Phase 1 Study of Intravenous Oncolytic Poxvirus (vvDD) in Patients With Advanced Solid Cancers

Overview

Journal Mol Ther

Publisher Cell Press

Specialties Molecular Biology
Pharmacology

Date 2016 May 21

PMID 27203445

Citations 86

Authors

Stephanie Downs-Canner

Zong Sheng Guo

Roshni Ravindranathan

Caroline J Breitbach

Mark E OMalley

Heather L Jones

Anne Moon

Judith Andrea McCart

Yongli Shuai

Herbert J Zeh

David L Bartlett

Affiliations

Soon will be listed here.

Abstract

We have conducted a phase 1 study of intravenous vvDD, a Western Reserve strain oncolytic vaccinia virus, on 11 patients with standard treatment-refractory advanced colorectal or other solid cancers. The primary endpoints were maximum tolerated dose and associated toxicity while secondary endpoints were pharmacokinetics, pharmacodynamics, immune responses, and antitumor activity. No dose-limiting toxicities and treatment related severe adverse events were observed. The most common adverse events were grades 1/2 flu-like symptoms. Virus genomes were detectable in the blood 15-30 minutes after virus administration in a dose-dependent manner. There was evidence of a prolonged virus replication in tumor tissues in two patients, but no evidence of virus replication in non-tumor tissues, except a healed injury site and an oral thrush. Over 100-fold of anti-viral antibodies were induced in patients' sera. A strong induction of inflammatory and Th1, but not Th2 cytokines, suggested a potent Th1-mediated immunity against the virus and possibly the cancer. One patient showed a mixed response on PET-CT with resolution of some liver metastases, and another patient with cutaneous melanoma demonstrated clinical regression of some lesions. Given the confirmed safety, further trials evaluating intravenous vvDD in combination with therapeutic transgenes, immune checkpoint blockade or complement inhibitors, are warranted.

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References

Kaufman H, Kohlhapp F, Zloza A . Oncolytic viruses: a new class of immunotherapy drugs. Nat Rev Drug Discov. 2015; 14(9):642-62. PMC: 7097180. DOI: 10.1038/nrd4663. View

Rajani K, Parrish C, Kottke T, Thompson J, Zaidi S, Ilett L . Combination Therapy With Reovirus and Anti-PD-1 Blockade Controls Tumor Growth Through Innate and Adaptive Immune Responses. Mol Ther. 2015; 24(1):166-74. PMC: 4754544. DOI: 10.1038/mt.2015.156. View

Zamarin D, Holmgaard R, Subudhi S, Park J, Mansour M, Palese P . Localized oncolytic virotherapy overcomes systemic tumor resistance to immune checkpoint blockade immunotherapy. Sci Transl Med. 2014; 6(226):226ra32. PMC: 4106918. DOI: 10.1126/scitranslmed.3008095. View

Cripe T, Ngo M, Geller J, Louis C, Currier M, Racadio J . Phase 1 study of intratumoral Pexa-Vec (JX-594), an oncolytic and immunotherapeutic vaccinia virus, in pediatric cancer patients. Mol Ther. 2014; 23(3):602-8. PMC: 4351466. DOI: 10.1038/mt.2014.243. View

Lichty B, Breitbach C, Stojdl D, Bell J . Going viral with cancer immunotherapy. Nat Rev Cancer. 2014; 14(8):559-67. DOI: 10.1038/nrc3770. View

Freeman A, Zakay-Rones Z, Gomori J, Linetsky E, Rasooly L, Greenbaum E . Phase I/II trial of intravenous NDV-HUJ oncolytic virus in recurrent glioblastoma multiforme. Mol Ther. 2005; 13(1):221-8. DOI: 10.1016/j.ymthe.2005.08.016. View

Ganly I, Kirn D, Eckhardt G, Rodriguez G, Soutar D, Otto R . A phase I study of Onyx-015, an E1B attenuated adenovirus, administered intratumorally to patients with recurrent head and neck cancer. Clin Cancer Res. 2000; 6(3):798-806. View

Evgin L, Acuna S, de Souza C, Marguerie M, Lemay C, Ilkow C . Complement inhibition prevents oncolytic vaccinia virus neutralization in immune humans and cynomolgus macaques. Mol Ther. 2015; 23(6):1066-1076. PMC: 4817751. DOI: 10.1038/mt.2015.49. View

Chalikonda S, Kivlen M, OMalley M, Eric Dong X, McCart J, Gorry M . Oncolytic virotherapy for ovarian carcinomatosis using a replication-selective vaccinia virus armed with a yeast cytosine deaminase gene. Cancer Gene Ther. 2007; 15(2):115-25. PMC: 2975702. DOI: 10.1038/sj.cgt.7701110. View

10.

