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2014 ; 2
(ä): 31
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Myeloid derived suppressor and dendritic cell subsets are related to clinical
outcome in prostate cancer patients treated with prostate GVAX and ipilimumab
#MMPMID26196012
Santegoets SJ
; Stam AG
; Lougheed SM
; Gall H
; Jooss K
; Sacks N
; Hege K
; Lowy I
; Scheper RJ
; Gerritsen WR
; van den Eertwegh AJ
; de Gruijl TD
J Immunother Cancer
2014[]; 2
(ä): 31
PMID26196012
show ga
BACKGROUND: 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 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. METHODS: Patients 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. RESULTS:
Significant 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. CONCLUSIONS: Our 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.