Summary
Purpose This open-labeled, phase I clinical trial was designed to determine the safety and tolerability of percutaneous intralesional administration of wild-type oncolytic revovirus type 3 Dearing (Reolysin®) in cancer patients with accessible and evaluable disease, who had otherwise failed to improve on standard cancer interventions. Experimental Design An escalating dose of Reolysin® starting from up to 1010 plague forming units (PFU) was administered to each cohort of three patients per dose level. Viral shedding, reovirus neutralizing antibody response, toxicity and clinical response were assessed. Results Nineteen patients with various advanced solid tumors were treated. The most common toxicities related to treatment were grade 2 (or less) local erythema and transient flu like symptoms. Viral shedding was not seen in cerebral spinal fluid (CSF), urine and stool samples in all patients. Rising viral antibody titres were seen in all patients. In addition, we observed some evidence of local target tumor response activity in 7/19 patients (37 %) at the end of six or more weeks follow-up, with one patient exhibiting a complete response (CR), two a partial response (PR), and four stable disease (SD) to the local injected lesion. Conclusions Reolysin® is well tolerated given intralesionaly, with DLT/MTD not reached at a dose of 1010 PFU. The favorable toxicity profile, lack of viral shedding and possible therapeutic activity has made this unattenuated oncolytic reovirus an attractive cancer therapeutic agent for ongoing clinical studies, including in the setting of locally advanced accessible disease for palliation of symptoms.
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Dock G (1904) Rabies virus vaccintion in a patient with cervical carcinoma. Amer J Med Sci 127:563
Deweese TL, Van Der Poel H, Li SD, Mikhak B, Drew R, Goemann M, Hamper U, Dejong R, Detorie N, Rodriguez R, Haulk T, Demarzo AM, Piantadosi S, Yu DC, Chen Y, Henderson DR, Carducci MA, Nelson WG, Simons JW (2001) A phase I trial of Cv706, a replication-competent, Psa selective oncolytic adenovirus, for the treatment of locally recurrent prostate cancer following radiation Therapy. Cancer Res 61:7464–7472
Pecora AL, Rizvi N, Cohen GI, Meropol NJ, Sterman D, Marshall JL, Goldberg S, Gross P, O’neil JD, Groene WS, Roberts MS, Rabin H, Bamat MK, Lorence RM (2002) Phase I trial of intravenous administration of Pv701, an oncolytic virus, in patients with advanced solid cancers. J Clin Oncol 20:2251–2266
Vasey PA, Shulman LN, Campos S, Davis J, Gore M, Johnston S, Kirn DH, O’neill V, Siddiqui N, Seiden MV, Kaye SB (2002) Phase I trial of intraperitoneal injection of the E1b-55-Kd-Gene—deleted adenovirus Onyx-015 (Dl1520) given on days 1 through 5 every 3 weeks in patients with recurrent/refractory epithelial ovarian cancer. J Clin Oncol 20:1562–1569
Chiocca EA, Abbed KM, Tatter S, Louis DN, Hochberg FH, Barker F, Kracher J, Grossman SA, Fisher JD, Carson K, Rosenblum M, Mikkelsen T, Olson J, Markert J, Rosenfeld S, Nabors LB, Brem S, Phuphanich S, Freeman S, Kaplan R, Zwiebel J (2004) A phase I open-label, dose-escalation, multi-institutional trial of injection with an E1b-attenuated adenovirus, Onyx-015, into the peritumoral region of recurrent malignant gliomas, in the adjuvant setting. Mol Ther 10:958–966
Reid TR, Freeman S, Post L, Mccormick F, Sze DY (2005) Effects of Onyx-015 among metastatic colorectal cancer patients that have failed prior treatment with 5-Fu/Leucovorin. Cancer Gene Therapy 12:673–681
Freeman AI, Zakay-Rones Z, Gomori JM, Linetsky E, Rasooly L, Greenbaum E, Rozenman-Yair S, Panet A, Libson E, Irving CS, Galun E, Siegal T (2006) Phase I/Ii trial of intravenous Ndv-huj oncolytic virus in recurrent glioblastoma multiforme. Mol Ther 13:221–228
Laurie SA, Bell JC, Atkins HL, Roach J, Bamat MK, O’neil JD, Roberts MS, Groene WS, Lorence RM (2006) A phase I clinical study of intravenous administration of Pv701, an oncolytic virus, using two-step desensitization. Clin Cancer Res 12:2555–2562
