Evaluation of pharmacodynamic (PD) biomarkers in patients with metastatic pancreatic cancer treated with BL-8040, a novel CXCR4 antagonist.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 276-276 ◽  
Author(s):  
Manuel M. Hidalgo ◽  
Ron Epelbaum ◽  
Valeriya Semenisty ◽  
Ravit Geva ◽  
Talia Golan ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Flow Cytometry ◽  
Immune Cells ◽  
Immune Cell ◽  
Cell Subset ◽  
Fold Increase ◽  
Cell Infiltration ◽  
Metastatic Pancreatic Cancer ◽  
Cxcr4 Antagonist ◽  
Open Label

276 Background: BL-8040 is a novel CXCR4 antagonist being developed for multiple oncology indications. Preclinical studies demonstrated that BL-8040 increases the number of immune cells in peripheral blood and promotes CD8+ T cell infiltration into orthotropic pancreatic mouse tumors, reducing tumor load. BL-8040 is being evaluated in a Phase 2a, multicenter, open label trial in patients with metastatic pancreatic cancer (the COMBAT study). Patients are undergoing a 5-day period of monotherapy in which they receive daily doses of BL-8040, followed by 21-day cycles in which patients receive one dose of pembrolizumab and 3 doses/week of BL-8040 until disease progression or discontinuation. To date, 32 patients have been enrolled. Methods: On Day 1 and Day 5, blood samples were taken at pre- and post-dosing, to evaluate peripheral immune cell subset frequency by flow cytometry. In addition, core biopsies were taken from liver metastases, where possible, to assess immune cell infiltration into tumors and the tumor microenvironment (TME). Results: Here we present interim PD biomarker data from the BL-8040 monotherapy portion of the trial. Flow cytometry shows that BL-8040 monotherapy caused an approximately two-fold reduction in frequency of peripheral T regulatory cells, but had no effect on the frequency of T cells, NKT cells or cell populations that contain B cells (CD3- CD56-). Additionally, BL-8040 remained bound to CXCR4 on peripheral immune cells throughout the period of monotherapy. Analysis of available biopsies (N = 7) shows an up to 15-fold increase in the CD3+ population, and up to two-fold increase of CD8+ cells, in the tumor periphery and TME of 43% (3/7) of the patients after five days of BL-8040 monotherapy compared to baseline. Conclusions: In summary, the PD biomarker results in humans support the proposed mechanism of action for BL-8040 that was based on preclinical mouse models. Analysis of tumor biopsies is ongoing, with an emphasis on investigating the effects of BL-8040 on tumor-resident immune cells and the TME. Clinical trial information: NCT02826486.

Evaluation of pharmacodynamic (PD) biomarkers in patients with metastatic pancreatic cancer treated with BL-8040, a novel CXCR4 antagonist.

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. 88-88 ◽  
Author(s):  
Manuel M. Hidalgo ◽  
Ron Epelbaum ◽  
Valeriya Semenisty ◽  
Ravit Geva ◽  
Talia Golan ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Flow Cytometry ◽  
Immune Cells ◽  
Immune Cell ◽  
Cell Subset ◽  
Fold Increase ◽  
Cell Infiltration ◽  
Metastatic Pancreatic Cancer ◽  
Cxcr4 Antagonist ◽  
Open Label

