Attached is the abstract for Ipilimumab at 2014 ASCO in the poster presentation.
Abstract:
Background: Adoptive cell therapy (ACT) is currently one of the most effective treatments for stage IV malignant melanoma. Clinical studies have indicated a link between prior anti-CTLA-4 treatment (e.g. Ipilimumab), and a favorable response to subsequent ACT. Methods: We compared phenotype and functionality of T cells generated from melanoma biopsies harvested from Ipilimumab naïve patients with patients that had received treatment with Ipilimumab within six month prior to tumor removal. Tumor biopsies were obtained from 32 stage IV melanoma patients (16 treated with Ipilimumab and 16 ipilimumab naive). T cells were cultured and expanded according to the rapid expansion protocol. Cells were stained for intra- and extracellular markers and subjected to flow cytometric analysis. Additionally, combinatorial coding with MHC-I multimers and co-culture assays with autologous tumor cells were performed in order to assess tumor-specific responses. Results: Analysis for phenotypic markers revealed several significant differences related to prior treatment. Importantly, cultured cells from Ipilimumab treated patients showed a median ten-fold higher expression of CD27 in CD8+ T cells, compatible with a more naïve phenotype, and two-fold higher expression of intracellular CTLA-4 in both CD4+ and CD8+ positive T cells. Furthermore, both TIM-3 and LAG-3 were more abundantly expressed in CD8+ T cells from Ipilimumab treated patients. We detected no difference in reactivity towards autologous tumor cells. Combinatorial coding revealed frequent responses toward common tumor associated antigens in both groups of patients. Conclusions: Despite several weeks of culture, Ipilimumab appeared to have lasting impact on the phenotype of expanded tumor infiltrating T cells. We observed higher expression of CD27, which previously has been linked to a favorable outcome of ACT, and up regulation of markers associated with immune suppression, possibly due to homeostatic regulation of the T cells. Over all, results indicate that influx of T cells with a less exhausted phenotype may underlie the favorable effect of pre-treatment with Ipilimumab and ACT in the setting of metastatic malignant melanoma.
