Safety and tolerability of intratumorally administered OH2, an oncolytic herpes simplex virus 2, in patients with advanced solid tumors: A phase I dose escalation clinical study.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3139-3139
Author(s):  
Jing Huang ◽  
Bo Zhang ◽  
Jialin Tang ◽  
Qing Chang ◽  
Rui Zhang ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Oncolytic Viruses ◽  
Potential Clinical Benefit ◽  
Oncolytic Herpes Simplex Virus ◽  
Systemic Treatments ◽  
Simplex Virus

3139 Background: There have been limited reports concerning treatment outcomes of oncolytic viruses in solid tumors other than melanoma. OH2 is a genetically engineered oncolytic herpes simplex virus type 2 designed to selectively amplify in tumor cells and express GM-CSF to enhance tumor-specific immune responses. Methods: We conducted an open-label, single-center, phase 1 study. Eligible pts were 18-75 years of age; had histologically confirmed advanced solid tumor; had progressed after standard systemic treatments. Pts were required to have tumor(s) deemed safe to inject, with a longest diameter of at least 0.5cm. Other eligibility criteria included measurable lesion as per RECIST v1.1; ECOGPS score of 0-1 and adequate organ functions. A 3+3 dose-escalation strategy was used in the study and 3 dose levels (106, 107 and 108 CCID50/mL) of OH2 were assessed. OH2 was administered intratumorally every 3 weeks for the first cycle and every 2 weeks.Treatment may continue afterwards in ptswith potential clinical benefit at the discretion of the investigators. The primary objective was the safety and tolerability of OH2 injection as defined by the dose limiting toxicities (DLTs) within the first 3 weeks of therapy, and the maximum tolerated dose (MTD). Secondary objectives included efficacy and immunogenicity of OH2. Results: 11 pts were enrolled between April 17, 2019 and November 4, 2019. The median follow-up duration was 8.36 months (95%CI: 5.64-11.08). OH2 was well-tolerated as no DLTs were reported and no MTD reached. Before the end of the DLT assessment period,1 pt withdrew consent, and 1 pt died of arrhythmia unrelated to OH2, with negative OH2 DNA copies in serum, urine and saliva samples. Most treatment-related adverse events (TRAEs) observed were of grade 1-2, except that 1 pt in the 108 CCID50/mL group developed grade 3 fever. The most common TRAEs were fever (n =5) and blood bilirubin level increase (n = 4). There were no grade 4 or 5 TRAEs. One pt(rectal cancer) had PR and 2 (appendix cancer and ovarian cancer) had SD as per RECIST v1.1. One patient (esophageal cancer) achieved iPR as per iRECIST criteria. The duration of follow-up for the 2 responders were 9.70 months and 8.36 months, respectively, and both had ongoing responses. Notably, regression of a non-injected lesion was observed in 1 patient. Conclusions: OH2 had a favorable safety profile with no DLTs and MTD. The dose expansion study in selected tumor types is currently underway. Clinical trial information: NCT03866525 .

scholarly journals The Novel Oncolytic Herpes Simplex Virus Type-1 (HSV-1) VC2 Promotes Long-lasting, Systemic Anti-melanoma Tumor Immune Responses and Increased Survival in an Immunocompetent B16F10-derived Mouse Melanoma Model

2020 ◽  
Author(s):  
Ifeanyi Kingsley Uche ◽  
Natalie Fowlkes ◽  
Luan Vu ◽  
Tatiane Watanabe ◽  
Mariano Carossino ◽  
...  
Keyword(s):  
T Cells ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Response Rates ◽  
Oncolytic Viruses ◽  
Oncolytic Virotherapy ◽  
Oncolytic Herpes Simplex Virus ◽  
Simplex Virus ◽  
Hsv 1

