Assessment of blood and tissue myeloid derived suppressor cells (MDSC), clinicopathologic factors, and treatment response in urothelial carcinoma (UC) patients (pts) undergoing surgery.

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 362-362 ◽  
Author(s):  
Moshe Chaim Ornstein ◽  
C. Marcela Diaz-Montero ◽  
Patricia A. Rayman ◽  
Paul Elson ◽  
Samuel Haywood ◽  
...  
Keyword(s):  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Cell Cancer ◽  
Suppressor Cells ◽  
Complete Response ◽  
Intravesical Therapy ◽  
Blood Levels ◽  
Peripheral Blood Mononuclear ◽  
Clinicopathologic Factors ◽  
Mixed Histology

362 Background: MDSC are heterogeneous immunosuppressive cells with potential predictive/prognostic role in cancer. The association between MDSC, clinicopathologic factors and pathologic response in pts with UC merits evaluation. Methods: Peripheral blood and/or tissue was collected from 120 pts. MDSC were measured in fresh unfractionated whole blood (WB), in peripheral blood mononuclear cells (PBMC) and fresh tumor tissue. MDSCs were identified by flow cytometry in WB and defined as LinloCD33+/HLADR- ((T)otal MDSC). MDSC subsets were defined as LinloCD33+/HLADR- and (G)ranulocytic (CD15+CD14-), (M)onocytic (CD15-CD14+), (I)mmature (CD15-CD14-, CD11b+ ). MDSC populations were presented as % of live nucleated blood cells and as absolute numbers from WB. Spearman correlations (r) and Wilcoxon rank sum test were used to assess correlations between MDSC populations, clinicopathologic factors and pT0N0%. Results: Of 120 pts, 82 were non-metastatic: 58 had only blood, 23 had blood & tissue, 1 had only tissue available for analysis. Of these 82 non-metastatic pts, 70 were men, median age 68; 81 pts had primary UC histology, 1 small cell cancer, 24 had mixed UC histology; 24 had prior intravesical therapy, 34 had neoadjuvant therapy (79% cisplatin-based, 21% unknown), 4 pts had post-op recurrence. At cystectomy: 15/82 pT0, 22/82 pT3/4; 37/82 CIS; 8/78 pN+. Significant associations were seen between MDSC blood levels and mixed histology, CIS, pN+, and lower pT0N0% (Table). Tumor M-MDSCs were associated with pN+ (p=0.05). There was significant correlation between tumor and WB % M-MDSC (r=0.55, p=0.007), and tumor and WB % G-MDSC (r=0.46, p=0.03). Conclusions: Blood MDSC levels correlate with several clinicopathologic factors and may predict pathological complete response (pT0N0). Assessment of association between MDSC levels, outcome and immunotherapy response is ongoing including in metastatic pts. [Table: see text]

Myeloid derived suppressor cells (MDSC) and inflammatory biomarkers in metastatic urothelial carcinoma (mUC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 4548-4548
Author(s):  
Moshe Chaim Ornstein ◽  
C. Marcela Diaz-Montero ◽  
Patricia A. Rayman ◽  
Paul Elson ◽  
Samuel Haywood ◽  
...  
Keyword(s):  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Suppressor Cells ◽  
Inflammatory Biomarkers ◽  
Intravesical Therapy ◽  
Clinicopathologic Features ◽  
Peripheral Blood Mononuclear ◽  
Inflammatory Biomarker ◽  
Neutrophil Lymphocyte Ratio ◽  
Clinicopathologic Factors

