPI-progressors, whereas enrolled HCC & endometrial cancer will be CPI-naïve. The study’s objectives include assessment of preliminary anti-tumor activity, safety, & immuno-regulatory activity of the combination. Pts will receive IV VV1 once on D1 and IV C once every 3 weeks until confirmed disease progression or intolerable toxicity. Pts enrolled in one melanoma cohort will also receive IT VV1 administered to palpable lesions. Response will be assessed every 9 weeks per RECIST v1.1. The null hypothesis of each cohort’s ORR will be tested versus a one-sided alternative yielding a Type I error rate of 5% and power of 80%. Cohorts will be expanded based on signal of activity. Clinical trial information: NCT .

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Susceptibility of head and neck cancer to an attenuated model of the oncolytic vesicular stomatitis virus expressing suicide genes

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e14604 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. e14604-e14604

Author(s):

M. Porosnicu ◽

J. Liu ◽

D. Lyles

Keyword(s):

Head And Neck ◽

Tumor Cells ◽

Cell Lines ◽

Vesicular Stomatitis Virus ◽

Nude Mice ◽

Suicide Gene ◽

Oncolytic Viruses ◽

Vesicular Stomatitis ◽

Hnscc Cell

e14604 Background: The predominant loco-regional progression of head and neck squamous cell carcinoma (HNSCC) makes it suitable for testing oncolytic viruses. Recent work from several laboratories including ours has focused on developing vesicular stomatitis virus (VSV) as a replication-competent anticancer viral vector. Attenuated strains, such as M protein mutant VSV (M51R) are more likely to be promoted in clinical research. The major shortcoming of viral therapy is related to the large proportion of tumor cells remaining uninfected. We are addressing this limitation in two ways: the expression of the cytosine deaminase-uracil phosphoribosyltransferase (C:U) suicide gene by the rVSV vector, expected to produce a strong bystander effect and the exploitation of the radiosensitizing potential of the 5-FU chemo-drug produced intratumorally, as well as of the VSV virus itself. Methods: We determined the extent of defectiveness in interferon pathways and susceptibility to oncolytic VSV in a collection of HNSCC cell lines and in patient HN primary tumor cells. We employed gene array to screen for differences in gene expression in sensitive and resistant models. We have generated the rVSV-C:U and M51R-C:U viruses and we tested our collection of HNSCC cell models to infection with these viruses in the presence and absence of 5-FC. In vivo experiments were performed on a localized and on a metastatic SQ-20B model of HNSCC in nude mice. Results: 1) the primary patient HNC cells are more resistant than the HNC cell lines to the M51R-VSV; 2) the activation of IFN pathways and /or alterations of AKT pathway is contributing to resistance to VSVs. 3) Addition of the suicide gene to the attenuated VSV provided significantly more oncolytic effect in vitro and in vivo. The efficacy and the radiosensitizing potential of M51R- C:U on a nude mice model of HNSCC (SQ-20B) will be presented. Conclusions: M51R-VSV has increased efficiency and radiosensitizing effect on HNSCC models. We can define an optimal approach to testing VSV vectors for treatment of HNSCC, with a clinical trial in HNSCC patients as our next goal. Finally, we have important new information, both from cell lines and patient tissues, for proof-of-principle that cancers can down-regulate antiviral responses. No significant financial relationships to disclose.

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417 Design and rationale of a phase 1 study evaluating AMG 256, a novel, targeted, IL-21 receptor agonist and anti-PD-1 antibody, in patients with advanced solid tumors

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0417 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A443-A443

Author(s):

Gregory Durm ◽

Sophia Frentzas ◽

Erik Rasmussen ◽

Saltanat Najmi ◽

Nooshin Sadraei

Keyword(s):

