Abstract
2600 Background: ADCC plays a role in antitumor activity of IgG1 mAb by inducing immune cell-mediated lysis of tumor cells. We evaluated ADCC ability before and under cetuximab-based treatment and examined its impact on treatment outcome. Methods: 29 patients (17 men, 12 women, median age 72, range 51-84) with metastatic wild-type KRAS CRC treated with chemotherapy (irinotecan or Folfiri) plus cetuximab were prospectively enrolled. ADCC ex-vivo was measured before starting treatment and every 2 months during treatment (1 to 7 measurements/patient, 12 patients with >2 measurements). 400 000 purified Natural Killer cells (CD3- CD56+) from patients were incubated with 10 000 target cells (CAL166 cancer cell line expressing EGFR) and 10 µg/ml cetuximab (triplicates). Cytotoxicity was measured by the LDH-release assay. ADCC was expressed as the % of lyzed target cells. Gene polymorphisms of Fcγ receptors FCGR2a (131Arg>His) and FCGR3a (158Phe>Val) were analyzed (Allelic Discrimination assay). Results: The feasibility rate of ADCC measurement was 88%. ADCC basal values ranged between 30% and 100% (mean 62%, median 66%). Basal ADCC was not influenced by patient gender. A tendency for an increased ADCC basal value was observed in younger patients: median was 76% in the 6 patients ≤ 60 vs 56% in the 23 patients over 60 years-old (p = 0.031). FCGR2A and FCGR3A gene polymorphisms were not linked to basal ADCC. The evolution of individual ADCC ability before treatment and 2 months later revealed a significant drop in ADCC following treatment initiation (intra-patient comparison, n=18, p=0.006), with an absolute median drop of 19%. This decrease was not sustained over time and intra-patient comparison between basal value and 4-month measurement was not significant. 25 patients were assessable for survival (11 deaths). Basal ADCC values were not related to survival. Conclusions: A new generation of mAb is currently being developed with the aim to amplify ADCC. Present data illustrate the feasibility of ADCC measurement in mAb-treated patients and reveal an initial drop in ADCC under treatment that may reflect the variable chemotherapy-induced impact on host immunity.
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