4548 Background: MDSC are potent immunosuppressive cells with prognostic implications in many solid tumors. We previously reported significant correlations between MDSC and clinicopathologic features in localized UC. We hypothesized that different MDSC populations may correlate with inflammatory biomarkers and clinicopathologic features in mUC. Methods: Peripheral blood samples were collected from 46 mUC pts. MDSCs were measured in fresh unfractionated whole blood (WB) and in peripheral blood mononuclear cells (PBMC). MDSCs were identified by flow cytometry in WB and defined as LinloCD33+/HLADR- [(T)otal MDSC]. MDSC subsets were defined as (G)ranulocytic (CD15+CD14-), (M)onocytic (CD15-CD14+), (I)mmature (CD15-CD14-), or CD11b+. MDSC populations were presented as % of live nucleated blood cells and as absolute numbers from WB. Spearman correlations (r) and Wilcoxon rank sum test were used to assess correlations between MDSC populations & clinicopathologic factors. Results: Of 46 pts:78% men, median age at diagnosis 69 (31-83), 33% never smokers, 76% pure UC, 76% bladder primary, 28% prior intravesical therapy, 35% prior neoadjuvant chemotherapy, 56% prior cystectomy, 83% overweight/obese. G-MDSC was the predominant subset in WB (43%) and PBMC (39%), although M-MDSC were almost equally predominant in PBMC (35%). There was a correlation between the WB and PBMC values of T-, I-, and M- MDSC (p≤0.05). Higher % WB I-MDSC correlated with lower blood neutrophil/lymphocyte ratio (NLR) (p = 0.009), while higher WB G-MDSC and %PBMC G-MDSC were associated with higher NLR (p = 0.03 and p = 0.02, respectively). Higher I-MDSC / G-MDSC ratio was associated with lower NLR (r = -0.35, p = .02) and with various clinicopathologic parameters. Conclusions: HigherI-MDSC / G-MDSC ratio correlates inversely with NLR, which is considered an inflammatory biomarker and had prognostic value in other studies. The mechanism of MDSC interaction with inflammatory response in mUC pts merits evaluation and is being investigated in a larger cohort of UC pts on chemotherapy or immunotherapy (with longer follow up).

Correlation of myeloid-derived suppressor cells (MDSC) with pathologic complete response (pCR), recurrence free survival (RFS), and overall survival (OS) in patients with urothelial carcinoma (UC) undergoing cystectomy.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 437-437
Author(s):  
Jaleh Fallah ◽  
C. Marcela Diaz-Montero ◽  
Patricia A. Rayman ◽  
Wei (Auston) Wei ◽  
Iris Yeong- Fung Sheng ◽  
...  
Keyword(s):  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Pathologic Complete Response ◽  
Suppressor Cells ◽  
Complete Response ◽  
Rank Test ◽  
Peripheral Blood Mononuclear ◽  
One Year ◽  
Circulating Levels

437 Background: MDSCs play an important role in maintaining a tumor immunosuppressive microenvironment. The association of circulating levels of MDSCs with pCR (pT0N0) and outcomes was investigated in patients (pts) with non-metastatic UC undergoing cystectomy. Methods: Peripheral blood samples from pts with non-metastatic UC was collected. MDSCs were measured in freshly purified peripheral blood mononuclear cells, using flow cytometry. Total (T) MDSC was defined as CD33+/HLADR-. T-MDSC subtypes were polymorphonuclear (PMN-MDSC: CD15+/CD14-), monocytic (M-MDSC: CD15-/CD14+], and uncommitted (UC-MDSC: CD15-/CD14-]. MDSC populations were presented as % of live nucleated blood cells. Wilcoxon rank sum test was used to compare MDSCs between pCR groups. Kaplan-Meier and log-rank test were used to analyze RFS and OS. Results: MDSC data were available for 124 pts (106 male, 18 female), median age 68, 28 (23%) never smokers, 93 (75%) pure UC. Thirty four pts (27%) received intravesical BCG; 49 (39%) received neoadjuvant chemotherapy (NAC); 22 (19%) had pCR (pT0N0) following surgery. PMN-MDSC was the dominant subtype (42%) and frequency of UC-MDSC and M-MDSC was 40% and 17%, respectively. Circulating levels of T-MDSC and PMN-MDSC were significantly lower in pCR patients than those in non-pCR patients (Table). Sixteen deaths were observed and 21 pts recurred after surgery. The median follow-up time of patients alive was 18.7 months (range 0.3-42.4). The median OS or RFS of all patients was not reached. One-year and two-year OS rates were 94% and 83%, respectively. One-year and two-year RFS rates were 82% and 69%, respectively. There was no association between MDSC subtypes with OS or RFS. Conclusions: Total- and PMN-MDSC subtypes in blood were significantly correlated with pCR in pts with non-metastatic UC who undergo cystectomy. The relatively short follow-up may impact the association with RFS and OS; additional follow-up is needed. [Table: see text]