Oncolytic virotherapy (OVT) is now understood to be an immunotherapy that uses viral infection to liberate tumor antigens in an immunogenic context to promote the development of anti-tumor immune responses. The only currently FDA approved oncolytic virotherapy, T-Vec™, is a modified herpes simplex virus type I (HSV-1). While T-Vec™ is associated with limited response rates its modest efficacy supports the continued development of novel OVT viruses. Herein, we test the efficacy of a recombinant HSV-1, VC2, as an OVT in a syngeneic B16F10-derived mouse model of melanoma. VC2 possesses mutations that block its ability to enter neurons via axonal termini. This greatly enhances its safety profile by precluding the virus’s ability to establish latent infection. VC2 has been shown to be a safe, effective vaccine against both HSV-1 and HSV-2 infection in mice, guinea pigs, and non-human primates. We found that VC2 slows tumor growth rates and that VC2 treatment significantly enhances survival of tumor-engrafted, VC2-treated mice over control treatments. VC2-treated mice that survived initial tumor engraftment were resistant to a second engraftment as well as colonization of lungs by intravenous introduction of tumor cells. We found that VC2 treatment induced substantial increases in intratumoral T-cells and a decrease in immunosuppressive T-regulatory cells. This immunity was critically dependent on CD8+ T-cells and less dependent on CD4+ T-cells. Our data provide significant support for the continued development of VC2 as an OVT for the treatment of human and animal cancers. Importance Current oncolytic virotherapies possess limited response rates. However, when certain patient selection criteria are used, oncolytic virotherapy response rates have been shown to increase. This, in addition to the increased response rates of oncolytic virotherapy in combination with other immunotherapies, suggests that oncolytic viruses possess significant therapeutic potential for the treatment of cancer. As such, it is important to continue to develop novel oncolytic viruses as well as support basic research into their mechanisms of efficacy. Our data demonstrate significant clinical potential for VC2, a novel Type 1 oncolytic herpes simplex virus. Additionally, due to the high rates of survival and the dependence on CD8+ T-cells for efficacy, our model will enable study of the immunological correlates of protection for VC2 oncolytic virotherapy and oncolytic virotherapy in general. Understanding the mechanisms of efficacious oncolytic virotherapy will inform the rational design of improved oncolytic virotherapies.

scholarly journals Preclinical Evaluation of Engineered Oncolytic Herpes Simplex Virus for the Treatment of Pediatric Solid Tumors

PLoS ONE ◽  
2014 ◽  
Vol 9 (1) ◽  
pp. e86843 ◽  
Author(s):  
Michael L. Megison ◽  
Lauren A. Gillory ◽  
Jerry E. Stewart ◽  
Hugh C. Nabers ◽  
Elizabeth Mroczek-Musulman ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Solid Tumors ◽  
Preclinical Evaluation ◽  
Pediatric Solid Tumors ◽  
Oncolytic Herpes Simplex Virus ◽  
Simplex Virus

Oncolytic herpes simplex virus therapy for peripheral nerve tumors

2007 ◽  
Vol 22 (6) ◽  
pp. 1-6 ◽  
Author(s):  
Deva S. Jeyaretna ◽  
Samuel D. Rabkin ◽  
Robert L. Martuza
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Peripheral Nerve ◽  
Insertional Mutagenesis ◽  
Dominant Negative ◽  
Oncolytic Viruses ◽  
Platelet Factor ◽  
Peripheral Nerve Sheath Tumors ◽  
Oncolytic Herpes Simplex Virus ◽  
Simplex Virus