Francis L, Guo Z, Liu Z, Ravindranathan R, Urban J, Sathaiah M . Modulation of chemokines in the tumor microenvironment enhances oncolytic virotherapy for colorectal cancer. Oncotarget. 2016; 7(16):22174-85. PMC: 5008353. DOI: 10.18632/oncotarget.7907. View

11.

Guo Z, Parimi V, OMalley M, Thirunavukarasu P, Sathaiah M, Austin F . The combination of immunosuppression and carrier cells significantly enhances the efficacy of oncolytic poxvirus in the pre-immunized host. Gene Ther. 2010; 17(12):1465-75. PMC: 2982886. DOI: 10.1038/gt.2010.104. View

12.

Kim M, Breitbach C, Moon A, Heo J, Lee Y, Cho M . Oncolytic and immunotherapeutic vaccinia induces antibody-mediated complement-dependent cancer cell lysis in humans. Sci Transl Med. 2013; 5(185):185ra63. DOI: 10.1126/scitranslmed.3005361. View

13.

McCart J, Ward J, Lee J, Hu Y, Alexander H, Libutti S . Systemic cancer therapy with a tumor-selective vaccinia virus mutant lacking thymidine kinase and vaccinia growth factor genes. Cancer Res. 2001; 61(24):8751-7. View

14.

Liu Z, Ravindranathan R, Li J, Kalinski P, Guo Z, Bartlett D . CXCL11-Armed oncolytic poxvirus elicits potent antitumor immunity and shows enhanced therapeutic efficacy. Oncoimmunology. 2016; 5(3):e1091554. PMC: 4839379. DOI: 10.1080/2162402X.2015.1091554. View

15.

Parato K, Breitbach C, Le Boeuf F, Wang J, Storbeck C, Ilkow C . The oncolytic poxvirus JX-594 selectively replicates in and destroys cancer cells driven by genetic pathways commonly activated in cancers. Mol Ther. 2011; 20(4):749-58. PMC: 3321594. DOI: 10.1038/mt.2011.276. View

16.

Nishimura C, Nomura M, Kitaoka M, Takeuchi Y, Kimura M . Complement requirement of the neutralizing antibody appearing after immunization with smallpox vaccine. Jpn J Microbiol. 1968; 12(2):256-9. DOI: 10.1111/j.1348-0421.1968.tb00393.x. View

17.

Kemeny N, Brown K, Covey A, Kim T, Bhargava A, Brody L . Phase I, open-label, dose-escalating study of a genetically engineered herpes simplex virus, NV1020, in subjects with metastatic colorectal carcinoma to the liver. Hum Gene Ther. 2006; 17(12):1214-24. DOI: 10.1089/hum.2006.17.1214. View

18.

Naik A, Chalikonda S, McCart J, Xu H, Guo Z, Langham G . Intravenous and isolated limb perfusion delivery of wild type and a tumor-selective replicating mutant vaccinia virus in nonhuman primates. Hum Gene Ther. 2006; 17(1):31-45. DOI: 10.1089/hum.2006.17.31. View

19.

Small E, Carducci M, Burke J, Rodriguez R, Fong L, van Ummersen L . A phase I trial of intravenous CG7870, a replication-selective, prostate-specific antigen-targeted oncolytic adenovirus, for the treatment of hormone-refractory, metastatic prostate cancer. Mol Ther. 2006; 14(1):107-17. DOI: 10.1016/j.ymthe.2006.02.011. View

20.

Pecora A, Rizvi N, Cohen G, Meropol N, Sterman D, Marshall J . Phase I trial of intravenous administration of PV701, an oncolytic virus, in patients with advanced solid cancers. J Clin Oncol. 2002; 20(9):2251-66. DOI: 10.1200/JCO.2002.08.042. View