A Phase 1 Clinical-Pharmacodynamic Study of the Farnesyltransferase Inhibitor Tipifarnib in Combination with the Proteasome Inhibitor Bortezomib in Advanced Acute Leukemias.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1945-1945 ◽  
Author(s):  
Jeffrey E. Lancet ◽  
Elliott F. Winton ◽  
Robert K. Stuart ◽  
Michelle Burton ◽  
Christopher Cubitt ◽  
...  
Keyword(s):  
Western Blot ◽  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Combined Therapy ◽  
Sensory Neuropathy ◽  
Complete Response ◽  
Peripheral Blood Mononuclear ◽  
Acute Leukemias ◽  
Blood Mononuclear Cells

Abstract Combination therapy utilizing 2 novel agents with independent mechanisms of action and non-overlapping toxicities may be useful in the setting of advanced cancers. Tipifarnib (T) is an orally bioavailable farnesyltranferase inhibitor with documented single-agent activity in acute myeloid leukemia (AML). Bortezomib (B) is a broad inhibitor of proteasomal function, approved for treatment in multiple myeloma and mantle cell lymphoma. Preclinical studies indicated synergistic activity between these 2 agents for eliciting apoptosis within leukemia and myeloma cell lines and ex-vivo cells adhered to fibronectin. In this phase I combination trial, we studied the effect of combined effect of T plus B in patients with advanced acute leukemias. Objectives: The primary endpoint was toxicity assessment. Secondary endpoints included effect of combined therapy on signaling intermediates, including p-AKT, Bim, Bax, and NF-kB, as well as effects on farnesyltransferase (FT) and the proteasome activity. Eligibility: Patients with AML, ALL, or CML-BC who had received < 3 cycles of prior therapy were eligible. Methods: Patients received T on days 1–14 and B on days 1, 4, 8, and 11. Cycles were repeated every 21 days. Dose escalation occurred using cohorts of 3–6 patients. The starting dose was T: 300 mg/m2 and B: 1.0 mg/m2 Bone marrow aspirate was obtained at baseline, day 8, and between day 15 and the start of the next cycle. Measurement of signaling intermediates were performed in Ficoll-enriched leukemic marrow blasts using Western Blot (p-AKT, Bax, Bim) and ELISA (NF-kB). FT and proteasomal activity were directly measured within peripheral blood mononuclear cells (PBMC) using previously described methods. Results: To date, 27 patients have been enrolled at 3 centers. Four patients were ineligible after screening, and 23 patients have been treated. Median age was 69 years (range 48–84) Diagnosis: AML=25, ALL=1, MDS=1. Accrual to the 4th and final dosing cohort has occurred, without maximum tolerated dose being reached at the 4th and final planned dosing cohort (T: 600 mg/m2 and B: 1.3 mg/m2). Six patients received ≥ 2 cycles of treatment. Dose-limiting toxicities to date have included: nausea/diarrhea (1 patient), sensory neuropathy (1 patient), and fatigue (1 patient). Common drug-related (> 10%) non dose-limiting toxicities included: infection/febrile neutropenia, diarrhea, nausea, vomiting, sensory neuropathy, and fatigue, most of which were grade 1 or 2. FTase inhibition within peripheral blood mononuclear cells (PBMC) was measured serially in 8 patients to date, with a median of 70% inhibition by day 8, and with 5 out of 6 evaluable patients having sustained inhibition at day 22. Proteasome function within PBMCs was reduced by a median of 44.3% in 7 patient samples pre-infusion and 1 hour post-infusion on day 8. Proteasome activity within PBMCs at day 22 was decreased from baseline in 5 out of 7 patient samples tested. Compared to baseline, NF-kB binding activity within leukemic blasts at day 8 was decreased by a median of 39% at in 10 out of 14 paired samples. No significant change in expression of p-AKT, Bax, or Bim, as measured by Western Blot, was detected at day 8. Two patients achieved clinical response; 1 patient had a complete response and another patient had complete response with incomplete count recovery. Four others had stable disease following cycle 1. Conclusion: combined therapy with T + B was well tolerated and demonstrated inhibition of several relevant target signals within leukemic blasts and PBMCs. In addition, clinical activity was seen in 2 patients to date. Accrual to the trial is ongoing and updated clinical and pharmacodynamic data will be presented.

