Abstract
BackgroundCancer-related disturbances in myeloid lineage development, marked by high levels of myeloid-derived suppressor cells (MDSC) and impaired dendritic cell (DC) development, are associated with poor clinical outcome due to immune escape and therapy resistance. Redressing this balance may therefore be of clinical benefit. Here we investigated the effects of combined Prostate GVAX/ipilimumab immunotherapy on myeloid subsets in peripheral blood of castration-resistant prostate cancer (CRPC) patients as well as the putative predictive value of baseline and on-treatment myeloid parameters on clinical outcome.MethodsPatients with CRPC (n = 28) received thirteen intradermal administrations of Prostate GVAX, consisting of two allogeneic GM-CSF-transduced and irradiated prostate cancer cell lines (LN-CaP and PC3) and six infusions of escalating doses of anti-CTLA4/ipilimumab. Frequencies and activation status of peripheral blood DC (PBDC) and MDSC were determined before, during and after treatment by flowcytometric analysis and related to clinical benefit.ResultsSignificant treatment-induced activation of conventional and plasmacytoid DC subsets (cDC and pDC) was observed, which in the case of BDCA1/CD1c+ cDC1 and MDC8+/6-sulfoLacNAc+ inflammatory cDC3 was associated with significantly prolonged overall survival (OS), but also with the development of autoimmune-related adverse events. High pre-treatment levels of CD14+HLA-DR−monocytic MDSC (mMDSC) were associated with reduced OS. Unsupervised clustering of these myeloid biomarkers revealed particular survival advantage in a group of patients with high treatment-induced PBDC activation and low pretreatment frequencies of suppressive mMDSC in conjunction with our previously identified lymphoid biomarker of high pretreatment CD4+CTLA4+ T cell frequencies.ConclusionsOur data demonstrate that DC and MDSC subsets are affected by prostate GVAX/ipilimumab therapy and that myeloid profiling may contribute to the identification of patients with possible clinical benefit of Prostate GVAX/ipilimumab treatment.Electronic supplementary materialThe online version of this article (doi:10.1186/s40425-014-0031-3) contains supplementary material, which is available to authorized users.
Highlights
Cancer-related disturbances in myeloid lineage development, marked by high levels of myeloid-derived suppressor cells (MDSC) and impaired dendritic cell (DC) development, are associated with poor clinical outcome due to immune escape and therapy resistance
To study whether peripheral blood DC (PBDC) and MDSC subsets are affected by prostate GVAX/ipilimumab therapy, extensive myeloid subset monitoring was performed
immune-related adverse events (IRAE) were more frequent in patients that benefited from treatment (i.e. partial responses (PR) and stable disease (SD); p = 0.0015), the development of IRAE was not associated with survival ([11]; Additional file 1: Figure S1)
Summary
Cancer-related disturbances in myeloid lineage development, marked by high levels of myeloid-derived suppressor cells (MDSC) and impaired dendritic cell (DC) development, are associated with poor clinical outcome due to immune escape and therapy resistance. Redressing this balance may be of clinical benefit. We investigated the effects of combined Prostate GVAX/ipilimumab immunotherapy on myeloid subsets in peripheral blood of castration-resistant prostate cancer (CRPC) patients as well as the putative predictive value of baseline and on-treatment myeloid parameters on clinical outcome. We recently reported the combined immunotherapy of a GM-CSF-engineered allogeneic tumor cell-based vaccine (Prostate GVAX) and ipilimumab in patients with mCRPC to be safe and clinically active [11]; clinical results included partial responses (PR) and a relatively long survival as compared to survival rates observed in control arms of recent Phase III trials [2,3,4]
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