Analysis of therapeutic and immunologic effects of R(24) anti-GD3 monoclonal antibody in 37 patients with metastatic melanoma.
BACKGROUND
Antitumor effects of antibodies against ganglioside antigens of melanoma have been reported, but neither optimal doses nor mechanisms have been established.


METHODS
This Phase IB trial of the murine immunoglobulin IgG(3) monoclonal antibody R(24) against disialoganglioside GD3 was conducted with 37 patients to define better the dose-response relation and mechanism of action of R(24) in patients with metastatic melanoma.


RESULTS
Dose-limiting toxicity consisted of a pulmonary capillary leak syndrome in 3 of 5 patients in the 80 mg/M(2)/day dosage tier. Serial blood and tumor biopsy samples were obtained prior to therapy and on Days 5, 9, and 22 following R(24) infusion. Tumor biopsy-infiltrating lymphocytes were enumerated in peritumoral, endotumoral, and perivascular compartments: endotumoral CD4(+) and CD8(+) T cells and HLA-DR(+) T cells increased over time on R(24) antibody. Endotumoral CD4 lymphoid infiltrate activation (DR expression) and antibody-dependent cytotoxicity were the greatest in the one patient who achieved a complete response.


CONCLUSIONS
Clinical response was associated with depression in natural killer (CD56(+) and CD56(+)DR(+)) blood cells (P = 0.03) and was associated with R(24) dosage (P = 0.01). A complete response that lasted 2 years and a partial response that lasted 2 months occurred at a dose of 1 mg/M(2)/day. The limited number of clinical responses observed in this trial hampered the correlation of antitumor and immune parameters but provided a rational foundation for the future evaluation of antiganglioside antibodies.
Kirkwood
J M
JM
Department of Medicine, University of Pittsburgh Medical Center, PA 15213-2582, USA.
Mascari
R A
RA
Edington
H D
HD
Rabkin
M S
MS
Day
R S
RS
Whiteside
T L
TL
Vlock
D R
DR
Shipe-Spotloe
J M
JM
D000328:Adult; D000368:Aged; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005732:Gangliosides / Q000276:immunology / Q000627:therapeutic use*; D006684:HLA-DR Antigens / Q000032:analysis; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology / Q000627:therapeutic use; D007694:Killer Cells, Natural; D008213:Lymphocyte Activation; D016246:Lymphocytes, Tumor-Infiltrating; D008297:Male; D008545:Melanoma / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008875:Middle Aged; D012878:Skin Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D005732:Gangliosides; D006684:HLA-DR Antigens; D007074:Immunoglobulin G