Solid Tumors ◽

Tumor Immunity ◽

Renal Cell ◽

Phase 1 ◽

List Type ◽

Solid Organ ◽

Advanced Solid Tumors ◽

Phase 1 Study ◽

Drug Study ◽

Interleukin 21

BackgroundCheckpoint inhibitors are a promising therapy for patients with solid tumors; however, many patients require additional therapies to maximize clinical benefit or overcome resistance.1 The type-1 cytokine interleukin-21 (IL-21) is a promising candidate for combination and has shown clinical activity in melanoma and renal cell cancer.2 IL-21 has also shown improved efficacy when combined with anti-programmed death (PD)-1 antibodies in preclinical models.3 4 AMG 256 is a mutated IL-21 cytokine fused to an anti-PD-1 antibody to combine IL-21 pathway stimulation with checkpoint inhibition—a strategy that is designed to prime and extend the activity of cytotoxic and memory T cells and induce anti-tumor immunity. This first-in-human (FIH) study will assess safety, tolerability, and estimated dosing of AMG 256 monotherapy in patients with advanced solid tumors.MethodsThis is a FIH, multicenter, non-randomized, open-label, phase 1 study (NCT04362748) of AMG 256 in patients with advanced solid tumors. The planned sample size is approximately 100 patients in two parts: part 1 will evaluate safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and determine the maximum tolerated dose (MTD), part 2 will evaluate the MTD determined in part 1 to further characterize the safety profile and preliminary tumor response. AMG 256 will be delivered by intravenous (IV) infusion. Enrollment criteria include adults with life expectancy of > 3 months, ECOG performance status ≤ 2, histologically or cytologically confirmed metastatic or locally advanced solid tumors not amenable to curative treatment with surgery or radiation, and at least one measurable lesion ≥ 10 mm that has not undergone biopsy within 3 months of screening scan. Exclusion criteria include primary brain tumor, untreated or symptomatic brain metastases, currently receiving treatment in another investigational device or drug study, or less than 28 days since ending treatment on another investigational device or drug study, history of solid organ transplantation or major surgery within 28 days of study day 1, live vaccine therapy within 4 weeks prior to study day 1, and active infection requiring oral or IV therapy. The primary endpoints are incidence of dose-limiting toxicities and adverse events, MTD, and recommended phase 2 dose. Secondary objectives will evaluate PK parameters, preliminary antitumor activity (objective response, duration of response, progression-free survival, disease control rate, duration of stable disease, overall survival), and immunogenicity of AMG 256 via incidence of anti-AMG 256 antibodies.ResultsN/AConclusionsN/AAcknowledgements• The authors thank the investigators, patients, and study staff who are contributing to this study.• The study was sponsored and funded by Amgen Inc. • Medical writing support was provided by Christopher Nosala (Amgen Inc.).Trial RegistrationNCT04362748Ethics ApprovalThe study was approved by all institutional ethics boards.ReferencesKluger HM, Tawbi HA, Ascierto ML, et al. Defining tumor resistance to PD-1 pathway blockade: recommendations from the first meeting of the SITC Immunotherapy Resistance Taskforce. J Immunother Cancer 2020;8:e000398.Thompson JA, Curti BD, Redman BG, et al. Phase I study of recombinant interleukin-21 in patients with metastatic melanoma and renal cell carcinoma. J Clin Oncol 2008;26:2034–2039.Lewis KE, Selby MJ, Masters G, et al. Interleukin-21 combined with PD-1 or CTLA-4 blockade enhances antitumor immunity in mouse tumor models. Oncoimmunology. 2017;7:e1377873.Shen S, Sckisel G, Sahoo A, et al. Engineered IL-21 cytokine muteins fused to anti-PD-1 antibodies can improve CD8+ T cell function and anti-tumor immunity. Front Immunol 2020;11:832.

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Natural killer T cell immunotherapy combined with oncolytic vesicular stomatitis virus or reovirus treatments differentially increases survival in mouse models of ovarian and breast cancer metastasis

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-002096 ◽

2021 ◽

Vol 9 (3) ◽

pp. e002096

Author(s):

Simon Gebremeskel ◽

Adam Nelson ◽

Brynn Walker ◽

Tora Oliphant ◽

Lynnea Lobert ◽

...

Keyword(s):

