Phase I trial of intraperitoneal administration of an oncolytic measles virus strain engineered to express carcinoembryonic antigen for recurrent ovarian cancer.
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.
Galanis
Evanthia
E
Division of Medical Oncology, Department of Molecular Medicine, Mayo Clinic, Gonda 10-141, 200 First Street Southwest, Rochester, MN 55905, USA. galanis.evanthia@mayo.edu
Hartmann
Lynn C
LC
Cliby
William A
WA
Long
Harry J
HJ
Peethambaram
Prema P
PP
Barrette
Brigitte A
BA
Kaur
Judith S
JS
Haluska
Paul J
PJ
Aderca
Ileana
I
Zollman
Paula J
PJ
Sloan
Jeff A
JA
Keeney
Gary
G
Atherton
Pamela J
PJ
Podratz
Karl C
KC
Dowdy
Sean C
SC
Stanhope
C Robert
CR
Wilson
Timothy O
TO
Federspiel
Mark J
MJ
Peng
Kah-Whye
KW
Russell
Stephen J
SJ
D015746:Abdominal Pain / Q000209:etiology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002272:Carcinoembryonic Antigen / Q000235:genetics / Q000378:metabolism*; D002522:Chlorocebus aethiops; D005221:Fatigue / Q000209:etiology; D005260:Female; D005334:Fever / Q000209:etiology; D006801:Humans; D007274:Injections, Intraperitoneal; D008459:Measles virus / Q000235:genetics / Q000502:physiology*; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D050130:Oncolytic Virotherapy / Q000009:adverse effects / Q000379:methods; D050504:Oncolytic Viruses / Q000235:genetics / Q000502:physiology*; D010051:Ovarian Neoplasms / Q000473:pathology / Q000628:therapy*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000009:adverse effects; D016896:Treatment Outcome; D014709:Vero Cells
D002272:Carcinoembryonic Antigen; D011993:Recombinant Fusion Proteins