Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

PD-L1 blockade in combination with carboplatin as immune induction in metastatic lobular breast cancer: the GELATO-trial

ABSTRACT: Invasive lobular breast cancer (ILC) is the second most common histological breast cancer subtype but published data on trials specific for ILC are so far lacking. Translational research revealed that a subset of ILCs may be immune-related and more sensitive to DNA-damaging agents such as platinum. In murine ILC models, synergy between immune checkpoint blockade and platinum has been observed. Here, we tested this concept in the phase II, GELATO-trial (NCT03147040), in which patients with metastatic ILC were treated with weekly carboplatin (AUC 1.5) as immune induction treatment for 12 weeks and atezolizumab (PD-L1 blockade; every three weeks) from the third week onwards until disease progression. Four out of 23 evaluable patients had a partial response (17%, 95%CI 5-39%) and two patients had stable disease for at least 24 weeks, resulting in a clinical benefit rate of 26% (95%CI 10-48%). Out of these six patients, four patients had triple-negative ILC (TN-ILC). In serial biopsies of metastatic lesions, we observed higher CD8 T-cell infiltration, expression of immune checkpoints, and exhausted T cells upon carboplatin/PD-L1 blockade. This is the first report of a clinical trial specifically for ILC and we demonstrate promising anti-tumor activity of atezolizumab with carboplatin as immune induction, in particular for TN-ILC. While activity of carboplatin/PD-L1 blockade in classical ER+ ILC was limited, our translational data yield important insights for the design of highly needed clinical trials in ILC.

PROVIDER: EGAS00001006902 | EGA |

REPOSITORIES: EGA

ACCESS DATA

Json Xml

Similar Datasets

High gene expression of IL8 in peripheral blood mononuclear cells from bladder cancer patients is associated with nonresponders to atezolizumab

Project description:Elevated plasma interleukin-8 (IL8) has been associated with poor outcome to immune checkpoint blockade. Here we performed single cell RNAseq with peripheral blood mononuclear cells (PBMCs) of patients treated with atezolizumab (anti-PD-L1 mAb) from bladder cancer from a Phase II trial IMvigor210. We found that high IL8 gene expression is enriched in nonresponders to atezolizumab

2020-02-14 | GSE145281 | GEO

ML29755 RNA-seq data

Project description:Programmed death-ligand 1 (PD-L1) expression has been associated with response to PD-1/PD-L1 inhibition, but responses are also seen in patients with PD-L1 negative tumors when assessed immunohistochemically (IHC) with various antibodies. To help elucidate these findings, we performed a positron emission tomography (PET) imaging study in human with the anti-PD-L1 antibody atezolizumab labeled with Zirconium-89 (89Zr) prior to treatment with atezolizumab to assess normal tissue distribution and evaluate tumor tracer uptake. Additionally, to help explain why some patients respond to checkpoint inhibitors despite low or absent PD-L1 expression, we compared PD-L1 expression and immune phenotypes based on both CD8 IHC and RNA sequencing of post-tracer biopsies to tumor tracer uptake (SUVmax).

2018-06-12 | GSE115594 | GEO

PD-L1 blockade-induced temporal single cell dynamics in triple negative breast cancer

Project description:Despite the progress in immunotherapies, leading immune checkpoint inhibitors are only effective in a subset of patients. The efficacy of atezolizumab, an anti-PD-L1 antibody, in triple negative breast cancer (TNBC) is limited for unknown reasons. We utilized single-cell RNA- and ATAC-sequencing to examine the dynamics of immune cells in metastatic TNBC patients treated with paclitaxel or its combination with atezolizumab. We found that paclitaxel selectively damaged tumor-reactive T cells while atezolizumab was effective in a small set of patients with high levels of baseline B cells and CXCL13+ T cells. B cells concertedly expanded with CXCL13+ T cells in responsive patients following paclitaxel plus atezolizumab treatment. Our data highlight the importance of potential tumor-reactive T cells and their orchestrators in the effective response to anti-PD-L1 therapies, and reveal drawbacks of existing clinical trials for TNBC.

