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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.

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)

Bottom Line: Redressing this balance may therefore be of clinical benefit.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Oncology, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, The Netherlands.

ABSTRACT

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.

No MeSH data available.


Related in: MedlinePlus

Increased monocyte activation following Prostate GVAX/ipilimumab therapy is associated with prolonged survival. Frequencies and activation status of circulating CD14+ monocytes were determined before (w0), during (w4, w8, w12, w16, w20, w24) and after (fu) Prostate GVAX/ipilimumab treatment by flowcytometric analysis. A) Mean percentage (of PBMC) ± SEM and B) mean activation ± SEM of CD14+ monocytes is shown before, during and after Prostate GVAX/ipilimumab treatment for 28 patients, divided by clinical PSA response: partial PSA response (PR; black squares), disease stabilization or (SD; white squares) or disease progression (PD; grey squares). Activation is given as med. Fluorescence Index (med. FI) and calculated by dividing the med. fluorescence (med. fl) of CD40 antibody by the med. fl of the isotype control antibody. C) Kaplan Meier curve for treatment-induced increases in activation of monocytes. Number of patients and corresponding median survival for each group are given. Differences between pre- and on- or post-treatment were analyzed with the repeated measures ANOVA with a post-hoc Dunnett’s multiple comparisons test. Differences were considered significant when p < 0.05, as indicated with asterisks (* p < 0.05, ** p < 0.01).
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Fig2: Increased monocyte activation following Prostate GVAX/ipilimumab therapy is associated with prolonged survival. Frequencies and activation status of circulating CD14+ monocytes were determined before (w0), during (w4, w8, w12, w16, w20, w24) and after (fu) Prostate GVAX/ipilimumab treatment by flowcytometric analysis. A) Mean percentage (of PBMC) ± SEM and B) mean activation ± SEM of CD14+ monocytes is shown before, during and after Prostate GVAX/ipilimumab treatment for 28 patients, divided by clinical PSA response: partial PSA response (PR; black squares), disease stabilization or (SD; white squares) or disease progression (PD; grey squares). Activation is given as med. Fluorescence Index (med. FI) and calculated by dividing the med. fluorescence (med. fl) of CD40 antibody by the med. fl of the isotype control antibody. C) Kaplan Meier curve for treatment-induced increases in activation of monocytes. Number of patients and corresponding median survival for each group are given. Differences between pre- and on- or post-treatment were analyzed with the repeated measures ANOVA with a post-hoc Dunnett’s multiple comparisons test. Differences were considered significant when p < 0.05, as indicated with asterisks (* p < 0.05, ** p < 0.01).

Mentions: When patients were divided by treatment response, decreases in the frequency of monocytes were found to be selectively associated with PR (Figure 2A), which, like observed for PBDC subsets, was paralleled by increased activation (Figure 2B). Of note, although these were clear trends, they did not reach statistical significance. Similarly to the cDC1/BDCA1 and cDC3/SLAN-DC subsets, treatment-induced increases of CD40 med. FI on CD14+ monocytes was associated with prolonged OS (median survival 57 vs. 21 months, p = 0.0749; Figure 2C and Table 1).Figure 2


Myeloid derived suppressor and dendritic cell subsets are related to clinical outcome in prostate cancer patients treated with prostate GVAX and ipilimumab.

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)

Increased monocyte activation following Prostate GVAX/ipilimumab therapy is associated with prolonged survival. Frequencies and activation status of circulating CD14+ monocytes were determined before (w0), during (w4, w8, w12, w16, w20, w24) and after (fu) Prostate GVAX/ipilimumab treatment by flowcytometric analysis. A) Mean percentage (of PBMC) ± SEM and B) mean activation ± SEM of CD14+ monocytes is shown before, during and after Prostate GVAX/ipilimumab treatment for 28 patients, divided by clinical PSA response: partial PSA response (PR; black squares), disease stabilization or (SD; white squares) or disease progression (PD; grey squares). Activation is given as med. Fluorescence Index (med. FI) and calculated by dividing the med. fluorescence (med. fl) of CD40 antibody by the med. fl of the isotype control antibody. C) Kaplan Meier curve for treatment-induced increases in activation of monocytes. Number of patients and corresponding median survival for each group are given. Differences between pre- and on- or post-treatment were analyzed with the repeated measures ANOVA with a post-hoc Dunnett’s multiple comparisons test. Differences were considered significant when p < 0.05, as indicated with asterisks (* p < 0.05, ** p < 0.01).
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Related In: Results  -  Collection

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Fig2: Increased monocyte activation following Prostate GVAX/ipilimumab therapy is associated with prolonged survival. Frequencies and activation status of circulating CD14+ monocytes were determined before (w0), during (w4, w8, w12, w16, w20, w24) and after (fu) Prostate GVAX/ipilimumab treatment by flowcytometric analysis. A) Mean percentage (of PBMC) ± SEM and B) mean activation ± SEM of CD14+ monocytes is shown before, during and after Prostate GVAX/ipilimumab treatment for 28 patients, divided by clinical PSA response: partial PSA response (PR; black squares), disease stabilization or (SD; white squares) or disease progression (PD; grey squares). Activation is given as med. Fluorescence Index (med. FI) and calculated by dividing the med. fluorescence (med. fl) of CD40 antibody by the med. fl of the isotype control antibody. C) Kaplan Meier curve for treatment-induced increases in activation of monocytes. Number of patients and corresponding median survival for each group are given. Differences between pre- and on- or post-treatment were analyzed with the repeated measures ANOVA with a post-hoc Dunnett’s multiple comparisons test. Differences were considered significant when p < 0.05, as indicated with asterisks (* p < 0.05, ** p < 0.01).
Mentions: When patients were divided by treatment response, decreases in the frequency of monocytes were found to be selectively associated with PR (Figure 2A), which, like observed for PBDC subsets, was paralleled by increased activation (Figure 2B). Of note, although these were clear trends, they did not reach statistical significance. Similarly to the cDC1/BDCA1 and cDC3/SLAN-DC subsets, treatment-induced increases of CD40 med. FI on CD14+ monocytes was associated with prolonged OS (median survival 57 vs. 21 months, p = 0.0749; Figure 2C and Table 1).Figure 2

Bottom Line: Redressing this balance may therefore be of clinical benefit.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Oncology, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, The Netherlands.

ABSTRACT

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.

No MeSH data available.


Related in: MedlinePlus