The pharmacokinetics of recombinant human granulocyte-macrophage colony- stimulating factor (rhGM-CSF), induction of anti-GM-CSF antibodies, and clinical effects related to the induction of the antibodies were analyzed in patients with metastatic colorectal carcinoma (CRC) who were not on chemotherapy (n = 20, nonimmunocompromised patients). rhGM- CSF (250 micrograms/m2/d; Escherichia coli-derived) was administered subcutaneously for 10 days every month for 4 months. Eight patients with multiple myeloma (MM) on intensive chemotherapy followed by rhGM- CSF treatment were also included (immunocompromised patients). After a single injection of GM-CSF at the first cycle in CRC patients, the maximum calculated concentration (Cmax) was 5.24 +/- 0.56 ng/mL; the half life (T1/2) was 2.91 +/- 0.8 hours; and the area under the concentration curve (AUC) was 30.86 +/- 6.03 hours x ng/mL (mean +/- SE). No anti-GM-CSF antibodies were detected. During the subsequent cycles, 95% of the CRC patients developed anti-GM-CSF IgG antibodies, which significantly altered the pharmacokinetics of rhGM-CSF at the third and fourth cycles with decreased Cmax (2.87 +/- 0.57 ng/mL; P < .05), T1/2 (1.57 +/- 0.2 hours; P < .05), and AUC (14.90 +/- 4.10 hours x ng/mL; P < .005). The presence of anti-GM-CSF antibodies significantly reduced the GM-CSF-induced enhancement of granulocytes, and there was a clear tendency for a decreased increment of monocytes. Antibodies diminished systemic side effects of rhGM-CSF. Only 1 of 8 MM patients showed a very low anti-GM-CSF antibody titer after GM-CSF therapy, as shown by enzyme-linked immunosorbent assay and Western blot. Therefore, in nonimmunocompromised patients, exogenous nonglycosylated GM-CSF induced an anti-GM-CSF IgG antibody response in practically all patients, which seemed to be of clinical significance. In immunocompromised patients, virtually no significant antibody response was shown.

Although metabolic response assessed by FDG-PET reflects radiological tumor volume changes, the sensitivity and specificity are too low to support the routine use of PET in mCRC. Furthermore, PET failed to reflect long-term outcome and can, thus, not be used as surrogate end point for hard endpoint benefit.

A therapeutic trial using repeated doses of a mouse monoclonal antibody against the tumor-associated antigen (TAA) CO17-1A in metastatic colorectal carcinomas was carried out. Metastatic lesions sampled by repeated thick needle (1.2 mm) biopsies during therapy were examined immunohistochemically for the presence of various TAAs, mouse IgG, complement, and infiltrating leukocytes. The CO17-1A was consistently expressed in all cases along the basement membrane of tumor glands and could only be demonstrated on cryostat sections whereas the TAAs GICA19-9, GA73-3, and Br55-2 were also visualized in B5-fixed paraffin-embedded biopsies. The CO17-1A and GA73-3 were predominantly present at the basal region in contrast to the GICA 19-9 and Br55-2 which were predominant at the luminal and the apical region of the tumor glands. Antigenic modulation was not seen either after 24-72 h or during prolonged treatment. In all cases the infused mouse IgG was detected, from 24 h after infusion up to 6-8 weeks, mainly along the basal region of tumor glands. In 13/14 posttreatment biopsies, complement factor C3 was found at the same sites as mouse IgG. In 6 out of 9 posttreatment biopsies an increase in mononuclear cells (monocytes, natural killer (NK) cells and/or T cells) was observed. Monocytes were close to the tumor cells whereas NK cells and T cells were predominantly scattered in the stroma.

The window design in asymptomatic patients with mCRC can be safely applied to assess the activity and safety of novel cytostatic agents like enzastaurin.

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