✓Oncolytic viruses are one of many emerging cancer therapies. The surgical management of peripheral nerve tumors carries an inherent risk of damaging the nerves involved and so the search for novel therapies with reduced risk of morbidity continues. In this review the authors discuss the use of oncolytic herpes simplex virus (HSV) in the treatment of peripheral nerve tumors. Herpes simplex virus has a number of characteristics that make it a useful oncolytic vector, including its large, sequenced genome that can accommodate multiple transgenes, its lack of insertional mutagenesis, its ability to infect a wide array of cell types in various species, and the availability of well-established antiviral therapies to treat it. The efficacy of oncolytic HSV therapy against schwannomas and malignant peripheral nerve sheath tumors has been studied in multiple experimental models both in vitro and in vivo. The virus utilizes cell pathways unique to tumors to enhance its oncolytic efficacy, preferentially and effectively targeting and destroying peripheral nerve tumor cells without harming normal cells. This effect is augmented by trans-genes expressing antiangiogenic factors, such as dominant-negative fibroblast growth factor receptor and platelet factor 4, and displays synergy with chemotherapy. Different oncolytic HSV vectors have been tested, including hrR3, G207, and G47Δ. In addition, new animal models have been developed to test the efficacy of oncolytic HSV therapy in peripheral nerve tumors. The safety of oncolytic HSV is well-established and has been tested in nonhuman primates and in human clinical trials.

scholarly journals Replication and Spread of Oncolytic Herpes Simplex Virus in Solid Tumors

Viruses ◽  
2022 ◽  
Vol 14 (1) ◽  
pp. 118
Author(s):  
Bangxing Hong ◽  
Upasana Sahu ◽  
Matthew P. Mullarkey ◽  
Balveen Kaur
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Solid Tumors ◽  
Tumor Cells ◽  
Stromal Cells ◽  
Tumor Antigens ◽  
Oncolytic Herpes Simplex Virus ◽  
Promising Treatment ◽  
Simplex Virus ◽  
Insight Into

Oncolytic herpes simplex virus (oHSV) is a highly promising treatment for solid tumors. Intense research and development efforts have led to first-in-class approval for an oHSV for melanoma, but barriers to this promising therapy still exist that limit efficacy. The process of infection, replication and transmission of oHSV in solid tumors is key to obtaining a good lytic destruction of infected cancer cells to kill tumor cells and release tumor antigens that can prime anti-tumor efficacy. Intracellular tumor cell signaling and tumor stromal cells present multiple barriers that resist oHSV activity. Here, we provide a review focused on oncolytic HSV and the essential viral genes that allow for virus replication and spread in order to gain insight into how manipulation of these pathways can be exploited to potentiate oHSV infection and replication among tumor cells.

scholarly journals Plasma Amyloid-β in Relation to Antibodies Against Herpes Simplex Virus, Cytomegalovirus, and Chlamydophila pneumoniae

2021 ◽  
pp. 1-7
Author(s):  
Karin Lopatko Lindman ◽  
Bodil Weidung ◽  
Jan Olsson ◽  
Maria Josefsson ◽  
Anders Johansson ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Antimicrobial Properties ◽  
Amyloid Β ◽  
Chlamydophila Pneumoniae ◽  
Immunosorbent Assays ◽  
Simplex Virus ◽  
Ig G ◽  
Xmap Technology

Background: Amyloid-β (Aβ), the key constituent of Alzheimer’s disease (AD) plaques, has antimicrobial properties. Objective: To investigate the association between plasma Aβ and antibodies against the AD-related pathogens herpes simplex virus (HSV), cytomegalovirus (CMV), and C. pneumoniae. Methods: Plasma from 339 AD cases, obtained on average 9.4 years (±4.00) before diagnosis, and their matched controls were analyzed for Aβ40 and Aβ42 concentrations with Luminex xMAP technology and INNOBIA plasma Aβ-form assays. Enzyme-linked immunosorbent assays were utilized for analyses of anti-HSV immunoglobulin (Ig) G, anti-HSV1 IgG, anti-HSV2 IgG, anti-CMV IgG, and anti-C. pneumoniae IgG. Follow-up samples were available for 163 of the cases. Results: Presence and levels of anti-HSV1 IgG, anti-HSV2 IgG, anti-CMV IgG, and anti-C. pneumoniae IgG did not correlate with concentrations of Aβ42 or Aβ40 in cases or controls. Conclusion: Levels of plasma Aβ were not associated with antibodies against different AD-related Spathogens.

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