Engineered Measles Virus As A Novel Oncolytic Therapy Against Prostate Cancer

January 25, 2009 at 8:00 am Leave a comment


UroToday.com – In this study we report for the first time the antitumor activity of oncolytic measles virus (MV) derivatives against prostate cancer cell lines and xenografts.1 We used engineered derivatives of the measles vaccine strain MV-Edm, including MV-CEA which is an MV-Edm strain genetically modified to express human CEA that is currently tested in two phase I clinical trials in our institution.2,3



To better visualize in vivo infection of prostate cancer xenografts, we applied an MV-Edm strain (MV-Luc) which expresses a codon-optimized derivative of the firefly luciferase reporter gene. MV-Luc localization and spread was monitored using bioluminescent imaging. We demonstrated viral replication and persistence in the tumors for more than 2 weeks. To increase the translatability of our preclinical work, we used the MV-CEA virus in our therapeutic efficacy experiments. This virus is approved for testing in humans.



Our results underline the excellent oncolytic potential of MV-CEA against both hormone sensitive and hormone refractory prostate cancer in vitro and in vivo. We also confirmed that MV-CEA viral gene expression kinetics could be monitored by CEA measurement. We chose to test the oncolytic efficacy of recombinant MV-Edm strains in three commonly used prostate cancer cell lines corresponding both to the more advanced, androgen-insensitive (PC-3, DU-145) as well as the androgen-sensitive stage of prostate cancer (LNCaP). Following infection by MV-CEA of PC-3 and DU-145 at a multiplicity of infection (MOI) of 0.001 to 1.0, widespread cytopathic effect was observed with eradication of the prostate cancer cell culture monolayers. Intratumoral administration of MV-CEA in mice bearing PC-3 xenografts resulted in statistically significant tumor regression (P=0.004) and prolongation of survival (P=0.001).



This current effort can be viewed as the initial step in utilizing measles strains as novel antitumor agents against prostate cancer. One potential limitation of MV-CEA is the fact that CEA levels have been found to be moderately elevated in approximately 1/3 of newly-diagnosed prostate cancer patients, thus making difficult the distinction between CEA expression due to viral replication or due to the disease itself.4 For this reason we are currently exploring the oncolytic efficacy of another MV-Edm derivative, MV-NIS, against prostate cancer. MV-NIS is currently tested at Mayo Clinic in a phase I clinical trial against multiple myeloma.5 This virus has been genetically engineered to express the human thyroidal sodium iodide symporter (NIS), a reporter gene that that can concentrate radioisotopes inside cells. Radioactivity generated by the trapped isotopes can be detected by  camera, PET or SPECT/CT. Furthermore, increased intracellular trapping of the radioisotope 131I can cause direct radiation damage to tumor cells and thereby enhance the therapeutic effect of MV-NIS.



Although the ultimate goal is the development of an effective intravenous viral treatment for patients with hormone refractory metastatic prostate cancer, which will likely also involve the development of oncolytic strains retargeted against prostate-specific receptors, locoregional administration in patients with locally recurrent prostate cancer represents a logical first step. Based on our results as well as the safety of MV-Edm derivatives such as MV-CEA and MV-NIS in clinical trials against other tumor types to date, MV-CEA could be an excellent candidate for clinical testing against prostate cancer.



References:

1. Msaouel P, Iankov ID, Allen C, Morris JC, Von Messling V, Cattaneo R, Koutsilieris M, Russell SJ, Galanis E: Engineered measles virus as a novel oncolytic therapy against prostate cancer. Prostate (2008): in press.


2. NCT00408590: Oncolytic Virus Therapy in Treating Patients With Progressive, Recurrent, or Refractory Ovarian Epithelial Cancer or Primary Peritoneal Cancer. NIH, Bethesda, MD, USA (2008). http://www.clinicaltrials.gov/ct2/show/NCT00408590


3. NCT00390299: Viral Therapy in Treating Patients With Recurrent Glioblastoma Multiforme. NIH, Bethesda, MD, USA (2008). http://www.clinicaltrials.gov/ct2/show/NCT00390299


4. Neufeld L, Dubin A, Guinan P, Nabong R, Ablin RJ, Bush IM: Carcinoembryonic antigen in the diagnosis of prostate carcinoma. Oncology 1974;29(5):376-381.


5. NCT00450814: Vaccine Therapy With or Without Cyclophosphamide in Treating Patients With Recurrent or Refractory Multiple Myeloma. NIH, Bethesda, MD, USA (2008).


http://www.clinicaltrials.gov/ct2/show/NCT00450814



Written by Pavlos Msaouel, Ianko D. Iankov, Cory Allen, John C. Morris, Veronika von Messling, Roberto Cattaneo, Michael Koutsilieris, Stephen J. Russell, and Evanthia Galanis as part of Beyond the Abstract on UroToday.com



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