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Clinical Trial
. 2016 Jun;27(2):69-78.
doi: 10.1089/humc.2016.031.

Design of a Phase I Clinical Trial to Evaluate M032, a Genetically Engineered HSV-1 Expressing IL-12, in Patients with Recurrent/Progressive Glioblastoma Multiforme, Anaplastic Astrocytoma, or Gliosarcoma

Daxa M Patel  1 , Paul M Foreman  1 , L Burt Nabors  2 , Kristen O Riley  1 , G Yancey Gillespie  1 , James M Markert  1
Affiliations
Clinical Trial

Design of a Phase I Clinical Trial to Evaluate M032, a Genetically Engineered HSV-1 Expressing IL-12, in Patients with Recurrent/Progressive Glioblastoma Multiforme, Anaplastic Astrocytoma, or Gliosarcoma

Daxa M Patel et al. Hum Gene Ther Clin Dev. 2016 Jun.

Abstract

M032 is a second-generation oncolytic herpes simplex virus (oHSV) that selectively replicates in tumor cells. M032 kills tumor cells directly through oncolytic replication and then proceeds to infect tumor cells in proximity, continuing the process of tumor destruction. In addition to this direct oncolytic activity, the virus carries a therapeutic payload-thus acting as a gene therapy vector-and causes the tumor cell to synthesize and secrete the immunity-stimulating protein interleukin-12 (IL-12) before cell death. (1) Human IL-12 is expressed and promotes an immune response against surviving tumor cells, increasing the antitumor effect of the therapy. IL-12 also produces an antiangiogenic effect, by interfering with the production of new tumor blood vessels necessary for tumor growth. Thus, M032 oHSV exerts antitumor effects through three distinct potential mechanisms. The virus has also been genetically engineered to minimize toxic effects for the patient. Preclinical animal models support the safety of intracranial inoculation with M032 in two relevant species (mouse and nonhuman primate). This clinical protocol outlines the dose-escalating phase I study for evaluation of M032 in patients with recurrent or progressive malignant glioma.

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Figures

<b>Figure 1.</b>
Figure 1.
Schematic representation of mIL-12-expressing HSV (M002). Line 1 illustrates the HSV-1 (F) Δ305 genome, which contains a 700 bp deletion within the tk gene, as indicated by the Δ symbol. UL and US represent the unique long and unique short sequences, respectively. The inverted repeat sequences are indicated by a, b, and c, with subscripts n and m representing variable numbers of a sequences. a1 and as represent the a sequences flanking the UL and US terminal repeats. Line 2 shows the sequence arrangement of the recombinant HSV R3659. The BstEII–StuI fragment within the γ134.5 gene was replaced by the chimeric α27-tk gene in the inverted sequences ab (shown above) and b′a′ (not shown) flanking the UL sequence. Line 3 shows the sequence arrangements of the relevant regions in the recombinant mIL-12-expressing HSV M001 (tk−) or M002 (tk+). NcoI restriction sites are indicated. (Copyright [2000] National Academy of Sciences, U.S.A. Reproduced with permission from PNAS [Parker et al.]).
<b>Figure 2.</b>
Figure 2.
Immunocompetent C57BL/6xDBA/2 F1 hybrid mice were injected intracranially with 4C8 mouse glioma cells, followed in 7 days by saline or the viruses shown. Median survivals were determined by Kaplan–Meier plots and are shown on the figure. Log rank analyses of these survival values confirmed the significantly prolonged survival-afforded mice treated with M002, compared with R3659 (p = 0.00007) or G207 (p = 0.0003). In addition, about 20% of the M002-treated mice were apparently “cured” with no evidence of remaining 4C8 glioma cells histologically when the experiment was terminated. (Reproduced with permission from Oxford University Press [Hellums et al.]).
<b>Figure 3.</b>
Figure 3.
Immunocompetent BALB/c mice were injected subcutaneously with 1 × 105 neuro-2A cells. When tumors attained 200 mm3 in volume, they were injected with 50 liters of saline or 5 × 107 PFU of HSV R3659 or M002. Tumor volumes were measured every 3 days, and the average percentage increase in volume was calculated relative to the treatment date.
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References

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