Polyinosinic-polycytidylic acid complexed with poly-L-lysine and carboxymethylcellulose in combination with interleukin 2 in patients with cancer: clinical and immunological effects.
We have performed a phase IB study of polyinosinic-polycytidylic acid complexed with poly-L-lysine and carboxymethylcellulose (poly-ICLC) in combination with interleukin 2 (IL-2) in 25 patients with a variety of cancers. Patients received weekly or biweekly poly-ICLC by i.m. injection, at doses ranging from 0.01 to 1.0 mg/m2, for 1 month. This was followed by 2 months of outpatient therapy with biweekly i.m. poly-ICLC in combination with IL-2 (3 x 10(6) units/m2) given i.v. by 24-h continuous infusion twice weekly, using a portable infusion pump. No objective tumor responses were observed. Toxicity was moderate at all poly-ICLC doses tested and increased only slightly following the addition of IL-2. No increases in peripheral blood natural killer (NK) activity were observed after treatment with poly-ICLC alone. However, high dose poly-ICLC (greater than or equal to 0.3 mg/m2) in combination with IL-2 resulted in NK activity greater than that seen using the same dose of IL-2 in combination with lower poly-ICLC doses. Increases in the number and percentage of CD56+ cells were evident only after initiation of IL-2 therapy and were unaffected by the poly-ICLC dose. In the majority of patients, these increases were preferentially associated with the subset of CD56+ cells coexpressing CD8, while the CD56+/CD16+ population was elevated to a lesser extent. Moderate increases in serum neopterin levels and 2',5'-oligoadenylate synthetase activity in peripheral blood mononuclear cells were noted at 72 h following initial treatment with 1.0 mg/m2 poly-ICLC. No induction of alpha or gamma interferon was detected. This study shows that the addition of poly-ICLC to a well tolerated IL-2 regimen can significantly enhance NK activity. Poly-ICLC can be used to enhance IL-2-induced NK lytic activity without increases in the dose and, therefore, the toxicity of IL-2 treatment.
Ewel
C H
CH
Clinical Services Program, Program Resources, Inc./DynCorp, National Cancer Institute-Frederick Cancer Research Development Center, Maryland 21702.
Urba
W J
WJ
Kopp
W C
WC
Smith
J W
JW
Steis
R G
RG
Rossio
J L
JL
Longo
D L
DL
Jones
M J
MJ
Alvord
W G
WG
Pinsky
C M
CM
D015703:Antigens, CD / Q000032:analysis; D001708:Biopterins / Q000031:analogs & derivatives / Q000097:blood; D002266:Carboxymethylcellulose Sodium / Q000627:therapeutic use / Q000633:toxicity* / Q000031:analogs & derivatives; D003602:Cytotoxicity, Immunologic; D004341:Drug Evaluation; D005260:Female; D006801:Humans; D007376:Interleukin-2 / Q000627:therapeutic use / Q000633:toxicity*; D007694:Killer Cells, Natural / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D019798:Neopterin; D011070:Poly I-C / Q000627:therapeutic use / Q000633:toxicity*; D011107:Polylysine / Q000627:therapeutic use / Q000633:toxicity* / Q000031:analogs & derivatives
D015703:Antigens, CD; D007376:Interleukin-2; D001708:Biopterins; D011107:Polylysine; D019798:Neopterin; C019531:poly ICLC; D002266:Carboxymethylcellulose Sodium; D011070:Poly I-C