Therapy of colorectal carcinoma with monoclonal antibodies (MAb17-1A) alone and in combination with granulocyte monocyte-colony stimulating factor (GM-CSF).
A mouse monoclonal antibody (MAb17-1A) (IgG2A) against colorectal carcinoma cells was used to treat patients with metastatic disease. Major direct effector functions of MAb seem to be ADCC (antibody dependent cellular cytotoxicity), CDC (complement dependent cytolysis) and apoptosis ('programmed cell death'). Thus, a high tumor cell saturation of the MAb should be achieved. Increasing doses of MAb to the patients increased the total area under the concentration curve and thus the exposure of tumor cells to MAb. However, the response rate (with complete + partial + minor response + stable disease defined as response) was not augmented. In total, 10/52 (19%) patients responded and in fact lower doses (less than 2 g) might induce a higher response frequency (9/52) than higher doses (greater than 2 g) (1/52). During treatment, the numbers of cytotoxic cells (lymphocytes and monocytes) increases in the tumor lesion and complement components were deposited. As ADCC may be important, effector mechanism attempts were made to augment the cytolytic capability of the effector cells by simultaneously giving the patients GM-CSF. The combination of MAb17-1A + GM-CSF augmented the ADCC activity of blood mononuclear cells and a heavy infiltration of monocytes could be noted in the tumor. Out of 15 available patients 6 (40%) showed a response.
Mellstedt
H
H
Department of Oncology, Karolinska Hospital, Stockholm, Sweden.
Frödin
J E
JE
Ragnhammar
P
P
Masucci
G
G
Ljungberg
A
A
Hjelm
A L
AL
Fagerberg
J
J
Lindemalm
C
C
Osterborg
A
A
Wersäll
P
P
D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000920:Antibody-Dependent Cell Cytotoxicity; D015179:Colorectal Neoplasms / Q000276:immunology / Q000628:therapy*; D004334:Drug Administration Schedule; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000627:therapeutic use*; D006801:Humans; D007074:Immunoglobulin G / Q000032:analysis / Q000627:therapeutic use*; D012074:Remission Induction
D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G; D016178:Granulocyte-Macrophage Colony-Stimulating Factor