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Multi-omics analysis of serial samples from metastatic TNBC patients on PARP inhibitor monotherapy provide insight into rational PARP inhibitor therapy combinations

ABSTRACT: In a pilot study, we evaluated the safety and efficacy of olaparib/durvalumab combination treatment in mTNBC patients and the feasibility of real-time deep analysis of serial tumor samples from triple negative breast cancer patients to identify mechanisms of resistance and treatment opportunities. This study used the SMMART analytic platform at OHSU KCI and incorporated comprehensive multi-omic analysis of serial liquid and tumor biopsies. Deep analysis of longitudinal biopsies combined with a robust computational biology pipeline identified multiple PARPi-induced changes in immune activation, DNA damage checkpoint activation, apoptosis and signaling pathways including RTK, PI3K-AKT and RAS-MAPK. These emergent tumor and immune state changes could act as biomarker targets to be used in selecting patient specific combination therapies.

PROVIDER: EGAS00001005479 | EGA |

REPOSITORIES: EGA

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Diverse immune suppressing cancer communications with myeloid cells prevent T cell activation and recruitment and provide resistance to cell cycle inhibitor therapy

Project description:Cancer cells evolve and acquire the ability to develop resistance to therapy and change their environment. A key mechanism involves altering communication with non-malignant cells in the tumor microenvironment (TME). By corrupting the signals for growth and survival, evolving tumors engineer a pro-tumor TME which contributes to the development of treatment resistance. However, the specific interactions between malignant and non-malignant cells that predispose drug resistance and their changes during treatment remain widely unknown. Here we examined the composition, communication, and phenotypic diversity of tumor-associated cell populations in serial biopsies from the FELINE clinical trial. Early-stage ER+ breast cancers receiving endocrine therapy (letrozole) alone or in combination with the CDK4/6 cell cycle inhibitor ribociclib were analyzed using single-cell RNA sequencing (scRNAseq). Our analyses reveal cancer cells from ribociclib resistant tumors stimulate macrophage differentiation towards an immune-suppressive phenotype through upregulation of a broad diversity of cytokines and growth factors. This shift in phenotype leads to reduced macrophage cell IL-15/-18 crosstalk with CD8+ T-cell via IL-2/15RA/18R receptors, resulting in reduced T-cell activation and recruitment. Given cell cycle inhibitors known inhibitory effect on immune cell activation, in addition to also blocking cancer cell proliferation, maintenance of immune stimulatory cellular populations and signals that promote T-cell abundance and cytotoxicity is critical for treatment response. Our results show how altered communication promotes an immune-cold TME that predisposes tumors to develop CDK4/6 inhibitor resistance. A successful treatment strategy will require both the prevention of cancer division and also activation of a cytotoxic T-cell response.

2024-12-11 | GSE211434 | GEO

Systemically administered HMGN1 immunostimulatory peptide with anti-PD-L1 antibody exerts synergistic antitumor effects

Project description:In this study, we explore a new combination therapy of anti-PD-L1 antibody with an immunostimulatory peptide derived from an alarmin high mobility group nucleosome binding protein 1 (HMGN1). Combination treatement of HMGN1 immunostimulatory peptide with anti-PD-L1 antibody exerted robust anti-tumor effects in Colon26 subtaneous murine model. To understand transcriptomic differences of immune cell population in the tumor-bearing mice after treated with single-agent or combination therapy of HMGN1 with anti-PD-L1 antibody, we performed transcriptome analysis on tumor tissue using 5’end Serial Analysis of Gene Expression (SAGE)-sequencing with an Ion 540 Chef kit, an Ion 540 Chip kit, and an Ion S5 Sequencer (Thermo Fisher Scientific).

2021-11-02 | GSE139291 | GEO

Epigenetic priming enhances anti-tumor immunity in resistant ovarian cancer [RNA-Seq]

Project description:Here we describe the clinical and biological activity of guadecitabine, a second generation HMA, given in a low dose as a priming strategy before pembrolizumab, a humanized anti-PD1 antibody in a clinical trial for patients with recurrent, platinum resistant ovarian cancer. The methylomic and transcriptomic effects of the combination demonstrate readily activation of the anti-tumor immunity. High dimensional immune profiling of periferal mononuclear cells (PBMCs) and tumor biopsies obtained before and after treatment show distinct immune profiles and tissue architectural features associated with clinical benefit. Our study provides an in-depth view of the immune milieu of platinum resistant ovarian cancer and of the effects of the combination of HMAs and pembrolizumab on the interactions between immune cell populations and tumor cells.

2022-06-20 | GSE188249 | GEO

Epigenetic priming enhances anti-tumor immunity in resistant ovarian cancer [methylation array]

2022-06-20 | GSE186825 | GEO

NanoString immune gene expression analysis of PARP inhibitor and STING agonist treated mouse breast tumors

Project description:This study aimed to assess changes in immune gene expression and immune-related pathways in mouse tumors from syngeneic mice treated with combined PARP inhibitor and STING agonist therapy. The objective was to identify differentially expressed genes related to immune oncology in response to the combination treatment as compared to single treatments, in order to gain mechanistic insight into the enhanced anti-tumor efficacy of the combination treatment.

