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
Restricted accessResearch articleFirst published online June, 2016
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
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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References
1.
ClinicalTrials.gov.. Genetically Engineered HSV-1 Phase 1 Study (M032-HSV-1). U.S. National Institutes of Health, 2014.
2.
AndreanskySS, HeB, GillespieGY, et al.The application of genetically engineered herpes simplex viruses to the treatment of experimental brain tumors. Proc Natl Acad Sci U S A, 1996; 93:11313–11318.
3.
LevineA. Principles and Practice of Oncology. (Lippincott Williams and Wilkins, New York). 1989.
4.
ParkerJN, BauerDF, CodyJJ, et al.Oncolytic viral therapy of malignant glioma. Neurotherapeutics, 2009; 6:558–569.
5.
FriedmanGK, PresseyJG, ReddyAT, et al.Herpes simplex virus oncolytic therapy for pediatric malignancies. Mol Ther, 2009; 17:1125–1135.
6.
MarkertJM, ParkerJN, BuchsbaumDJ, et al.Oncolytic HSV-1 for the treatment of brain tumours. Herpes, 2006; 13:66–71.
7.
ShahAC, BenosD, GillespieGY, et al.Oncolytic viruses: Clinical applications as vectors for the treatment of malignant gliomas. J Neurooncol, 2003; 65:203–226.
8.
ChouJ, KernER, WhitleyRJ, et al.Mapping of herpes simplex virus-1 neurovirulence to gamma 134.5, a gene nonessential for growth in culture. Science, 1990; 250:1262–1266.
9.
ChouJ, RoizmanB. The gamma 1(34.5) gene of herpes simplex virus 1 precludes neuroblastoma cells from triggering total shutoff of protein synthesis characteristic of programed cell death in neuronal cells. Proc Natl Acad Sci U S A, 1992; 89:3266–3270.
10.
MarkertJM, MedlockMD, RabkinSD, et al.Conditionally replicating herpes simplex virus mutant, G207 for the treatment of malignant glioma: Results of a phase I trial. Gene Ther, 2000; 7:867–874.
11.
HellumsEK, MarkertJM, ParkerJN, et al.Increased efficacy of an interleukin-12-secreting herpes simplex virus in a syngeneic intracranial murine glioma model. Neuro Oncol, 2005; 7:213–224.
12.
ParkerJN, GillespieGY, LoveCE, et al.Engineered herpes simplex virus expressing IL-12 in the treatment of experimental murine brain tumors. Proc Natl Acad Sci U S A, 2000; 97:2208–2213.
13.
ParkerJN, MelethS, HughesKB, et al.Enhanced inhibition of syngeneic murine tumors by combinatorial therapy with genetically engineered HSV-1 expressing CCL2 and IL-12. Cancer Gene Ther, 2005; 12:359–368.
14.
CarusoM, Pham-NguyenK, KwongYL, et al.Adenovirus-mediated interleukin-12 gene therapy for metastatic colon carcinoma. Proc Natl Acad Sci U S A, 1996; 93:11302–11306.
15.
ChuaAO, ChizzoniteR, DesaiBB, et al.Expression cloning of a human IL-12 receptor component. A new member of the cytokine receptor superfamily with strong homology to gp130. J Immunol, 1994; 153:128–136.
16.
TodaM, MartuzaRL, KojimaH, et al.In situ cancer vaccination: An IL-12 defective vector/replication-competent herpes simplex virus combination induces local and systemic antitumor activity. J Immunol, 1998; 160:4457–4464.
17.
BramsonJL, HittM, AddisonCL, et al.Direct intratumoral injection of an adenovirus expressing interleukin-12 induces regression and long-lasting immunity that is associated with highly localized expression of interleukin-12. Hum Gene Ther, 1996; 7:1995–2002.
18.
WuCY, DemeureC, KiniwaM, et al.IL-12 induces the production of IFN-gamma by neonatal human CD4 T cells. J Immunol, 1993; 151:1938–1949.
19.
GatelyMK, DesaiBB, WolitzkyAG, et al.Regulation of human lymphocyte proliferation by a heterodimeric cytokine, IL-12 (cytotoxic lymphocyte maturation factor). J Immunol, 1991; 147:874–882.
20.
ManettiR, ParronchiP, GiudiziMG, et al.Natural killer cell stimulatory factor (interleukin 12 [IL-12]) induces T helper type 1 (Th1)-specific immune responses and inhibits the development of IL-4-producing Th cells. J Exp Med, 1993; 177:1199–1204.
21.
VoestEE, KenyonBM, O'ReillyMS, et al.Inhibition of angiogenesis in vivo by interleukin 12. J Natl Cancer Inst, 1995; 87:581–586.
22.
Asselin-PaturelC, LassauN, GuinebretiereJM, et al.Transfer of the murine interleukin-12 gene in vivo by a Semliki Forest virus vector induces B16 tumor regression through inhibition of tumor blood vessel formation monitored by Doppler ultrasonography. Gene Ther, 1999; 6:606–615.
23.
KikuchiT, JokiT, AkasakiY, et al.Antitumor activity of interleukin 12 against interleukin 2-transduced mouse glioma cells. Cancer Lett, 1999; 135:47–51.
24.
MikamiT, KurisuK, KiyaK, et al.Antitumor effect of recombinant human lymphotoxin on a tumor line of human malignant glioma. Hiroshima J Med Sci, 1989; 38:103–107.
25.
MarkertJM, CodyJJ, ParkerJN, et al.Preclinical evaluation of a genetically engineered herpes simplex virus expressing interleukin-12. J Virol, 2012; 86:5304–5313.
26.
RothJC, CassadyKA, CodyJJ, et al.Evaluation of the safety and biodistribution of M032, an attenuated herpes simplex virus type 1 expressing hIL-12, after intracerebral administration to aotus nonhuman primates. Hum Gene Ther Clin Dev, 2014; 25:16–27.
27.
MarkertJM, LiechtyPG, WangW, et al.Phase Ib trial of mutant herpes simplex virus G207 inoculated pre-and post-tumor resection for recurrent GBM. Mol Ther, 2009; 17:199–207.
28.
MarkertJM, RazdanSN, KuoHC, et al.A phase 1 trial of oncolytic HSV-1, G207, given in combination with radiation for recurrent GBM demonstrates safety and radiographic responses. Mol Ther, 2014; 22:1048–1055.
29.
StorerBE. Design and analysis of phase I clinical trials. Biometrics, 1989; 45:925–937.
