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Effect of prior exposure to herpes simplex virus 1 on viral vector-mediated tumor therapy in immunocompetent mice
1Molecular Neurosurgery Laboratory, Department of Neurosurgery, Georgetown University Medical School, Washington DC 20007, USA.
Abstract:
Replication-competent, attenuated mutants of herpes simplex virus type 1 (HSV-1) have been shown to be efficacious for tumor therapy. However, these studies did not address the consequences of prior exposure to HSV, as will be the case with many patients likely to receive this therapy. Two strains of mice, A/J and BALB/c, were infected with wild-type HSV-1 by intraperitoneal injection and the immune response was determined by plaque reduction assay for neutralizing antibody and ELISA for IgG and IgM. Syngeneic tumors, N18 neuroblastoma and CT26 colon carcinoma, were implanted subcutaneously in HSV-1 seropositive and naive A/J and BALB/c mice, respectively. Established tumors were subsequently treated intratumorally with a multi-mutated HSV-1, G207. G207 inhibited tumor growth to a similar extent whether the mice were seropositive or not. We next examined the effect of multiple intratumoral inoculations of a 10-fold lower dose of G207 on tumor growth. In the multiple treatment group (biweekly for 3 weeks), 75% of tumors were cured, whereas no cures were seen in the single treatment group. We conclude that HSV seropositivity should not deleteriously affect the efficacy of G207 tumor therapy, and multiple inoculations of virus should be considered for clinical evaluation.
Insights
Prior herpes simplex virus (HSV) exposure does not hinder G207 oncolytic virus therapy. Multiple G207 treatments significantly improved tumor cure rates in mice, suggesting potential for enhanced cancer treatment.
Area of Science:
- Oncolytic virotherapy
- Immunology
- Cancer research
Background:
- Replication-competent, attenuated herpes simplex virus type 1 (HSV-1) mutants show promise for tumor therapy.
- The impact of pre-existing anti-HSV immunity on oncolytic virus efficacy remains largely unaddressed.
Purpose of the Study:
- To investigate the effect of prior HSV-1 exposure on the efficacy of G207, a multi-mutated HSV-1 oncolytic virus.
- To evaluate the impact of single versus multiple intratumoral G207 inoculations on tumor growth and cure rates.
Main Methods:
- Mice (A/J and BALB/c) were infected with wild-type HSV-1 to establish seropositivity.
- Neutralizing antibody titers (plaque reduction assay) and specific IgG/IgM levels (ELISA) were measured.
- Syngeneic neuroblastoma (N18) and colon carcinoma (CT26) tumors were implanted in seropositive and naive mice.
- Tumors were treated intratumorally with either a single dose or multiple biweekly doses of G207.
Main Results:
- G207 demonstrated similar tumor growth inhibition in both HSV-1 seropositive and naive mice after a single treatment.
- Multiple intratumoral G207 inoculations (biweekly for 3 weeks) resulted in a 75% cure rate.
- No cures were observed in the single-treatment group, irrespective of HSV serostatus.
Conclusions:
- Pre-existing immunity to HSV-1 does not appear to negatively impact the efficacy of G207 oncolytic virus therapy.
- Multiple administrations of G207 significantly enhance tumor eradication compared to single treatments.
- Further clinical evaluation of multiple G207 inoculations is warranted for optimizing cancer therapy.
