A pilot study of monoclonal antibody cG250 and low dose subcutaneous IL-2 in patients with advanced renal cell carcinoma.
The chimeric monoclonal antibody cG250 recognizes the CAIX/MN antigen. cG250 induces antibody-dependent cellular cytotoxicity (ADCC) responses in vitro that can be enhanced by IL-2. We studied the effects of adding daily low-dose subcutaneous IL-2 to cG250 for treatment of clear cell renal cell carcinoma (RCC). The primary endpoints of the trial were toxicity and immunological effects (human anti-chimeric antibodies [HACA], ADCC, natural killer [NK] and lymphokine-activated killer cell [LAK] activity); secondary endpoints were cG250 biodistribution and pharmacokinetics (PK) and tumour response rates. Eligible patients had unresectable metastatic or locally advanced clear cell RCC with measurable or evaluable disease. Nine patients were treated with six doses of cG250 (10 mg/m(2)/week, first and fifth doses trace-labelled with (131)I), and 1.25 x 10(6) IU/m(2)/day IL-2 for six weeks. Treatment was generally well tolerated with no adverse events attributable to cG250. Two patients required a 50% dose reduction of IL-2 due to toxicity. No HACA was detected. (131)I-labeled cG250 showed excellent targeting of tumour deposits. (131)I cG250 PK: T(1/2)alpha 20.16 +/- 6.59 h, T(1/2)beta 126.21 +/- 34.04 h, CL 39.67 +/- 23.06 mL/h, Cmax 5.12 +/- 0.86 microg/mL, V(1) 3.88 +/- 1.05 L. IL-2 did not affect cG250 PK. A trend for increased percentage of circulating CD3-/CD16+CD56+ NK cells was observed. Some patients showed enhanced ADCC or LAK activity. No antitumour responses were observed. In conclusion, weekly cG250 with daily low-dose subcutaneous IL-2 is well tolerated. IL-2 does not influence cG250 biodistribution or increase HACA.
Davis
Ian D
ID
Ludwig Institute for Cancer Research, Victoria, Australia. Ian.Davis@ludwig.edu.au
Liu
Zhanqi
Z
Saunders
Wayne
W
Lee
Fook-Thean
FT
Spirkoska
Violeta
V
Hopkins
Wendie
W
Smyth
Fiona E
FE
Chong
Geoffrey
G
Papenfuss
Anthony T
AT
Chappell
Bridget
B
Poon
Aurora
A
Saunder
Timothy H
TH
Hoffman
Eric W
EW
Old
Lloyd J
LJ
Scott
Andrew M
AM
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000920:Antibody-Dependent Cell Cytotoxicity; D000951:Antigens, Neoplasm / Q000276:immunology*; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000276:immunology*; D002292:Carcinoma, Renal Cell / Q000000981:diagnostic imaging / Q000276:immunology* / Q000628:therapy*; D005260:Female; D006801:Humans; D007376:Interleukin-2 / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000276:immunology / Q000628:therapy*; D015979:Killer Cells, Lymphokine-Activated / Q000276:immunology; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D011877:Radionuclide Imaging
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; C106533:G250 monoclonal antibody; D007376:Interleukin-2; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases
J Urol. 2004 Jun;171(6 Pt 1):2461-6
15126876
J Nucl Med. 2004 Aug;45(8):1412-21
15299069
Int J Cancer. 1986 Oct 15;38(4):489-94
2428759
J Clin Oncol. 1993 Apr;11(4):738-50
8478666
Int J Cancer. 1994 Feb 15;56(4):609-14
7509324
Biometrics. 1996 Sep;52(3):992-1001
8805764
J Immunother Emphasis Tumor Immunol. 1996 May;19(3):184-91
8811493
J Clin Oncol. 1997 Apr;15(4):1529-37
9193349
Cancer Immunol Immunother. 1998 Aug;46(6):318-26
9756416
Clin Cancer Res. 1996 Apr;2(4):669-77
9816217
Clin Cancer Res. 1998 Nov;4(11):2729-39
9829736
J Clin Oncol. 2005 Jan 1;23(1):133-41
15625368
Cochrane Database Syst Rev. 2005;(1):CD001425
15674877
Clin Cancer Res. 2005 May 15;11(10):3714-21
15897568
J Clin Oncol. 2005 Sep 20;23(27):6540-8
16170161
Clin Cancer Res. 2005 Oct 1;11(19 Pt 2):7178s-7186s
16203819
Biomarkers. 2005 Nov;10 Suppl 1:S83-6
16298916
J Urol. 2006 Jan;175(1):57-62
16406869
Cancer Biother Radiopharm. 2006 Jun;21(3):263-8
16918303
N Engl J Med. 2007 Jan 11;356(2):115-24
17215529
N Engl J Med. 2007 Jan 11;356(2):125-34
17215530
CA Cancer J Clin. 2007 Jan-Feb;57(1):43-66
17237035
Lancet Oncol. 2007 Apr;8(4):304-10
17395103
N Engl J Med. 2007 May 31;356(22):2271-81
17538086
Cancer Immun. 2007;7:13
17705349
Clin Cancer Res. 1999 Oct;5(10 Suppl):3268s-3274s
10541374
J Clin Oncol. 1999 Aug;17(8):2530-40
10561319
J Clin Oncol. 1999 Sep;17(9):2859-67
10561363
Br J Cancer. 1999 Oct;81(4):741-6
10574265
J Urol. 2000 Feb;163(2):408-17
10647643
J Urol. 2000 Apr;163(4):1090-5; quiz 1295
10737472
Cancer Immunol Immunother. 2002 May;51(3):171-7
11941456
Clin Cancer Res. 2003 Feb;9(2):802-11
12576453
Folia Biol (Praha). 2003;49(2):74-7
12779016
Urol Clin North Am. 2003 Aug;30(3):623-31
12953760
Br J Cancer. 2004 Mar 8;90(5):985-90
14997194