Serial measurements of myeloid derived suppressor cells (MDSC) in metastatic urothelial carcinoma (mUC) patients (pts) treated with immune checkpoint inhibitors (CI).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e16005-e16005
Author(s):  
Moshe Chaim Ornstein ◽  
C. Marcela Diaz-Montero ◽  
Patricia A. Rayman ◽  
Paul Elson ◽  
Samuel Haywood ◽  
...  
Keyword(s):  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Checkpoint Inhibitors ◽  
Suppressor Cells ◽  
Sample Collection ◽  
Peripheral Blood Mononuclear ◽  
Signed Rank ◽  
Metastatic Setting ◽  
Never Smokers ◽  
Ecog Ps

e16005 Background: MDSC are a heterogeneous population of immunosuppressive cells with potentially predictive implications in UC pts receiving CI. We hypothesized that MDSC populations may change after CI exposure. Methods: Serial peripheral blood samples were collected from mUC pts treated with CI. MDSC were measured in fresh unfractionated whole blood (WB) and in peripheral blood mononuclear cells (PBMC). MDSC were identified by flow cytometry in WB and defined as LinloCD33+/HLADR- [(T)otal MDSC]. MDSC subsets were defined as (G)ranulocytic (CD15+CD14-), (M)onocytic (CD15-CD14+), (I)mmature (CD15-CD14-), or CD11b+. MDSC populations were presented as % of live nucleated blood cells and as absolute numbers from WB. The Wilcoxon signed rank and rank sum tests were used to assess changes in MDSC populations while on CI. Results: 17 pts treated with CI (9 atezolizumab [A], 8 pembrolizumab [P]) had ≥ 2 MDSC samples for analysis. Median age at diagnosis was 71 (46-81), 12 men, 29% never smokers; 53% / 29% / 18% ECOG PS 0/1/2 and 59% visceral metastasis at the time of 1st sample collection. 10 pts received CI as 1st line therapy (Tx) in metastatic setting; 7 pts received chemotherapy as 1st-line Tx for mUC (6 platinum-based, 1 docetaxel) and CI as 2nd-line Tx. In 16 pts with samples before 1stdose, there was a relative decrease (median 36.3%, range -59.7 to +21.2) in PBMC % I-MDSCs between 1st and 2nd samples (p=0.06). Interestingly, PBMC %M-MDSC and %I-MDSC tended to increase compared to baseline in pts treated with P, while they tended to decrease in pts treated with A (Table). Conclusions: In this cohort of pts with mUC treated with CIs,MDSC changes differed based on CI (anti-PDL1 or anti-PD1). Further study in larger cohort with various prior Tx lines and longer follow up as well as correlations with Tx response, toxicity and outcomes are ongoing. [Table: see text]

