Herpes simplex virus oncolytic therapy for pediatric malignancies

Abstract

Despite improving survival rates for children with cancer, a subset of patients exist with disease resistant to traditional therapies such as surgery, chemotherapy, and radiation. These patients require newer, targeted treatments used alone or in combination with more traditional approaches. Oncolytic herpes simplex virus (HSV) is one of these newer therapies that offer promise for several difficult to treat pediatric malignancies. The potential benefit of HSV therapy in pediatric solid tumors including brain tumors, neuroblastomas, and sarcomas is reviewed along with the many challenges that need to be addressed prior to moving oncolytic HSV therapy from the laboratory to the beside in the pediatric population.

Figure 1

Schematic representation of the derivation of G207 HSV. Chou et al. deleted both copies of the γ₁34.5 gene from HSV strain F, a temperature-sensitive clinical isolate (HSV-1(F)) to create recombinant virus R3616.¹¹ Only one of the two deletions is shown for simplicity. This deletion ablated the ability of the virus to overcome interferon resistance in normal cells and made the virus aneurovirulent. Mineta et al.¹² modified R3616 by inserting the Escherichia coli β-galactosidase gene (lacZ) to produce a functional deletion of the HSV U_L39 gene, which encodes the heavy chain or ribonucleotide reductase (infected cell protein 6—ICP6), as described by Goldstein and Weller.¹³⁷ This second disabling deletion was performed to ensure added safety for intracerebral human trials.⁷

Figure 2

Schematic representation of the derivation of 1716 HSV. In clinical isolate strain 17+ HSV, a 759 bp deletion was produced that extended from the DR₁/Ub boundary in the “a” sequence to remove 105 bp on the 5′ end of the R_L open reading frame.¹³ This deletion was produced in both long-repeat regions (terminal repeat-long, inverted repeat-long) of the HSV genome, but only the deletion for the TR_L is shown for simplicity. The strain 17+ HSV had a LD₅₀ of <10 PFU, whereas the 1716 mutant was significantly neuroattenuated with a LD₅₀ of 7 × 10⁶ PFU.

Figure 3

Schematic representation of the derivation of R7020 (aka NV1020). This virus was constructed for the purpose of creating a vaccine for HSV-1 and HSV-2 that would be administered by intramuscular injection of living virus.¹³⁸ HSV-1(F) was initially deleted for thymidine kinase (U_L23) and U_L24. The internal set of the inverted repeats, containing α0, α4, γ₁34.5, ORF O, and ORF P, was replaced with a novel construct that contained U_L23 fused to the α4 promoter-regulatory region and 3′ to a series of HSV-2 genes (U_S2, HSV protein kinase, U_S5, glycoproteins G, D, and I, as well as a portion of E). The terminal inverted repeat remained intact. Thus, this chimeric virus, containing both HSV-1 and HSV-2 sequences, has been extensively tested in both rodent and primate species for safety (LD₅₀ = 2.7 × 10⁶ PFU versus 3.8 × 10² PFU for HSV-1(F)) and genetic stability.^138,139