Breast Cancer ◽

Vesicular Stomatitis Virus ◽

Cell Activation ◽

Tumor Burden ◽

Oncolytic Viruses ◽

Nkt Cell ◽

Cell Immunotherapy ◽

Vesicular Stomatitis ◽

Better Than

BackgroundOncolytic viruses reduce tumor burden in animal models and have generated promising results in clinical trials. However, it is likely that oncolytic viruses will be more effective when used in combination with other therapies. Current therapeutic approaches, including chemotherapeutics, come with dose-limiting toxicities. Another option is to combine oncolytic viruses with immunotherapeutic approaches.MethodsUsing experimental models of metastatic 4T1 breast cancer and ID8 ovarian peritoneal carcinomatosis, we examined natural killer T (NKT) cell-based immunotherapy in combination with recombinant oncolytic vesicular stomatitis virus (VSV) or reovirus. 4T1 mammary carcinoma cells or ID8 ovarian cancer cells were injected into syngeneic mice. Tumor-bearing mice were treated with VSV or reovirus followed by activation of NKT cells via the intravenous administration of autologous dendritic cells loaded with the glycolipid antigen α-galactosylceramide. The effects of VSV and reovirus on immunogenic cell death (ICD), cell viability and immunogenicity were tested in vitro.ResultsVSV or reovirus treatments followed by NKT cell activation mediated greater survival in the ID8 model than individual therapies. The regimen was less effective when the treatment order was reversed, delivering virus treatments after NKT cell activation. In the 4T1 model, VSV combined with NKT cell activation increased overall survival and decreased metastatic burden better than individual treatments. In contrast, reovirus was not effective on its own or in combination with NKT cell activation. In vitro, VSV killed a panel of tumor lines better than reovirus. VSV infection also elicited greater increases in mRNA transcripts for proinflammatory cytokines, chemokines, and antigen presentation machinery compared with reovirus. Oncolytic VSV also induced the key hallmarks of ICD (calreticulin mobilization, plus release of ATP and HMGB1), while reovirus only mobilized calreticulin.ConclusionTaken together, these results demonstrate that oncolytic VSV and NKT cell immunotherapy can be effectively combined to decrease tumor burden in models of metastatic breast and ovarian cancers. Oncolytic VSV and reovirus induced differential responses in our models which may relate to differences in virus activity or tumor susceptibility.

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A first-in-human, phase 1 study of the NEDD8 activating enzyme E1 inhibitor TAS4464 in patients with advanced solid tumors

Investigational New Drugs ◽

10.1007/s10637-020-01055-5 ◽

2021 ◽

Author(s):

Noboru Yamamoto ◽

Toshio Shimizu ◽

Kan Yonemori ◽

Shigehisa Kitano ◽

Shunsuke Kondo ◽

...

Keyword(s):

Liver Function ◽

Solid Tumors ◽

Dose Escalation ◽

Enzyme Inhibitor ◽

Phase 1 ◽

Maximum Tolerated Dose ◽

Primary Objective ◽

Open Label ◽

Phase 1 Study ◽

Open Label Phase

SummaryBackground This open-label, phase 1 study investigated TAS4464, a potent NEDD8-activating enzyme inhibitor, in patients with advanced/metastatic solid tumors (JapicCTI-173,488; registered 13/01/2017). The primary objective was dose-limiting toxicities (DLTs). Maximum-tolerated dose (MTD) was investigated using an accelerated titration design. Methods The starting 10-mg/m2 dose was followed by an initial accelerated stage (weekly dosing; n = 11). Based on liver function test (LFT) results, a 14-day, 20-mg/m2 dose lead-in period was implemented (weekly dosing with lead-in; n = 6). Results Abnormal LFT changes and gastrointestinal effects were the most common treatment-related adverse events (AEs). DLTs with 56-mg/m2 weekly dosing occurred in 1/5 patients; five patients had grade ≥ 2 abnormal LFT changes at 40- and 56-mg/m2 weekly doses. Further dose escalation ceased because of the possibility of severe abnormal LFT changes occurring. DLTs with weekly dosing with lead-in occurred in 1/5 patients at a 56-mg/m2 dose; MTD could not be determined because discontinuation criteria for additional enrollment at that particular dose level were met. As no further enrollment at lower doses occurred, dose escalation assessment was discontinued. Serious treatment-related AEs, AEs leading to treatment discontinuation, and DLTs were all related to abnormal LFT changes, suggesting that TAS4464 administration could affect liver function. This effect was dose-dependent but considered reversible. Complete or partial responses to TAS4464 were not observed; one patient achieved prolonged stable disease. Conclusions MTD could not be determined due to TAS4464 effects on liver function. Further evaluation of the mechanism of NEDD8-activating enzyme inhibitor-induced abnormal liver function is required. Trial registration number JapicCTI-173,488 (registered with Japan Pharmaceutical Information Center). Registration date 13 January 2017

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Mechanisms that allow vaccination against an oncolytic vesicular stomatitis virus-encoded transgene to enhance safety without abrogating oncolysis

Scientific Reports ◽

10.1038/s41598-021-94483-z ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Amanda W. K. AuYeung ◽

Robert C. Mould ◽

Ashley A. Stegelmeier ◽

Jacob P. van Vloten ◽

Khalil Karimi ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Vesicular Stomatitis Virus ◽