Sonpavde G, Thompson TC, Jain RK, Ayala GE, Kurosaka S, Edamura K, Tabata KI, Ren CZ, Goltsov AA, Mims MP, Hayes TG, Ittmann MM, Wheeler TM, Gee A, Miles BJ, Kadmon D (2011) Glipr1 tumor suppressor gene expressed by adenoviral vector as Neoadjuvant Intraprostatic injection for localized intermediate or high-risk prostate cancer preceding radical prostatectomy. Clin Cancer Res 17:7174–7182
Hwang TH, Moon A, Burke J, Ribas A, Stephenson J, Breitbach CJ, Daneshmand M, De Silva N, Parato K, Diallo JS, Lee YS, Liu TC, Bell JC, Kirn DH (2011) A mechanistic proof-of-concept clinical trial with Jx-594, a targeted multi-mechanistic Oncolytic Poxvirus, in patients with metastatic melanoma. Mol Ther 19:1913–1922
Nakao A, Kasuya H, Sahin TT, Nomura N, Kanzaki A, Misawa M, Shirota T, Yamada S, Fujii T, Sugimoto H, Shikano T, Nomoto S, Takeda S, Kodera Y, Nishiyama Y (2011) A phase I dose-escalation clinical trial of Intraoperative direct Intratumoral injection of Hf10 Oncolytic virus in non-resectable patients with advanced pancreatic cancer. Cancer Gene Therapy 18:167–175
Parato KA, Senger D, Forsyth PAJ, Bell JC (2005) Recent progress in the battle between oncolytic viruses and tumours. Nat Rev Cancer 5:965–976
Rosen L, Spickard A, Evans HE (1963) Reovirus infections in human volunteers. American Journal Hygiene 77:29
Jackson GG, Muldoon RL (1973) Viruses causing common respiratory-infection in Man.4. Reoviruses and adenoviruses. J Infect Dis 128:811–866
Coffey MC, Strong JE, Forsyth PA, Lee PWK (1998) Reovirus therapy of tumors with activated ras pathway. Science 282:1332–1334
Bos JL (1989) Ras oncogenes in human cancer—a review. Cancer Res 49:4682–4689
Kelly K, Nawrocki S, Mita A, Coffey M, Giles FJ, Mita M (2009) Reovirus-based therapy for cancer. Expert Opin Biol Ther 9:817–830
Strong JE, Lee PWK (1996) The V-Erbb Oncogene confers enhanced cellular susceptibility to reovirus infection. J Virol 70:612–616
Strong JE, Coffey MC, Tang D, Sabinin P, Lee PWK (1998) The molecular basis of viral oncolysis: Usurpation of the ras signaling pathway by reovirus. EMBO J 17:3351–3362
Marcato P, Shmulevitz M, Pan D, Stoltz D, Lee PWK (2007) Ras transformation mediates reovirus oncolysis by enhancing virus uncoating, particle infectivity, and apoptosis-dependent release. Mol Ther 15:1522–1530
Clarke P, Meintzer SM, Wang YB, Moffitt LA, Richardson-Burns SM, Johnson GL, Tyler KL (2004) Jnk regulates the release of proapoptotic mitochondrial factors in reovirus-infected cells. J Virol 78:13132–13138
Connolly JL, Rodgers SE, Clarke P, Ballard DW, Kerr LD, Tyler KL, Dermody TS (2000) Reovirus-induced apoptosis requires activation of transcription factor Nf-Kappa B. J Virol 74:2981–2989
Alain T, Hirasawa K, Pon KJ, Nishikawa SG, Urbanski SJ, Auer Y, Luider J, Martin A, Johnston RN, Janowska-Wieczorek A, Lee PWK, Kossakowska AE (2002) Reovirus therapy of lymphoid malignancies. Blood 100:4146–4153
Hanel EG, Xiao ZW, Wong KK, Lee PWK, Britten RA, Moore RB (2004) A novel intravesical therapy for superficial bladder cancer in an orthotopic model: Oncolytic reovirus therapy. J Urol 172:2018–2022
Hirasawa K, Nishikawa SG, Norman KL, Alain T, Kossakowska A, Lee PWK (2002) Oncolytic reovirus against ovarian and colon cancer. Cancer Res 62:1696–1701
Norman KL, Coffey MC, Hirasawa K, Demetrick DJ, Nishikawa SG, Difrancesco LM, Strong JE, Lee PWK (2002) Reovirus oncolysis of human breast cancer. Human Gene Therapy 13:641–652
Wilcox ME, Yang WQ, Senger D, Rewcastle NB, Morris DG, Brasher PMA, Shi ZQ, Johnston RN, Nishikawa S, Lee PWK, Forsyth PA (2001) Reovirus as an oncolytic agent against experimental human malignant gliomas. Journal National Cancer Institute 93:903–912
Vidal L, Pandha HS, Yap TA, White CL, Twigger K, Vile RG, Melcher A, Coffey M, Harrington KJ, Debono JS (2008) A phase I study of intravenous oncolytic reovirus type 3 dearing in patients with advanced cancer. Clin Cancer Res 14:7127–7137
Gollamudi R, Ghalib MH, Desai KK, Chaudhary I, Wong B, Einstein M, Coffey M, Gill GM, Mettinger K, Mariadason JM, Mani S, Goel S (2010) Intravenous administration of reolysina (R), A live replication competent Rna virus is safe in patients with advanced solid tumors. Investigational New Drugs 28:641–649