Myeloid-Derived Suppressor Cells in Patients with Hodgkin Lymphoma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3662-3662
Author(s):  
Nunziatina Parrinello ◽  
Piera La Cava ◽  
Daniele Tibullo ◽  
Cesarina Giallongo ◽  
Orazio Di Bartolo ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Hodgkin Lymphoma ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Conflicts Of Interest ◽  
Suppressor Cells ◽  
Cell Number ◽  
Myeloid Derived Suppressor Cells ◽  
Peripheral Blood Mononuclear ◽  
Hla Dr

Abstract Abstract 3662 Poster Board III-598 Background Immune suppression and angiogenesis are mechanisms key to tumour growth and progression. Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of cells of myeloid origin and include immature macrophages, dendritic cells (DC) and other myeloid cells. In mice are phenotypically characterized as CD11b+Gr-1+ cells, while in human they have an immature phenotype, including lineage negative (Lin-), CD14-, HLA-DR-, CD15+, CD34+, CD11b+, CD33+, and CD13+ cells. MDSC reduce activated T-cell number and inhibit their function through different mechanisms including: L-arginine metabolism, nitric oxide (NO), up-regulation of reactive oxygen species (ROS), and secretion of immunosuppressive cytokines. MDSC also promote tumor-dependent angiogenesis as well as tumor metastasis. Their accumulation has been described in patients affected by some solid tumors but information on haematological neoplasms are lacking. Our study investigated by flow cytometry the presence of MSDC in the peripheral blood of patients affected by Hodgkin Lymphoma (HL). Methods We studied 14 patients with HL at diagnosis and 10 age-matched healthy controls (HC). Peripheral blood mononuclear cells were stained with the following monoclonal antibodies:CD11b, CD13, CD14, CD34, CD45, for 20 minutes at room temperature. After lysing red cells, cells were analyzed by flow cytometry. Results we observed a increased number of MDSC (CD11b+,CD13+,CD34+,CD14-, CD45+) in the peripheral blood of patients with HL compared to HC (13,37 ± 17,77 ×109/l vs 1,45± 0,98 ×109/l, p=0,0007). We also found that patients with advanced-stage Hodgkin disease (III and IV) have higher number of MDSC, compared to patients stage I and II (p= 0,04). Conclusion These data suggest a role for myeloid-derived suppressor cells in promoting tumor cell proliferation in hodgkin lymphoma. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Impact of Cytomegalovirus Infection and Genetic Background on the Frequencies of Peripheral Blood Suppressor Cells in Human Twins

Pathogens ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 963
Author(s):  
David Goldeck ◽  
Lisbeth Aagaard Larsen ◽  
Kaare Christensen ◽  
Klaus Hamprecht ◽  
Lilly Öttinger ◽  
...  
Keyword(s):  
T Cells ◽  
Peripheral Blood ◽  
Genetic Background ◽  
Mononuclear Cells ◽  
Suppressor Cells ◽  
Suppressor Cell ◽  
Minor Role ◽  
Peripheral Blood Mononuclear ◽  
Disease States ◽  
A Minor

Frequencies and proportions of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) in peripheral blood may be informative biomarkers for certain disease states. The influence of genetics and lifetime pathogen exposures on Treg and MDSC frequencies is largely unexplored. Cytomegalovirus (CMV) establishes a latent infection and causes an accumulation of late-differentiated CD8+ memory T cells, commonly associated with a lower frequency of naive cells. Here, analyzing peripheral blood mononuclear cells by multicolor flow cytometry, we found a tendency towards lower frequencies of CD4+CD25+FoxP3+ Tregs in CMV-seropositive than -seronegative middle-aged individuals (p = 0.054), whereas frequencies of lineage-negative CD14+HLA-DR-MDSCs were significantly lower in CMV-seropositive participants (p = 0.005). Assessing associations with the presence of antibodies against different CMV structural proteins, rather than merely assigning seropositivity or seronegativity, failed to yield any closer associations. Examining Treg subsets revealed at most a minor role of the individual’s genetic background, based on an analysis of monozygotic (MZ, n = 42) versus dizygotic (DZ, n = 39) twin pairs from the Danish Twin Registry. The same was true for MDSCs. These initial results suggest that an immunological history of exposures is more important than genetics in determining overall human suppressor cell levels.