88 Background: BL-8040 is a novel CXCR4 antagonist being developed for multiple oncology indications. Preclinical studies demonstrated that BL-8040 increases the number of immune cells in peripheral blood and promotes CD8+ T cell infiltration into orthotropic pancreatic mouse tumors, reducing tumor load. BL-8040 is being evaluated in a Phase 2a, multicenter, open label trial in patients with metastatic pancreatic cancer (the COMBAT study). Patients are undergoing a 5-day period of monotherapy in which they receive daily doses of BL-8040, followed by 21-day cycles in which patients receive one dose of pembrolizumab and 3 doses/week of BL-8040 until disease progression or discontinuation. To date, 32 patients have been enrolled. Methods: On Day 1 and Day 5, blood samples were taken at pre- and post-dosing, to evaluate peripheral immune cell subset frequency by flow cytometry. In addition, core biopsies were taken from liver metastases, where possible, to assess immune cell infiltration into tumors and the tumor microenvironment (TME). Results: Here we present interim PD biomarker data from the BL-8040 monotherapy portion of the trial. Flow cytometry shows that BL-8040 monotherapy caused an approximately two-fold reduction in frequency of peripheral T regulatory cells, but had no effect on the frequency of T cells, NKT cells or cell populations that contain B cells (CD3- CD56-). Additionally, BL-8040 remained bound to CXCR4 on peripheral immune cells throughout the period of monotherapy. Analysis of available biopsies (N = 7) shows an up to 15-fold increase in the CD3+ population, and up to two-fold increase of CD8+ cells, in the tumor periphery and TME of 43% (3/7) of the patients after five days of BL-8040 monotherapy compared to baseline. Conclusions: In summary, the PD biomarker results in humans support the proposed mechanism of action for BL-8040 that was based on preclinical mouse models. Analysis of tumor biopsies is ongoing, with an emphasis on investigating the effects of BL-8040 on tumor-resident immune cells and the TME. Clinical trial information: NCT02826486.

A phase II, open-label, randomized trial of durvalumab (D) with olaparib (O) or cediranib (C) in patients (pts) with leiomyosarcoma (LMS).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 11522-11522
Author(s):  
Olubukola Ayodele ◽  
Ben X Wang ◽  
Thomas D Pfister ◽  
Esmail Mutahar Al-Ezzi ◽  
Hal Berman ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Stable Disease ◽  
Immune Cells ◽  
Immune Cell ◽  
Tumor Infiltrating Lymphocytes ◽  
Fold Increase ◽  
Immune Checkpoint Blockade ◽  
Tumor Growth Rate ◽  
Open Label ◽  
Fluorescent Immunohistochemistry

11522 Background: The use of immune checkpoint blockade (ICB) in non-inflamed (cold) tumors is associated with limited clinical efficacy. Combination of ICB with certain molecularly targeted agents (MTA) is hypothesized to increase tumor immunogenicity by recruiting tumor infiltrating lymphocytes in cold tumors, such as LMS. Here, we present the results of LMS cohort treated on the DAPPER study (NCT03851614). Methods: LMS pts with ECOG 0-1 were randomized to either D+O (arm A), or D+C (arm B). In a 28-day cycle, D 1500mg i.v. q4w with either O 300mg bid po qd or C 20mg po qd 5d/week were administered. Overall response rates (ORR) were determined using RECISTv1.1. Evaluation of tumor kinetics (TK) was performed by calculating tumor growth rate (TGR) of target lesions on CT images at baseline and on-treatment, adjusted to account for the time difference between scans. TGR is expressed as % tumor growth/week (Ferte C et al. CCR, 2014). Additionally, paired FFPE samples (from baseline and on-treatment biopsies) were assessed using multispectral fluorescent immunohistochemistry (IHC) panel: CD3, CD8, CD20, CD68, FOXP3 and cytokeratin. Tumor areas were identified by a pathologist and immune cells were quantified using InForm image analysis software. Results: 25 metastatic LMS pts were randomized to arm A (n = 11) or B (n = 14) over 21 months. Median age was 53 years, 96% were females and 60% of pts had ≥3 lines of therapy. In 23 evaluable pts, no responses were seen, 7 pts had stable disease (SD) while 16 has progressive disease (PD). TK analysis was evaluable for 18 pts (arm A = 8, B = 10). 5/8 pts (62.5%) in arm A and 6/10 pts (60%) in arm B showed decreased TK (defined as TGRbaseline > TGRon-treatment). In 4/5 (80%) pts who had deceleration of TK in arm A, SD was maintained for ≥6 months. The reduction in TGR on treatment, compared to baseline was significant in arm A but not in arm B (measured as median % tumor growth/week of 0.5 vs 5.1, 95% CI 0.2-4.3, p = 0.035 in arm A; and 1.3 vs 2.9, 95% CI 0.2-2.7, p = 0.088 in arm B). The median PFS of arm A and B were 9 (95% CI 3-12.8) and 4 (95% CI 2.2-4.6) months respectively. There were no statistically significant differences in tumor-infiltrating immune cells when comparing baseline and on-treatment biopsies from arm A or B. In arm A, one pt with SD > 6 months had a 2.5-fold increase in CD8 (CD3+CD8+) T cells and a 7.6-fold increase in macrophages (CD68+). Conclusions: D+O or D+C resulted in stable disease in 30% of pts, mostly on arm A (D+O). TK analysis may identify pts with prolonged SD on treatment. Although a cold-to-hot immunophenotype change was not generally seen, changes in tumor infiltrating immune cell subsets were observed in one patient with prolonged stable disease. These findings support further molecular and immunophenotype characterization in LMS patients treated with D+O or D+C. Clinical trial information: NCT03851614.

