Immunological response induced by abagovomab as a maintenance therapy in patients with epithelial ovarian cancer: relationship with survival-a substudy of the MIMOSA trial

Abstract

Purpose: To determine whether abagovomab induces protective immune responses in ovarian cancer patients in first clinical remission. The present analysis is a substudy of monoclonal antibody immunotherapy for malignancies of the ovary by subcutaneous abagovomab trial (NCT00418574).

Methods: The study included 129 patients, 91 in the abagovomab arm and 38 in the placebo arm. Circulating CA125-specific cytotoxic T lymphocytes (CTL) were measured by a flow cytometry-based interferon-γ producing assay. Human antimouse antibody and anti-anti-idiotypic (Ab3) were assessed by ELISA. Patients were evaluated before starting the treatment and at different time points during induction and maintenance phases.

Results: A similar percentage of patients in both the placebo and abagovomab arms had CA125-specific CTL (26.3 and 31.8 %, respectively; p = 0.673 by Fisher's exact test). Patients with CA125-specific CTL in both arms tended to have an increased relapse-free survival (RFS, log-rank test p = 0.095) compared to patients without. Patients (n = 27) in the abagovomab arm without CA125-specific CTL but that developed Ab3 above the cutoff (defined as median Ab3 level at week 22) had a prolonged RFS compared to patients (n = 24) that did not develop Ab3 above the cutoff (log-rank test p = 0.019).

Conclusion: Abagovomab does not induce CA125-specific CTL. However, patients with CA125-specific CTL perform better than patients without, irrespective of abagovomab treatment. Abagovomab-induced Ab3 associate with prolonged RFS in patients without CA125-specific CTL. Further studies are needed to confirm these data and to assess the potential utility of these immunological findings as a tool for patient selection in clinical trial.

Fig. 1

Representative dot plots depicting the method to identify CA125-specific CTL as CD8⁺ T cells staining positively for CD69 and IFNγ. Dot plots show CD69/IFNγ intracellular staining in CD8⁺ T cells stimulated with CD28/CD49d cocktail and SEB (left plot), CD28/CD49d cocktail alone (middle plot) and CD28/CD49d cocktail and CA125 (right plot). Quadstat cursors are set by visual inspection in the left plot and kept identical in the middle and right plots. The frequency of double-positive CD69/IFNγ CD8⁺ T cells is reported in the upper right quadrant in each plot

Fig. 2

Scatterplot of individual CA125-specific CTL number over time. a Patients in the placebo arm. b Patients in the abagovomab arm. The interrupted line depicts the cutoff, as defined in the text. Number of patients at each time point is indicated. Wk week

Fig. 3

Kaplan–Meier estimates for RFS according to the presence (interrupted line) or absence (continuous line) of CA125-specific CTL

Fig. 4

Scatterplots of individual and median humoral immune response overtime. a HAMA levels. b Ab3 levels. The interrupted line depicts the cutoff, as defined in the text. Number of patients at each time point is indicated. Wk week

Fig. 5

Kaplan–Meier estimates for RFS. a Abagovomab-treated patients without CA125-specific CTL with Ab3 levels above cutoff (continuous line) and below cutoff (interrupted line). b Abagovomab-treated patients without CA125-specific CTL and with Ab3 levels above cutoff (continuous line) and patients without CA125-specific CTL in the placebo arm (interrupted line)