175PD - Effects of chemotherapy on ipilimumab-mediated increases in absolute lymphocyte count and activation of T-cells
|Date||29 September 2012|
|Event||ESMO Congress 2012|
|Session||Basic Science and Translational Research I|
|Topics|| Cancer Immunology and Immunotherapy
S.D. Chasalow1, J.D. Wolchok2, M. Reck3, S. Maier4, V. Shahabi5
Ipilimumab (IPI) is a fully human monoclonal antibody that binds CTLA-4 to augment an antitumor T-cell response. Consistent with the expected immune-stimulating effect, increases in absolute lymphocyte count (ALC) and activation of peripheral-blood T cells frequently have been observed in patients (pts) treated with IPI as monotherapy. Such changes thus appear to be indicators of the biological activity of IPI. Combining IPI with other treatments, such as chemotherapy (CT), may have the potential to enhance efficacy. However, CT may also interfere with the immune-stimulating effects of IPI. The current analysis investigated the effect of IPI on ALC and T cell activation in the presence of CT.Methods
ALC was measured in 3 trials of IPI + CT (n = 887). In CA184024, IPI or placebo (PLB) was combined with dacarbazine (DTIC) in metastatic melanoma (MM) pts. In CA184041, IPI in 2 different dosing schedules or PLB was combined with carboplatin/paclitaxel (CP) in lung cancer (NSCLC and SCLC) pts. In CA184078, IPI was combined with PLB, CP, or DTIC in MM pts. ALC assessments from baseline through the end of a 12- or 18-week dosing period were included. In CA184078, frequency of peripheral-blood activated (HLA-DR+) T cells at 0, 3, and 11 weeks from first treatment was assessed by flow cytometry. Extended linear models were used to estimate mean ALC and T cell frequencies as a function of time and treatment group.Results
In all 3 studies, mean ALC increased significantly (p < 0.0001 to p = 0.027) over time after initiation of treatment in the IPI-containing arms, with or without CT, but not in the PLB arms. In the IPI arms, mean ALC changes from baseline to the end of IPI dosing ranged from 0.45 to 0.75 x 109 cells/L. ALC increases were temporally associated with IPI, but not CT, dosing. In CA184078, mean relative and absolute frequencies of activated CD4+ and CD8+ T cells increased significantly after start of IPI treatment similarly in the 3 arms.Conclusions
Mean increases in ALC and activated T cells, similar to those seen with IPI monotherapy, were observed after treatment with IPI combined with CP or DTIC. This suggests that IPI maintains biological activity when administered with CT, thus supporting continued clinical evaluation of IPI/CT combination therapy.Disclosure
S.D. Chasalow: Employment by Bristol-Myers Squibb, Bristol-Myers Squibb stock ownership.
J.D. Wolchok: I am a consultant to Bristol-Myers Squibb, Merck and Glaxo Smith Kline. I have research support from Bristol-Myers Squibb.
M. Reck: Consultant/advisor to Bristol-Myers Squibb, Hoffmann-La Roche, Eli Lilly, Pfizer, AstraZeneca, and Daiichi Sankyo; compensated, self.
S. Maier: Employment by Bristol-Myers Squibb, Bristol-Myers Squibb stock ownership.
V. Shahabi: Employment by Bristol-Myers Squibb, Bristol-Myers Squibb stock ownership.