scholarly journals Immune Cell Modulation of the Extracellular Matrix Contributes to the Pathogenesis of Pancreatic Cancer

Biomolecules ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 901
Author(s):  
Ramiz S. Ahmad ◽  
Timothy D. Eubank ◽  
Slawomir Lukomski ◽  
Brian A. Boone
Keyword(s):  
Pancreatic Cancer ◽  
Extracellular Matrix ◽  
Immune Cells ◽  
Immune Cell ◽  
Treatment Strategies ◽  
Stellate Cells ◽  
Pancreatic Stellate Cells ◽  
Ductal Adenocarcinoma ◽  
Cellular Mechanisms ◽  
Novel Treatment Strategies

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with a five-year survival rate of only 9%. PDAC is characterized by a dense, fibrotic stroma composed of extracellular matrix (ECM) proteins. This desmoplastic stroma is a hallmark of PDAC, representing a significant physical barrier that is immunosuppressive and obstructs penetration of cytotoxic chemotherapy agents into the tumor microenvironment (TME). Additionally, dense ECM promotes hypoxia, making tumor cells refractive to radiation therapy and alters their metabolism, thereby supporting proliferation and survival. In this review, we outline the significant contribution of fibrosis to the pathogenesis of pancreatic cancer, with a focus on the cross talk between immune cells and pancreatic stellate cells that contribute to ECM deposition. We emphasize the cellular mechanisms by which neutrophils and macrophages, specifically, modulate the ECM in favor of PDAC-progression. Furthermore, we investigate how activated stellate cells and ECM influence immune cells and promote immunosuppression in PDAC. Finally, we summarize therapeutic strategies that target the stroma and hinder immune cell promotion of fibrogenesis, which have unfortunately led to mixed results. An enhanced understanding of the complex interactions between the pancreatic tumor ECM and immune cells may uncover novel treatment strategies that are desperately needed for this devastating disease.

scholarly journals Updates on Immunotherapy and Immune Landscape in Renal Clear Cell Carcinoma

Cancers ◽  
2021 ◽  
Vol 13 (22) ◽  
pp. 5856
Author(s):  
Myung-Chul Kim ◽  
Zeng Jin ◽  
Ryan Kolb ◽  
Nicholas Borcherding ◽  
Jonathan Alexander Chatzkel ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Cells ◽  
Immune Cell ◽  
Single Cell Analysis ◽  
Clear Cell ◽  
Cd8 T Cell ◽  
Cell Infiltration ◽  
Cellular Mechanisms ◽  
T Cell Infiltration ◽  
Immunological Mechanisms

