Phase I trial of a mouse monoclonal antibody against GD3 ganglioside in patients with melanoma: induction of inflammatory responses at tumor sites.
Twenty-one patients were entered into a phase I trial to evaluate toxicity, antitumor effects, and biological responses at tumor sites during treatment of R24, an immunoglobulin G3 (IgG3) mouse monoclonal antibody (mAb) against GD3 ganglioside. Toxicity was related to dose of R24. Urticaria and pruritus were the most prominent side effects, with nausea, vomiting, and diarrhea occurring at the highest dose levels. Partial responses were observed in four patients lasting from 6 to 46 weeks, and mixed responses were seen in two patients. Responses occurred as early as 4 weeks and as late as 10 weeks after beginning treatment. Twenty of the 21 patients developed human IgG antibodies against R24. Antimouse Ig antibodies were first detected at a median of 14 days after starting treatment, but three of the four patients who had a partial response developed the antimouse Ig responses later than 20 days. Peak serum levels of R24 were related to dose and ranged from a mean of 0.9 micrograms/mL at the lowest dose level (1 mg/m2/d) to 44 micrograms/mL at the highest dose (50 mg/m2/d). The amount of R24 reaching tumor sites corresponded to the dose administered, and R24 could be detected in tumors as late as 30 days after finishing treatment. Inflammation at tumor sites was observed during treatment. Biopsies of tumors taken before, during, and after treatment revealed that R24 induced deposition of complement components, increased numbers of mast cells with mast cell degranulation, and infiltration of T lymphocytes. These results suggest that treatment with R24 can produce a localized inflammatory response at tumor sites that is capable of producing tumor regression.
Vadhan-Raj
S
S
Memorial Sloan-Kettering Cancer Center, New York, NY 10021.
Cordon-Cardo
C
C
Carswell
E
E
Mintzer
D
D
Dantis
L
L
Duteau
C
C
Templeton
M A
MA
Oettgen
H F
HF
Old
L J
LJ
Houghton
A N
AN
D000328:Adult; D000368:Aged; D000818:Animals; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*; D004341:Drug Evaluation; D005260:Female; D005732:Gangliosides / Q000276:immunology*; D006801:Humans; D007249:Inflammation; D008297:Male; D008545:Melanoma / Q000276:immunology / Q000556:secondary / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D012878:Skin Neoplasms / Q000276:immunology / Q000628:therapy*
D000911:Antibodies, Monoclonal; D005732:Gangliosides; C026226:ganglioside, GD3