Galanis E, Markovic SN, Suman V, Nuovo G, Vile R, Coffey M, Linette G, Maples W, Zwiebel J, Kendra K (2011) Phase II trial of intravenous administration of Reolysin (Reovirus Serotype-3-Dearing Strain) in patients with metastatic melanoma. Mol Ther 19:1375
Comins C, Spicer J, Protheroe A, Roulstone V, Twigger K, White CM, Vile R, Melcher A, Coffey MC, Mettinger KL, Nuovo G, Cohn DE, Phelps M, Harrington KJ, Pandha HS (2010) Reo-10: A Phase I study of intravenous reovirus and docetaxel in patients with advanced cancer. Clin Cancer Res 16:5564–5572
Karapanagiotou E, Pandha HS, Hall G, Chester J, Melcher A, Coffey M, De Bono J, Gore Me, Nutting CM, Harrington KJ (2009) Phase I/Ii trial of oncolytic reovirus (Reolysin) in combination with Carboplatin/Paclitaxel in patients (Pts) with advanced solid cancers. J Clinical Oncology 27
Lolkema MP, Arkenau HT, Harrington K, Roxburgh P, Morrison R, Roulstone V, Twigger K, Coffey M, Mettinger K, Gill G, Evans TRJ, De Bono JS (2011) A phase I study of the combination of intravenous reovirus type 3 dearing and gemcitabine in patients with advanced cancer. Clin Cancer Res 17:581–588
Forsyth P, Roldan G, George D, Wallace C, Palmer CA, Morris D, Cairncross G, Matthews MV, Markert J, Gillespie Y, Coffey M, Thompson B, Hamilton M (2008) A phase I trial of intratumoral administration of reovirus in patients with histologically confirmed recurrent malignant gliomas. Mol Ther 16:627–632
Harrington KJ, Karapanagiotou EM, Roulstone V, Twigger KR, White CL, Vidal L, Beirne D, Prestwich R, Newbold K, Ahmed M, Thway K, Nutting CM, Coffey M, Harris D, Vile RG, Pandha HS, Debono JS, Melcher AA (2010) Two-stage phase I Dose-escalation study of intratumoral reovirus type 3 dearing and palliative radiotherapy in patients with advanced cancers. Clin Cancer Res 16:3067–3077
Clayman GL, El Naggar AK, Lippman SM, Henderson YC, Frederick M, Merritt JA, Zumstein LA, Timmons TM, Liu TJ, Ginsberg L, Roth JA, Hong WK, Bruso P, Goepfert H (1998) Adenovirus-mediated P53 gene transfer in patients with advanced recurrent head and neck squamous cell carcinoma. J Clin Oncol 16:2221–2232
Fujiwara T, Grimm EA, Mukhopadhyay T, Zhang WW, Owenschaub LB, Roth JA (1994) Induction of chemosensitivity in human lung-cancer cells in-vivo by adenovirus-mediated transfer of the wild-type P53 gene. Cancer Res 54:2287–2291
Nguyen DM, Spitz FR, Yen N, Cristiano RJ, Roth JA (1996) Gene therapy for lung cancer: enhancement of tumor suppression by a combination of sequential systemic cisplatin and adenovirus-mediated P53 gene transfer. J Thorac Cardiovasc Surg 112:1372–1376
Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, Van Oosterom AT, Christian MC, Gwyther SG (2000) New guidelines to evaluate the response to treatment in solid tumors. Journal National Cancer Institute 92:205–216
White CL, Twigger KR, Vidal L, De Bono JS, Coffey M, Heinemann L, Morgan R, Merrick A, Errington F, Vile RG, Melcher AA, Pandha HS, Harrington KJ (2008) Characterization of the adaptive and innate immune response to intravenous oncolytic reovirus (Dearing Type 3) during a phase i clinical trial. Gene Therapy 15:911–920
Qiao J, Wang HX, Kottke T, White C, Twigger K, Diaz RM, Thompson J, Selby P, De Bono J, Melcher A, Pandha H, Coffey M, Vile R, Harrington K (2008) Cyclophosphamide facilitates antitumor efficacy against subcutaneous tumors following intravenous delivery of reovirus. Clin Cancer Res 14:259–269
Acknowledgements
We thank all our participating patients, our research nurses and coordinators in TBCC. This work is funded by Oncolytics Biotech Inc. and Alberta Cancer Board.
Disclosure of potential conflicts of interest
M. Coffey and B. Thompson are employed by Oncolytics Biotech Inc and they both have an ownership interest in that company; D. Morris and P. Forsyth has received research grants from Oncolytics Biotech Inc.
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Morris, D.G., Feng, X., DiFrancesco, L.M. et al. REO-001: A phase I trial of percutaneous intralesional administration of reovirus type 3 dearing (Reolysin®) in patients with advanced solid tumors. Invest New Drugs 31, 696–706 (2013). https://doi.org/10.1007/s10637-012-9865-z
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DOI: https://doi.org/10.1007/s10637-012-9865-z