Several clinicopathological features of clear cell renal cell carcinomas (ccRCC) contribute to make an “atypical” cancer, including resistance to chemotherapy, sensitivity to anti-angiogenesis therapy and ICIs despite a low mutational burden, and CD8+ T cell infiltration being the predictor for poor prognosis–normally CD8+ T cell infiltration is a good prognostic factor in cancer patients. These “atypical” features have brought researchers to investigate the molecular and immunological mechanisms that lead to the increased T cell infiltrates despite relatively low molecular burdens, as well as to decipher the immune landscape that leads to better response to ICIs. In the present study, we summarize the past and ongoing pivotal clinical trials of immunotherapies for ccRCC, emphasizing the potential molecular and cellular mechanisms that lead to the success or failure of ICI therapy. Single-cell analysis of ccRCC has provided a more thorough and detailed understanding of the tumor immune microenvironment and has facilitated the discovery of molecular biomarkers from the tumor-infiltrating immune cells. We herein will focus on the discussion of some major immune cells, including T cells and tumor-associated macrophages (TAM) in ccRCC. We will further provide some perspectives of using molecular and cellular biomarkers derived from these immune cell types to potentially improve the response rate to ICIs in ccRCC patients.

scholarly journals Identification of immune-based prostate cancer subtypes using mRNA expression

2020 ◽  
Author(s):  
Jukun Song ◽  
Song He ◽  
Wei Wang ◽  
Jiaming Su ◽  
Dongbo Yuan ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Immune Response ◽  
Immune Cells ◽  
Immune Cell ◽  
Molecular Classification ◽  
Cell Types ◽  
Functional Enrichment ◽  
Cell Infiltration ◽  
Cell Subpopulation ◽  
Immune Cell Infiltration

Abstract Background Immune infiltration of Prostate cancer (PCa) was highly related to clinical outcomes. However, previous works failed to elucidate the diversity of different immune cell types that make up the function of the immune response system. The aim of the study was to uncover the composition of TIICs in PCa utilizing the CIBERSORT algorithm and further reveal the molecular characteristics of PCa subtypes. Method In the present work, we employed the CIBERSORT method to evaluate the relative proportions of immune cell profiling in PCa and adjacent samples, normal samples. We analyzed the correlation between immune cell infiltration and clinical information. The tumor-infiltrating immune cells of the TCGA PCa cohort were analyzed for the first time. The fractions of 22 immune cell types were imputed to determine the correlation between each immune cell subpopulation and clinical feature. Three types of molecular classification were identified via R-package of “CancerSubtypes”. The functional enrichment was analyzed in each subtype. The submap and TIDE algorithm were used to predict the clinical response to immune checkpoint blockade, and GDSC was employed to screen chemotherapeutic targets for the potential treatment of PCa. Results In current work, we utilized the CIBERSORT algorithm to assess the relative proportions of immune cell profiling in PCa and adjacent samples, normal samples. We investigated the correlation between immune cell infiltration and clinical data. The tumor-infiltrating immune cells in the TCGA PCa cohort were analyzed. The 22 immune cells were also calculated to determine the correlation between each immune cell subpopulation and survival and response to chemotherapy. Three types of molecular classification were identified. Each subtype has specific molecular and clinical characteristics. Meanwhile, Cluster I is defined as advanced PCa, and is more likely to respond to immunotherapy. Conclusions Our results demonstrated that differences in immune response may be important drivers of PCa progression and response to treatment. The deconvolution algorithm of gene expression microarray data by CIBERSOFT provides useful information about the immune cell composition of PCa patients. In addition, we have found a subtype of immunopositive PCa subtype and will help to explore the reasons for the poor effect of PCa on immunotherapy, and it is expected that immunotherapy will be used to guide the individualized management and treatment of PCa patients.

scholarly journals Correlation Between 18F-FDG Uptake and Immune Cell Infiltration in Metastatic Brain Lesions

2021 ◽  
Vol 11 ◽  
Author(s):  
Young-Sil An ◽  
Se-Hyuk Kim ◽  
Tae Hoon Roh ◽  
So Hyun Park ◽  
Tae-Gyu Kim ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Immune Cells ◽  
Immune Cell ◽  
Standardized Uptake Value ◽  
Brain Lesions ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
Ki 67 ◽  
Glucose Transporter 1 ◽  
Fdg Uptake

