CTLA-4 blockade with ipilimumab has proven to extend overall survival in advanced melanoma patients. Although it is a promising new therapy, response rates are still limited (10-20%) and immune related adverse events (IRAE) are frequent. Currently there is a need for predictive and pharmacodynamic biomarkers that can provide tools for patient preselection and IRAE screening. In addition to this, the mechanisms of action of ipilimumab are only partially understood. The present study shows the results of in-depth immune monitoring that was carried out in 42 advanced stage melanoma patients during ipilimumab treatment. Previous studies have mainly focused on monitoring T cell populations, but the possibility that ipilimumab treatment is affecting myeloid populations has also been taken into account in this work.
Blood samples were collected from patients at the following time points: Before treatment, and at the time of the second and fourth ipilimumab doses. Peripheral blood mononuclear cells (PBMCs) were isolated by density gradient centrifugation and stained for flow cytometric analysis within two hours of sample collection.
In the 42 patients included, median OS was 55 weeks from the start of treatment. Adverse events were observed in 16 patients (38%), including eight grade III-IV (19%). Patients were classified according to their response as PD (progressive disease, 57%), SD (stable disease, 23%) and PR (partial response, 20%).
Our data show that CD4 T cells are activated in response to treatment, as the frequency of ICOS+ CD4 T cells was significantly increased after the first ipilimumab dose and remained high throughout the study. In addition to this, we monitored a concomitant decrease in the frequency of granulocytic MDSCs (grMDSCs) during treatment. Further analysis showed that the populations of ICOS+ CD4 T cells and grMDSCs presented a statistically significant inverse correlation. The frequency of Arg1+ myeloid cells was also reduced after treatment, suggesting that not only the frequency of grMDSCs was affected, but their suppressive potential was also diminished. When monocytic MDSCs were analyzed, no significant changes in their frequency were observed, although a significant drop in the frequency of iNOS+ cells in the monocytic population suggests that at least one of their suppressive capabilities is weakened. In addition to these findings, an overall decrease in the frequency of regulatory T cells (Tregs) was also observed.
These results suggest that there may be more than one mechanism of action by which ipilimumab contributes to release the brake on the immune system. On one hand, blocking CTLA-4 results in a direct effect on the activation status of CD4+ T cells. On the other hand the observed reduction in Tregs and MDSCs (in frequency and suppressive potential) may contribute to significantly alleviate the suppression exerted on the immune system. These effects and their possible clinical implications should be further explored in order to fully understand the mechanisms of action of CTLA-4 blockade with ipilimumab.
Citation Format: Yago Pico de Coaña, Maria Wolodarski, Yuya Yoshimoto, Giusy Gentilcore, Isabel Poschke, Giuseppe V. Masucci, Johan Hansson, Rolf Kiessling. Immune monitoring of ipilimumab treated patients reveals enhanced CD4+ T cell activation correlated with diminished MDSCs. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A071.
- ©2016 American Association for Cancer Research.