Phase I Trial of Intraperitoneal Administration of an Oncolytic Measles Virus Strain Engineered to Express Carcinoembryonic Antigen for Recurrent Ovarian Cancer

Division of Medical Oncology, Department of Molecular Medicine, Mayo Clinic, Gonda 10-141, 200 First Street Southwest, Rochester, MN 55905, USA.
Cancer Research (Impact Factor: 9.33). 02/2010; 70(3):875-82. DOI: 10.1158/0008-5472.CAN-09-2762
Source: PubMed


Edmonston vaccine strains of measles virus (MV) have shown significant antitumor activity in preclinical models of ovarian cancer. We engineered MV to express the marker peptide carcinoembryonic antigen (MV-CEA virus) to also permit real-time monitoring of viral gene expression in tumors in the clinical setting. Patients with Taxol and platinum-refractory recurrent ovarian cancer and normal CEA levels were eligible for this phase I trial. Twenty-one patients were treated with MV-CEA i.p. every 4 weeks for up to 6 cycles at seven different dose levels (10(3)-10(9) TCID(50)). We observed no dose-limiting toxicity, treatment-induced immunosuppression, development of anti-CEA antibodies, increase in anti-MV antibody titers, or virus shedding in urine or saliva. Dose-dependent CEA elevation in peritoneal fluid and serum was observed. Immunohistochemical analysis of patient tumor specimens revealed overexpression of measles receptor CD46 in 13 of 15 patients. Best objective response was dose-dependent disease stabilization in 14 of 21 patients with a median duration of 92.5 days (range, 54-277 days). Five patients had significant decreases in CA-125 levels. Median survival of patients on study was 12.15 months (range, 1.3-38.4 months), comparing favorably to an expected median survival of 6 months in this patient population. Our findings indicate that i.p. administration of MV-CEA is well tolerated and results in dose-dependent biological activity in a cohort of heavily pretreated recurrent ovarian cancer patients.

Download full-text


Available from: Judith Salmon Kaur,
  • Source
    • "Oncolytic virotherapy is a promising prospect to complement current therapeutic strategies in oncology, since cancers resistant to conventional treatment regimens are unlikely to be crossresistant to oncolytic viruses (OLVs). Currently, numerous OLVs, including adenovirus [1] [2] [3], reovirus [4], measles virus [5], Newcastle disease virus [6], Seneca Valley virus [7], retrovirus [8], vaccinia virus [9], herpes simplex virus [10] and Coxsackie virus A21 [10] are in or have completed clinical trials for a variety of solid malignancies with encouraging results. Given the heterogeneity associated with hematological malignancies , combination therapy is a rational option widely practiced in oncology. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Through combining vaccine-derived measles and mumps viruses (MM), we efficiently targeted a wide range of hematopoietic cancer cell lines. MM synergistically killed many cell lines including acute myeloid leukemia (AML) cell lines. Further investigation suggested that enhanced oncolytic effect of MM was due to increased apoptosis induction. In an U937 xenograft AML mouse model, MM displayed greater tumor suppression and prolonged survival. Furthermore, MM efficiently killed blasts from 16 out of 20 AML patients and elicited more efficient killing effect on 11 patients when co-administered with Ara-C. Our results demonstrate that MM is a promising therapeutic candidate for hematological malignancies.
    Cancer Letters 09/2014; 354(2). DOI:10.1016/j.canlet.2014.08.034 · 5.62 Impact Factor
  • Source
    • "(MV- Wue) (Hummel et al., 2009). The control virus MV-Hedm will have a similar susceptibility to monoclonal anti-H antibodies and anti- MV antibodies present in human serum as oncolytic MVs tested clinically (NCT00450814; NCT00408590; US-0770; (NCT01503177; Galanis et al., 2010) as they differ from one another only by the transgene they encode. Since retargeted H glycoproteins are of a higher molecular weight their incorporation into the virons is confirmed by comparing their size to Hedm by immunoblotting for H (Fig. 2). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The measles virus (MV) vaccine lineage is a promising oncolytic but prior exposure to the measles vaccine or wild-type MV strains limits treatment utility due to the presence of anti-measles antibodies. MV entry can be redirected by displaying a polypeptide ligand on the Hemagglutinin (H) C-terminus. We hypothesized that retargeted MV would escape neutralization by monoclonal antibodies (mAbs) recognizing the H receptor-binding surface and be less susceptible to neutralization by human antisera. Using chimeric H proteins, with and without mutations that ablate MV receptor binding, we show that retargeted MVs escape mAbs that target the H receptor-binding surface by virtue of mutations that ablate infection via SLAM and CD46. However, C-terminally displayed domains do not mediate virus entry in the presence of human antibodies that bind to the underlying H domain. In conclusion, utility of retargeted oncolytic measles viruses does not extend to evasion of human serum neutralization.
    Virology 04/2014; s 454–455(1):237–246. DOI:10.1016/j.virol.2014.01.027 · 3.32 Impact Factor
  • Source
    • "The reliance of MV-Edm on CD46 receptor density allows the virus and its derivatives to discriminate between tumor and normal cells, infecting and lysing the former while sparing the latter. Phase I clinical trials have demonstrated the safety of these viruses for the treatment ovarian cancer and glioblastoma, where no dose-limiting toxicity has been observed following administration of the MV at doses up to 109 TCID50 delivered intraperiotoneally and 107 TCID50 for MV delivered through the central nervous system respectively [6,49]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Medulloblastoma is the most common type of pediatric brain tumor. Although numerous factors influence patient survival rates, more than 30% of all cases will ultimately be refractory to conventional therapies. Current standards of care are also associated with significant morbidities, giving impetus for the development of new treatments. We have previously shown that oncolytic measles virotherapy is effective against medulloblastoma, leading to significant prolongation of survival and even cures in mouse xenograft models of localized and metastatic disease. Because medulloblastomas are known to be highly vascularized tumors, we reasoned that the addition of angiogenesis inhibitors could further enhance the efficacy of oncolytic measles virotherapy. Toward this end, we have engineered an oncolytic measles virus that express a fusion protein of endostatin and angiostatin, two endogenous and potent inhibitors of angiogenesis. Oncolytic measles viruses encoding human and mouse variants of a secretable endostatin/angiostatin fusion protein were designed and rescued according to established protocols. These viruses, known as MV-hE:A and MV-mE:A respectively, were then evaluated for their anti-angiogenic potential and efficacy against medulloblastoma cell lines and orthotopic mouse models of localized disease. Medulloblastoma cells infected by MV-E:A readily secrete endostatin and angiostatin prior to lysis. The inclusion of the endostatin/angiostatin gene did not negatively impact the measles virus' cytotoxicity against medulloblastoma cells or alter its growth kinetics. Conditioned media obtained from these infected cells was capable of inhibiting multiple angiogenic factors in vitro, significantly reducing endothelial cell tube formation, viability and migration compared to conditioned media derived from cells infected by a control measles virus. Mice that were given a single intratumoral injection of MV-E:A likewise showed reduced numbers of tumor-associated blood vessels and a trend for increased survival compared to mice treated with the control virus. These data suggest that oncolytic measles viruses encoding anti-angiogenic proteins may have therapeutic benefit against medulloblastoma and support ongoing efforts to target angiogenesis in medulloblastoma.
    BMC Cancer 03/2014; 14(1):206. DOI:10.1186/1471-2407-14-206 · 3.36 Impact Factor
Show more