BackgroundThe purpose of this study was to investigate the correlation between 18F-fluorodeoxyglucose (FDG) uptake and infiltrating immune cells in metastatic brain lesions.MethodsThis retrospective study included 34 patients with metastatic brain lesions who underwent brain 18F-FDG positron emission tomography (PET)/computed tomography (CT) followed by surgery. 18F-FDG uptake ratio was calculated by dividing the standardized uptake value (SUV) of the metastatic brain lesion by the contralateral normal white matter uptake value. We investigated the clinicopathological characteristics of the patients and analyzed the correlation between 18F-FDG uptake and infiltration of various immune cells. In addition, we evaluated immune-expression levels of glucose transporter 1 (GLUT1), hexokinase 2 (HK2), and Ki-67 in metastatic brain lesions.ResultsThe degree of 18F-FDG uptake of metastatic brain lesions was not significantly correlated with clinical parameters. There was no significant relationship between the 18F-FDG uptake and degree of immune cell infiltration in brain metastasis. Furthermore, other markers, such as GLUT1, HK2, and Ki-67, were not correlated with degree of 18F-FDG uptake. In metastatic brain lesions that originated from breast cancer, a higher degree of 18F-FDG uptake was observed in those with high expression of CD68.ConclusionsIn metastatic brain lesions, the degree of 18F-FDG uptake was not significantly associated with infiltration of immune cells. The 18F-FDG uptake of metastatic brain lesions from breast cancer, however, might be associated with macrophage activity.

Identification of Immune-Related Prognostic Biomarkers in Pancreatic Cancer

2020 ◽  
Vol 12 (12) ◽  
pp. 1355-1367
Author(s):  
Xiaoyan Lin ◽  
Jiakang Ma ◽  
Kaikai Ren ◽  
Mingyu Hou ◽  
Bo Zhou ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Microenvironment ◽  
Risk Score ◽  
Immune Cells ◽  
Immune Cell ◽  
Cox Regression ◽  
Individual Treatment ◽  
Survival Prediction ◽  
Lasso Regression ◽  
Immune Related Genes

Immunotherapy for pancreatic cancer (PC) faces significant challenges. It is urgent to find immunerelated genes for targeted therapy. We aimed to identify immune-related messenger ribonucleic acids (mRNAs) with multiple methods of comprehensive immunoenrichment analysis in predicting survival of PC. PC genomics and clinical data were downloaded from TCGA. We analyzed relative enrichment of 29 immune cells using ssGSEA and classified PC samples into three immuneinfiltrating subgroups. Immune cell infiltration level and pathways were evaluated by ESTIMATE data and KEGG. Independent risk factors were derived from the combined analysis of WGCNA, LASSO regression and Cox regression analyses. Immune risk score was calculated according to four mRNAs to identify its value in predicting survival. PPI analysis was used to analyze the connections and potential pathways among genes. Finally, PC samples were classified into three immuneinfiltrating subgroups. Immunity high subgroup had higher immune score, soakage of immune cells, HLA/PD-L1 expression level, immune-related pathways enrichment and better survivability. Four potential prognostic immune-related genes (ITGB7, RAC2, DNASE1L3, and TRAF1) were identified. Immune risk score could be a potential survival prediction indictor with high sensitivity and specificity (AUC values = 0.708, HR = 1.445). A PPI network with seven nodes and five potential targeted pathways were generated. In conclusion, we estimated the state of immune infiltration in the PC tumor microenvironment by calculating stromal and immune cells enrichment with ssGSEA algorithms, and identified four prognostic immune-related genes that affect the proportion and distribution of immune cells infiltration in the tumor microenvironment. They lay a theoretical foundation to be important immunity targets of individual treatment in PC.

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