2021-09-15 | GSE169246 | GEO

Immunomodulatory effect of cisplatin and carboplatin in human and mouse cell line in vitro

Project description:The Phase 3 1L urothelial carcinoma (IMvigor130) trial revealed more favorable effects on overall survival with atezolizumab combined with gemcitabine and cisplatin (GemCis) than with atezolizumab combined with gemcitabine and carboplatin (GemCarbo). This study investigates the immunomodulatory effects of cisplatin vs carboplatin as a potential explanation for these clinical observations. GemCis compared with GemCarbo ± atezolizumab induced transcriptional changes in circulating immune cells, including upregulation of antigen presentation and T-cell activation programs. In vitro experiments demonstrated that cisplatin, compared with carboplatin, exerted direct immunomodulatory effects on cancer cells, promoting dendritic cell activation and antigen-specific T cell killing. These results underscore the key role of immune modulation in cisplatin's efficacy in urothelial carcinoma and highlight the potential importance of specific chemotherapy backbones for immune checkpoint blockade combination therapies.

2023-11-02 | GSE235066 | GEO

Soluble immune-checkpoint factors as a complementary biomarker for PD-1 blockade reflect exhaustion of antitumor immunity

Project description:BACKGROUND. Precise stratification of patients with non–small cell lung cancer (NSCLC) is needed for appropriate application of PD-1/PD-L1 blockade therapy. METHODS. We measured soluble (s) forms of the PD-L1, PD-1, and CTLA-4 in plasma of patients with advanced NSCLC before PD-1/PD-L1 blockade. Prospective biomarker finding trial (cohort A), 50 patients with pretreated NSCLC received nivolumab. In cohort B to E, retrospective observational study, soluble immune checkpoint molecules were evaluated for patients with advanced NSCLC treated with any PD-1/PD-L1 blockade (cohort B and C), cytotoxic chemotherapy (D) or targeted therapy (E). Blood samples were obtained from all patients and soluble immune checkpoint molecules were evaluated using a highly sensitive chemiluminescence-based assay. RESULTS. Nonresponsiveness to PD-1/PD-L1 blockade therapy was associated with higher concentrations of these soluble immune factors among patients with immune-reactive (hot) tumors. Such correlation was not observed in patients treated with cytotoxic chemotherapy or targeted therapies. Integrative analysis of tumor size, PD-L1 expression in tumor tissue (tPD-L1), and gene expression in tumor tissue and peripheral CD8+ T cells revealed that high concentrations of the three soluble immune factors were associated with hyper or terminal exhaustion of antitumor immunity. The combination of sPD-L1 and sCTLA-4 efficiently discriminated responsiveness among patients with immune-reactive tumors. CONCLUSION. Combinations of soluble immune factors might be able to identify patients unlikely to respond to PD-1/PD-L1 blockade as a result of terminal exhaustion of antitumor immunity. Our data suggest such a combination might provide a biomarker complementary to tPD-L1 for NSCLC patients.

2024-03-30 | GSE242860 | GEO

Gene expression profiles of PD-L1 SP142 expression in triple-negative breast cancer

Project description:The SP142 PD-L1 assay is a companion diagnostic for atezolizumab in metastatic triple-negative breast cancer (TNBC). The VENTANA SP142 assay was used to identify PD-L1 expression from TMA slides where PD-L1-positivity for an individual sample was defined as ≥1% of tumor-infiltrating immune cells as having PD-L1 expression. The PD-L1-positive gene signature consisted of 94 immune-related genes. The PD-L1-positive signature was predictive of pathologic complete response and survival outcome in multiple TNBC cohorts. In other malignancies treated with ICIs, the PD-L1-positive signature was associated with response and improved survival.

2021-07-14 | GSE157284 | GEO

PD-1/CD80+ small extracellular vesicles from immunocytes induce cold tumours featuring with enhanced adaptive immunosuppression

Project description:Only a minority of cancer patients benefit from immune checkpoint blockade therapy. Sophisticated cross-talk among different immune checkpoint pathways as well as interaction pattern of immune checkpoint molecules carried on circulating small extracellular vesicles (sEV) might contribute to the low response rate. Here we demonstrate that PD-1 and CD80 carried on immunocyte-derived sEVs (I-sEV) induce an adaptive redistribution of PD-L1 in tumour cells. The resulting decreased cell membrane PD-L1 expression and increased sEV PD-L1 secretion into the circulation contribute to systemic immunosuppression. PD-1/CD80+ I-sEVs also induce downregulation of adhesion- and antigen presentation-related molecules on tumour cells and impaired immune cell infiltration, thereby converting tumours to an immunologically cold phenotype. Moreover, synchronous analysis of multiple checkpoint molecules, including PD-1, CD80 and PD-L1, on circulating sEVs distinguishes clinical responders from those patients who poorly respond to anti-PD-1 treatment. Altogether, our study shows that sEVs carry multiple inhibitory immune checkpoints proteins, which form a potentially targetable adaptive loop to suppress antitumour immunity.