Cell Response ◽

Viral Infections ◽

T Cell Response ◽

Oncolytic Viruses ◽

Oncolytic Virotherapy ◽

Cell Immunity ◽

Vesicular Stomatitis

AbstractVaccination can prevent viral infections via virus-specific T cells, among other mechanisms. A goal of oncolytic virotherapy is replication of oncolytic viruses (OVs) in tumors, so pre-existing T cell immunity against an OV-encoded transgene would seem counterproductive. We developed a treatment for melanomas by pre-vaccinating against an oncolytic vesicular stomatitis virus (VSV)-encoded tumor antigen. Surprisingly, when the VSV-vectored booster vaccine was administered at the peak of the primary effector T cell response, oncolysis was not abrogated. We sought to determine how oncolysis was retained during a robust T cell response against the VSV-encoded transgene product. A murine melanoma model was used to identify two mechanisms that enable this phenomenon. First, tumor-infiltrating T cells had reduced cytopathic potential due to immunosuppression. Second, virus-induced lymphopenia acutely removed virus-specific T cells from tumors. These mechanisms provide a window of opportunity for replication of oncolytic VSV and rationale for a paradigm change in oncolytic virotherapy, whereby immune responses could be intentionally induced against a VSV-encoded melanoma-associated antigen to improve safety without abrogating oncolysis.

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AN IN VIVO STUDY OF VESICULAR STOMATITIS VIRUS (VSV)-CELL INTERACTION IN CNS OF INFECTED MICE

Journal of Neuropathology & Experimental Neurology ◽

10.1097/00005072-197605000-00088 ◽

1976 ◽

Vol 35 (3) ◽

pp. 340

Author(s):

Mauro C. Dal Canto ◽

Stanley G. Rabinowitz ◽

Terry C. Johnson

Keyword(s):

Vesicular Stomatitis Virus ◽

Cell Interaction ◽

In Vivo Study ◽

Vesicular Stomatitis

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480 A first-in-human phase I dose-escalation trial of the B7-H6/CD3 T-cell engager BI 765049 ± ezabenlimab (BI 754091) in patients with advanced solid tumors expressing B7-H6

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-sitc2021.480 ◽

2021 ◽

Vol 9 (Suppl 3) ◽

pp. A510-A510

Author(s):

Gerald Falchook ◽

David Spigel ◽

Manish Patel ◽

Babar Bashir ◽

Susanna Ulahannan ◽

...

Keyword(s):

T Cell ◽

T Cell Activation ◽

Dose Escalation ◽

Cell Activation ◽

Primary Objective ◽

List Type ◽

Open Label ◽

Eu Directive ◽

Dosing Regimens

BackgroundB7-H6 is a member of the B7 family of immune receptors, which is expressed in several solid tumor types but very little expression can be detected in normal tissues.1 2 BI 765049 is a novel IgG-like bispecific T-cell engager designed to bind simultaneously to B7-H6 on tumor cells and CD3 on T cells, resulting in cytolytic synapse formation and tumor lysis. Preclinical studies have demonstrated that BI 765049 monotherapy induced dose-dependent anti-tumor activity in humanized in vivo CRC tumor models. Consistent with the mode of action, the treatment with BI 765049 led to target cell apoptosis, local T-cell activation/proliferation and cytokine production in the tumor tissue, with PD-(L)1 upregulation.3 Activation of the PD-(L)1 provides the rationale for combining BI 765049 with a PD1 inhibitor.MethodsNCT04752215 is a first-in-human, open-label, dose-escalation trial of BI 765049 ± the PD-1 inhibitor, ezabenlimab. Adults with advanced, unresectable and/or metastatic CRC, NSCLC, HNSCC, hepatocellular, gastric or pancreatic carcinoma are eligible. Patients must have failed on, or be ineligible, for standard therapies. B7-H6 positivity must be confirmed at screening by central review (immunohistochemistry assay) in archived tissues/in-study fresh biopsies (except CRC). Patients must have ≥1 evaluable lesion (modified RECIST 1.1) outside of the central nervous system and adequate organ function. The primary objective is to determine the maximum tolerated dose (MTD) or recommended dose for expansion of BI 765049 ± ezabenlimab, based on dose-limiting toxicities during the MTD evaluation period. Further objectives are to evaluate safety, tolerability, PK/PD and preliminary efficacy of BI 765049 ± ezabenlimab. The trial may assess up to 4 dosing regimens: A (BI 765049 once every 3 weeks [q3w]); B1 (BI 765049 qw); B2 (BI 765049 qw with step-in doses); C (BI 765049 + ezabenlimab [q3w]). Dose escalation will be guided by a Bayesian Logistic Regression Model with overdose control that will be fitted to binary toxicity outcomes using a hierarchical modelling approach to jointly model all dosing regimens. Treatment will be allowed to continue until confirmed progressive disease, unacceptable toxicity, other withdrawal criteria or for a maximum duration of 36 months, whichever occurs first. Approximately 150–175 patients will be screened and ~120 patients enrolled. As of July 2021, patients are being recruited in early dose-escalation cohorts.AcknowledgementsMedical writing support for the development of this abstract, under the direction of the authors, was provided by Becky O’Connor, of Ashfield MedComms, an Ashfield Health company, and funded by Boehringer Ingelheim.Trial RegistrationNCT04752215ReferencesBrandt et al. J Exp Med 2009;206:1495–503.Boehringer Ingelheim. Data on file.Hipp et al. AACR Annual Meeting 2021.Ethics ApprovalThe trial will be carried out in compliance with the protocol, the ethical principles laid down in the Declaration of Helsinki, in accordance with the ICH Harmonized Guideline for Good Clinical Practice (GCP) and the EU directive 2001/20/EC/EU regulation 536/2014.