scholarly journals Heterogeneity of Response and Immune System Activity during Treatment with Nivolumab in Hepatocellular Carcinoma: Results from a Single-Institution Retrospective Analysis

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 213
Author(s):  
Ilario Giovanni Rapposelli ◽  
Serena De Matteis ◽  
Paola Lanuti ◽  
Martina Valgiusti ◽  
Giulia Bartolini ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cells ◽  
Mononuclear Cells ◽  
Suppressor Cells ◽  
Response Assessment ◽  
Complete Response ◽  
Lower Percentage ◽  
Peripheral Blood Mononuclear ◽  
Heterogeneous Behavior ◽  
New Perspective

Treatment of hepatocellular carcinoma (HCC) is rapidly evolving, with many new therapeutic options; in particular, immunotherapy (IT) is acquiring a major role, even in combination regimens. Despite these promising results, an important limitation is the lack of prognostic and predictive factors that prevent provision of a tool for patient stratification in order to select the most appropriate strategy. Furthermore, response assessment can be challenging with IT due to peculiar patterns such as mixed responses or pseudoprogression. We analyzed biological and clinical features from the first 10 HCC patients treated with nivolumab in our institution. Analysis of patterns of response in CT assessment revealed complete response in pulmonary lesions, along with heterogeneous behavior in the liver and other organ lesions. Peripheral blood mononuclear cells (PBMC) analysis in the first four patients showed unique alterations in a patient with poor prognosis, both at baseline (lower percentage of effector T cells, higher percentage of natural killer T [NK/T] cells) and during treatment with nivolumab (decrease in nonclassical monocytes, increase in monocytic myeloid-derived suppressor cells [MO-MDSC]), suggesting a possible prognostic role for these features. Although obtained in a small cohort of patients, our results open a new perspective for understanding mechanisms underlying IT outcomes in HCC patients.

Correlation of myeloid derived suppressor cell (MDSC) populations with clinicopathologic features in urothelial carcinoma (UC).

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 434-434
Author(s):  
Moshe Chaim Ornstein ◽  
C. Marcela Diaz-Montero ◽  
Pat A. Rayman ◽  
Paul Elson ◽  
Samuel Haywood ◽  
...  
Keyword(s):  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Prognostic Significance ◽  
Cleveland Clinic ◽  
Suppressor Cell ◽  
Clinicopathologic Features ◽  
Peripheral Blood Mononuclear ◽  
Myeloid Derived Suppressor Cell ◽  
Mixed Histology ◽  
Immunosuppressive Cells

434 Background: MDSC are a heterogeneous population of potent immunosuppressive cells with potential predictive/prognostic significance in solid tumors. The association between MDSC and clinicopathologic features in patients (pts) with UC was investigated. Methods: Peripheral blood from 26 non-metastatic UC pts scheduled to undergo cystectomy or nephroureterectomy at Cleveland Clinic was collected. MDSC were enumerated in fresh unfractionated blood (WB) and in peripheral blood mononuclear cells (PBMC). (T)otal MDSC were defined as CD33+/HLADR-; out of T-MDSC, (G)ranulocytic (CD15+CD14-), (M)onocytic (CD15-CD14+) and (I)mmature (CD15-CD14-) MDSC were identified. CD11b MDSC (Linlo/HLADR-/CD33+/CD11b+) were identified in WB. MDSC populations were presented as % of live nucleated blood cells and as absolute numbers from WB. Wilcoxon rank sum test was used to assess associations between MDSC populations and clinicopathologic features. Due to the exploratory nature of the study, p < .10 was considered significant. Results: Of 26 pts, 25 had surgery and 1 is under surveillance. 24 had both WB and PBMC data. 23/26 were men; median age 67. Of 26 pts, all had primarily UC histology; 7 had mixed UC histology, 11 had prior intravesical BCG, 12 neoadjuvant therapy (10 Gem/Cis, 1 Gem/Carbo, 1 unknown). Of 25 pts who had surgery, 5 had pT3/4 stage; 5 had LVI; 9 had CIS. All but 1 had negative LN. Higher levels of specific WB MDSC populations were associated with mixed histology (including squamous), CIS, and higher pT-stage (Table). When compared to a separate cohort of 11 pts with metastatic UC, the % G-MDSC in PBMC was lower in non-metastatic pts (median 0.3 vs. 1.47; p = .05). Conclusions: Although no single MDSC population correlated with all the evaluated clinicopathologic features, higher levels of certain MDSC populations appear to correlate with histology and pT stage. Further validation of blood and tissue is ongoing in a larger cohort. [Table: see text]

