Reovirus, adyuvante en células neoplásicas Ras-activadas y refractarias al tratamiento

Juan Ruiz-Cabezas, Angel Ricardo Rivera-Castro

Resumen


Los reovirus son relevantes en la terapia oncológica actual gracias a su capacidad lítica en células Ras-activadas. Se revisaron documentos expuestos en las reuniones de ASCO y Oncolytics, así como publicaciones disponibles en la base de datos de Clinical Cancer Research. Estudios preclínicos han revelado la asociación de Ras-GTP a tumores humanos, y la susceptibilidad de células neoplásicas in vitro, in vivo y ex vivo. Tres ensayos clínicos de Fase II demostraron la seguridad, eficacia y tolerabilidad en el uso de Reovirus. La combinación Reovirus-radioterapia, a bajas y altas dosis, aumenta sinérgicamente la citotoxicidad en tumores metastásicos con un control de la enfermedad del 93%. La combinación Reolysin-Paclitaxel-Carboplatino en cáncer de cabeza y cuello ha justificado el avance a Fase III. Debido a la elevada tasa de mortalidad relacionada a metástasis, la biodisponibilidad de Reovirus vía intravenosa debe ser mejorada a través del preacondicionamiento del huésped inmunocompetente con depleción Treg.

Palabras clave: Adyuvante; Células Ras-activadas; Reolysin; Reovirus

 

Reovirus, adjuvant in ras-activated neoplastic cells and treatment-refractory

ABSTRACT

Reoviruses are relevant in current cancer therapy through its lytic capacity in Ras-activated cells. We reviewed scientific material presented in the meetings of ASCO and Oncolytics, as well as publications available in the Clinical Cancer Research database. Preclinical studies have revealed the association of Ras-GTP in human tumors, and neoplastic cell susceptibility in vitro, in vivo and ex vivo. Three clinical trials of Phase II demonstrated the safety, efficacy, and tolerability in the use of Reovirus. The Reovirus-radiotherapy combination at low and high doses increase synergistically the cytotoxicity in metastatic tumors with a disease control of 93%. The Reolysin-Paclitaxel-Carboplatin combination in head and neck cancer has justified the progression to Phase III. Due to the high death rate related to metastasis, the bioavailability of intravenous Reovirus must be improved through the preconditioning of the immunocompetent host with Treg depletion.

Keywords: Adjuvant; Ras-activated cells; Reolysin; Reovirus


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Referencias


Etoh T, Himeno Y, Matsumoto T, Aramaki M, Kawano K, Nishizono A, et al. Oncolytic Viral Therapy for Human Pancreatic Cancer Cells by Reovirus. Clin Cancer Res. 2003 Mar;9(3):1128-23.

Norman K, Hirasawa K, Yang A, Shields M, Lee P. Reovirus oncolysis: The Ras/Ral/GEF/p38 pathway dictates host cell permissiveness to reovirus infection. PNAS. 2004 Jul;101(30):11099-104.

Twigger K, Vidal L, White C, DeBono J, Bhide S, Coffey M, et al. Enhanced In vitro and In vivo Cytotoxicity of Combined Reovirus and Radiotherapy. Clin Cancer Res. 2008 Feb;14(3):912-23.

Hirasawa K, Nishikawa S, Norman K, Alain T, Kossakowska A, Lee P. Oncolytic reovirus against ovarian and colon cancer. Cancer Research. 2002 Mar;62(6):1696-701.

Hirasawa K, Nishikawa S, Norman K, Coffey M, Thompson B, Yoon C, et al. Systemic reovirus therapy of mestastatic cancer in inmune-competent mice. Cancer Research. 2003 Jan;63(2):348-53.

Kottke T, Thompson J, Días R, Pulido J, Wilmon C, Coffey M, et al. Improved systemic delivery of oncolytic reovirus established tumors using preconditioning with cyclosphophamide-mediated Treg modulation and interleukin-2. Clin Cancer Res. 2009 Jan;15(2):561-69.

Strong J, Coffey M, Tang D, Sabinin P, Lee P. The molecular basis of viral oncolysis: usurpation of the Ras signaling pathway by reovirus. The EMBO Journal. 1998;17(12):3351-62.

Prestwich R., Errington F, Ilett E, Morgan R, Scott K, Kottke T, et al. Tumor infection by oncolytic reovirus primes adaptative antitumor immunity. Clin Cancer Res. 2008 Nov;14(22):7358-66.

Vidal L, Pandha H, Yap T, White C, Twigger K, Vile R, et al. A phase I study of intravenous oncolytic reovirus type 3 Dearing in patients with advanced cancer. Clin Cancer Res. 2008 Nov;14(21):7127-37.

Wu W, O’Reilly M, Langley R, Tsan R, Baker C, Bekele N, et al. Expression of epidermal growth factor (EGF)/transforming growth factor-A by human lung cancer cells determines their response to EGF receptor tyrosine kinase inhibition in the lungs of mice. Mol Cancer Ther. 2007 Oct;6(10):2652-63.

Chien Y, White M. RAL GTPases are linchpin modulators of human tumour-cell proliferation and survival. EMBO reports. 2003 Jul;4(8):800-6.

Prestwich R, Errington F, Steele L, Ilett E, Morgan R, Harrington K, et al. Reciprocal Human Dendritic Cell–Natural Killer Cell Interactions Induce Antitumor Activity Following Tumor Cell Infection by Oncolytic Reovirus. J Immunol. 2009 Oct;183(7):4312-21.

Harrington K. ONCY Investor Presentation. Conference Oncolytics. 2010 Nov 10; Chicago, IL, USA; 2010. p. 1-18.

Harrington K, Melcher A, Saunders M. Results of U.K. Phase II REOLYSIN® and Radiation Combination Clinical Trial. Final Report. Calgary, AB, Canadá: Oncolytics Biotech Inc; 2009 Apr 7.

Karapanagiotou E, Pandha H, Hall G, Chester J, Melcher A, Coffey M, et al. Phase I/II trial of oncolytic reovirus (Reolysin) in combination with carboplatin/paclitaxel in patients (pts) with advanced solid cancer. J Clin Oncol. 2009;27.15s.(suppl; abstr e14519)

Karapanagiotou M, Chester J, Pandha H, Gill G, Coffey M, Mettinger K, et al. A phase I/II study of oncolytic reovirus plus carboplatin/paclitaxel in patients with advanced solid cancers with emphasis on squamous cell carcinoma of the head and neck (SCCHN). J Clin Oncol. 2010;28:7s.(suppl; abstr 3080)

Mita A, Sankhala K, Sarantopoulos J, Carmona J, Okuno S, Goel S, et al. A phase II study of intravenous (IV) wild-.type reovirus (Reolysin) in the treatment of patients with bone and soft tissue sarcomas metastatic to the lung. J Clin Oncol. 2009;27:15s.(suppl; abstr 10524)


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