Pilot trial of intravenous infusion of a replication-selective adenovirus (ONYX-015) in combination with chemotherapy or IL-2 treatment in refractory cancer patients.
ONYX-015 is an adenovirus that selectively replicates in p53 dysfunctional or mutated malignant cells. We performed a pilot trial to determine the safety and feasibility of treatment with ONYX-015 delivered intravenously in patients with advanced malignancy. One cohort of five patients received ONYX-015 once a week for 6 weeks at a dose of 2 x 10(12) particles per infusion in combination with weekly infusions of irinotecan (CPT11, 125 mg per week) and 5-fluorouracil (5FU, 500 mg per week). A second cohort of five patients received the combination of ONYX-015 at a dose of 2 x 10(11) particles per week for 6 weeks in combination with interleukin 2 (IL 2, 1.1 x 10(6) units daily via subcutaneous injection for 5 days each week for 4 weeks). Toxicity attributable to ONYX-015 was limited to transient fever. All patients demonstrated elevations in neutralizing antibody titers within 4 weeks of the infusion of ONYX-015. Serum levels of IL-6, IL-10, tumor necrosis factor-alpha, and interferon-gamma increased within 6 hours of viral infusion, suggesting immune activation. This response was more pronounced in the cohort of patients who received 2 x 10(12) particles per infusion. Two patients demonstrated uptake of viral particles in malignant tissue by quantitative PCR. Electron microscopy confirmed selective cytoplasmic viral particles within malignant cells but not within adjacent normal tissue in a third patient. In conclusion ONYX-015 can be administered safely in combination with CPT11, 5FU or low-dose IL 2 and is able to access malignant tissue following intravenous infusion. Further investigation of ONYX-015, possibly with agents that may modulate replication activity, or duration of virus survival, is indicated.
US Oncology, Dallas, Texas 75246, USA. John.Nemunaitis@USOncology.com
John
J
Nemunaitis
Casey
C
Cunningham
Alex  W
A
Tong
Leonard
L
Post
George
G
Netto
A Scott
AS
Paulson
Dawn
D
Rich
Angela
A
Blackburn
Beverly
B
Sands
Brenda
B
Gibson
Britta
B
Randlev
Scott
S
Freeman
D000256:Adenoviridae / Q000235:genetics; D017501:Adenovirus E1B Proteins / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D003131:Combined Modality Therapy; D016207:Cytokines / Q000097:blood; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D015316:Genetic Therapy; D006801:Humans; D007167:Immunotherapy; D007262:Infusions, Intravenous; D007376:Interleukin-2 / Q000627:therapeutic use*; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000628:therapy*; D010865:Pilot Projects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D014765:Viral Vaccines / Q000627:therapeutic use*; D014779:Virus Replication
D017501:Adenovirus E1B Proteins; D016207:Cytokines; D007376:Interleukin-2; D016159:Tumor Suppressor Protein p53; D014765:Viral Vaccines; C464532:dl1520; D000077146:Irinotecan; D005472:Fluorouracil; D002166:Camptothecin