Serial changes in PD1/PDL1 expression in metastatic urothelial carcinoma (mUC) patients (pts) treated with immune checkpoint blockade (CPB).

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. 109-109
Author(s):  
Alice Tzeng ◽  
C. Marcela Diaz-Montero ◽  
Patricia A. Rayman ◽  
Jin Sub Kim ◽  
Paul G Pavicic ◽  
...  
Keyword(s):  
Peripheral Blood ◽  
Mixed Model ◽  
Mononuclear Cells ◽  
Suppressor Cells ◽  
Immune Checkpoint Blockade ◽  
Peripheral Blood Mononuclear ◽  
Blood Samples ◽  
Immune Marker ◽  
Marker Expression ◽  
Median Change

109 Background: Since CPB may alter immune marker expression in key immunomodulatory populations such as myeloid-derived suppressor cells (MDSC) and CD8+ cytotoxic T lymphocytes (CTL), we evaluated PD1/PDL1 expression in longitudinal samples from mUC pts treated with CPB. Methods: Serial peripheral blood samples were collected from mUC pts who received CPB. PD1/PDL1 and VISTA expression was measured in MDSC (CD33+HLADR−) and CTL (CD8+CD4−) from live peripheral blood mononuclear cells using flow cytometry. MDSC subsets were further defined as (G)ranulocytic (CD15+CD14−), (M)onocytic (CD15−CD14+), and (I)mmature (CD15−CD14−). PD1/PDL1 and VISTA expression was presented as % of each MDSC subset or CTL. Wilcoxon signed-rank tests and mixed-model regression analyses were performed to assess changes in immune marker expression after CPB. Results: Of 30 CPB-treated pts with ≥ 2 blood samples for analysis, 21 received anti-PDL1 (20 atezolizumab/1 avelumab; [A]) and 9 received anti-PD1 (pembrolizumab [P]). Median age at diagnosis was 69.5 (46–81), 77% men, 33% never smokers, 63% pure UC, 70% bladder primary, 20% prior intravesical BCG, 37% prior neoadjuvant chemotherapy, 63% prior cystectomy. Best overall responses to CPB were 3 PR/13 SD/5 PD (A) and 1 CR/1 PR/4 SD/3 PD (P). Successive doses of A correlated with decreased %PDL1+ M-MDSC, while those of P correlated with decreased %PD1+ M- and I- MDSC (Table). No significant changes in VISTA expression were detected. In 11 A-treated pts with samples before/after the 1st dose, %PDL1+ M- and I- MDSC decreased (median change −25.5 and −5.7; p = 0.02 and 0.03) and %PD1+ CTL increased (median change +2.4; p = 0.02) between 1st and 2nd samples. Conclusions: In this mUC pt cohort, distinct post-tx changes in %PD1/PDL1 in MDSC subsets and CTL occurred based on CPB (anti-PD1 vs anti-PDL1). Further analysis of correlations between CPB, immune marker expression, clinicopathologic factors, and outcomes is ongoing in a larger cohort. Mean absolute change in marker expression per dose in pts treated with CPB. [Table: see text]

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