2024-06-22 | PXD050744 | Pride

KIR Polymorphism is Associated with Primary Resistance to PD-1 Blockade in Lung Cancer

Project description:Adaptive immune escape of tumor cells by upregulation of ligands for programmed death 1 (PD-1) has been identified as an important and targetable pathway in many cancer types. Many clinical trials have demonstrated that targeting PD-1 or its ligand PD-L1 with immune checkpoint inhibitors (ICI) can restore anti-tumor immunity and induce durable remission. In patients with non-small cell lung cancer (NSCLC), several trials have demonstrated a survival benefit with ICI in patients with metastatic and locally advanced NSCLC.Yet, most patients have primary resistance to PD-1 or PD-L1 blockade during treatment: approximately 20% of unselected patients with NSCLC achieve a partial response while 40-50% have progressive disease as best response. Understanding mechanisms of primary resistance to PD-(L)1 blockade is important in the search for potentially targetable pathways and may ultimately allow discrimination between patients that benefit from PD-(L)1 blockade and those requiring combination or other approaches. We collected PBMCs and serum samples from 35 patients with NSCLC before and during PD-1 blockade treatment with nivolumab. We analyzed differentially expressed genes in CD8+ T cells from the peripheral blood of 5 patients with partial response and 5 patients with primary progressive disease to identify mechanisms of resistance to PD-1 therapy. Cells were collected from samples taken before and after 4 weeks of treatment.

2021-03-01 | GSE111414 | GEO

Expression data from CD8 T cells from LCMV-Clone13 infected mice after two weeks of control or anti-PD-L1 treatment

Project description:Blocking PD-1 can reinvigorate exhausted CD8 T cells (TEX) and improve control of chronic infections and cancer. One potential advantage of this immunotherapy is durable protection if immune memory can be established. It is unclear, however, whether blocking PD-1 can reprogram TEX into effector (TEFF) or durable memory T cells (TMEM). Here, we found reinvigoration of TEX by PD-L1 blockade caused re-acquisition of some features of TEFF, but minimal memory development. We used microarray analysis to profile exhausted cells from anti-PD-L1 mice after two weeks of treatment to study if PD-L1 blockade caused re-acquistion of some feature of effector or memory cells.

2016-10-31 | GSE86796 | GEO

Gene Expression profile for the characterization of PD-L1 blockade in melanoma model

Project description:Only a subset of patients responds to immune checkpoint blockade in melanoma. A preclinical model recapitulating the clinical activity of ICB would provide a valuable platform for mechanistic studies. We used melanoma tumors arising from an Hgftg;Cdk4R24C/R24C genetically engineered mouse (GEM) model to evaluate the efficacy of an anti-mouse PD-L1 antibody similar to the anti-human PD-L1 antibodies durvalumab and atezolizumab. Consistent with clinical observations for ICB in melanoma, anti-PD-L1 treatment elicited complete and durable response in a subset of melanoma-bearing mice. We also observed tumor growth delay or regression followed by recurrence. For early treatment assessment, we analyzed gene expression profiles, T cell infiltration, and T cell receptor (TCR) signatures in regressing tumors compared to tumors exhibiting no response to anti-PD-L1 treatment. We found that CD8+ T cell tumor infiltration corresponded to response to treatment, and that anti-PD-L1 gene signature response indicated an increase in antigen processing and presentation, cytokine-cytokine receptor interaction, and natural killer cell-mediated cytotoxicity. TCR sequence data suggest that an anti-PD-L1-mediated melanoma regression response requires not only an expansion of the TCR repertoire that is unique to individual mice, but also tumor access to the appropriate TCRs. Thus, this melanoma model recapitulated the variable response to ICB observed in patients and exhibited biomarkers that differentiate between early response and resistance to treatment, providing a valuable platform for prediction of successful immunotherapy.

2021-04-20 | GSE172320 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data