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Interferon Beta and Interferon Alpha 2a Differentially Protect Head and Neck Cancer Cells from Vesicular Stomatitis Virus-Induced Oncolysis

Journal of Virology ◽

10.1128/jvi.00757-15 ◽

2015 ◽

Vol 89 (15) ◽

pp. 7944-7954 ◽

Cited By ~ 17

Author(s):

Marlena M. Westcott ◽

Jingfang Liu ◽

Karishma Rajani ◽

Ralph D'Agostino ◽

Douglas S. Lyles ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Head And Neck ◽

Cancer Cells ◽

Tumor Cells ◽

Vesicular Stomatitis Virus ◽

Oncolytic Viruses ◽

Type I ◽

Normal Cells ◽

Vesicular Stomatitis

ABSTRACTOncolytic viruses (OV) preferentially kill cancer cells due in part to defects in their antiviral responses upon exposure to type I interferons (IFNs). However, IFN responsiveness of some tumor cells confers resistance to OV treatment. The human type I IFNs include one IFN-β and multiple IFN-α subtypes that share the same receptor but are capable of differentially inducing biological responses. The role of individual IFN subtypes in promoting tumor cell resistance to OV is addressed here. Two human IFNs which have been produced for clinical use, IFN-α2a and IFN-β, were compared for activity in protecting human head and neck squamous cell carcinoma (HNSCC) lines from oncolysis by vesicular stomatitis virus (VSV). Susceptibility of HNSCC lines to killing by VSV varied. VSV infection induced increased production of IFN-β in resistant HNSCC cells. When added exogenously, IFN-β was significantly more effective at protecting HNSCC cells from VSV oncolysis than was IFN-α2a. In contrast, normal keratinocytes and endothelial cells were protected equivalently by both IFN subtypes. Differential responsiveness of tumor cells to IFN-α and -β was further supported by the finding that autocrine IFN-β but not IFN-α promoted survival of HNSCC cells during persistent VSV infection. Therefore, IFN-α and -β differentially affect VSV oncolysis, justifying the evaluation and comparison of IFN subtypes for use in combination with VSV therapy. Pairing VSV with IFN-α2a may enhance selectivity of oncolytic VSV therapy for HNSCC by inhibiting VSV replication in normal cells without a corresponding inhibition in cancer cells.IMPORTANCEThere has been a great deal of progress in the development of oncolytic viruses. However, a major problem is that individual cancers vary in their sensitivity to oncolytic viruses. In many cases this is due to differences in their production and response to interferons (IFNs). The experiments described here compared the responses of head and neck squamous cell carcinoma cell lines to two IFN subtypes, IFN-α2a and IFN-β, in protection from oncolytic vesicular stomatitis virus. We found that IFN-α2a was significantly less protective for cancer cells than was IFN-β, whereas normal cells were equivalently protected by both IFNs. These results suggest that from a therapeutic standpoint, selectivity for cancer versus normal cells may be enhanced by pairing VSV with IFN-α2a.

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