2022-05-29 | GSE204858 | GEO

A Phase II Trial of Guadecitabine plus Atezolizumab in Metastatic Urothelial Carcinoma Progressing after Initial Immune Checkpoint Inhibitor Therapy (EPIC)

Project description:We designed a Phase II clinical trial testing the combination of guadecitabine (DNMTi) and atezolizumab (anti-PD-L1) with the goal to re-stimulate the immune mediated anticancer effects of immune checkpoint inhibitors (ICI) in metastatic urothelial carcinoma patients who were resistant to prior ICI treatment. No RECIST criteria responses were observed, however, patients could be separated into those with either progressive or stable disease outcomes. Analysis of the tumors did not show substantial DNA hypomethylation in the tumor or the upregulation of viral mimicry after two cycles of combination treatment. We did, however, observe that the therapy associated with immune activation of circulating immune cells and abundance of tumor-infiltrating CD8 T cells within the tumor, which were correlated with a longer survival outcome. Our results suggest that further studies to target the reprogramming of T cells with alternate methodologies may be of benefit in this disease setting.

2023-03-01 | GSE222933 | GEO

A Phase II Trial of Guadecitabine plus Atezolizumab in Metastatic Urothelial Carcinoma Progressing after Initial Immune Checkpoint Inhibitor Therapy (NGS)

2023-03-01 | GSE222932 | GEO

Ad-SGE-DKK3 Gene Therapy Against Resistance to Immune Checkpoint Blockade in Malignant Mesothelioma

Project description:This phase 2 study evaluates the combination of Ad-SGE-Dickkopf-3 (DKK3) gene therapy and nivolumab in patients with chemotherapy-refractory epithelioid malignant pleural mesothelioma (MPM). This clinical study was based on our preclinical study to overcome primary immune resistance by combining Ad-SGE-DKK3 gene therapy with anti-PD-1 therapy through DKK3-driven immune modulation in mesothelioma. The study enrolled 12 patients between 2019 and 2022, who were refractory to pemetrexed-platin-based chemotherapy. Treatment involved CT-guided intratumoral injections of Ad-SGE-DKK3 and systemic nivolumab administration. The primary goal was to assess the objective response rate (ORR), with secondary and exploratory objectives focusing on safety, durable clinical benefit (DCB), survival, and biomarker changes. Of the enrolled patients, 75% completed the Ad-SGE-DKK3 treatment protocol. The study observed a 16.6% ORR with 41.7% maintaining stable disease, which reached 58.3% DCB rate. The median overall survival was 14.5 months, and the median progression-free survival was 4.5 months. Adverse events of grade 3 were noted in 41.7% of patients. Serial analysis of tumor biopsies and serum biomarkers indicated that patients with DCB had increased tumor-infiltrating CD8 T cells, decreased circulating memory CD8 T cells, and sustained lower concentrations of soluble mesothelin and M-CSF than progressors. The combination therapy demonstrated a favorable safety profile and promising efficacy in this patient population. ClinicalTrials.gov identifier: NCT04013334

2024-07-30 | GSE273448 | GEO

Differential activity of treatment with protein kinase inhibitors on tumor phosphotyrosine profiles in patients with advanced cancer

Project description:Mass spectrometry-based phosphoproteomics of tumor tissue lysates provides a potential personalized medicine approach based on its ability to identify activated signaling pathways and novel drug targets. We performed a pilot study (NCT01636908) to determine the effect of protein kinase inhibitors (PKIs) on tyrosine-(pTyr)-phosphoproteomic profiles of serial tumor biopsies in patients with advanced cancer. Tumor needle biopsies were analyzed from 31 patients with advanced cancer before and after 2 weeks treatment with sorafenib (SOR), erlotinib (ERL), dasatinib (DAS), vemurafenib (VEM), sunitinib (SUN) or everolimus (EVE). pTyr-Phosphoproteomics of pre- and on-treatment biopsies was performed by phosphotyrosine immunoprecipitation followed by LC-MS/MS.

2019-04-18 | PXD008032 | Pride

JAK inhibitor overcomes resistance to immune checkpoint inhibitor treatment in gastric cancer peritoneal dissemination in mouse

Project description:Objective Cancer immunotherapy aims to unleash the immune system's potential against cancer cells, providing sustained relief for tumors responsive to immune checkpoint inhibitors (ICIs). While promising in gastric cancer (GC) trials, the efficacy of ICIs diminishes in the context of peritoneal dissemination. Our objective is to identify strategies to enhance the impact of ICI treatment specifically for cases involving peritoneal dissemination in GC. Design The therapeutic efficacy of anti-PD1, CTLA4 treatment alone, or in combination, was assessed using the YTN16 peritoneal dissemination tumor model mice. Peritoneum and peritoneal exudate cells were collected for subsequent analysis. Immunohistochemical staining, flow cytometry, and bulk RNA-sequence analyses were conducted to evaluate the tumor microenvironment (TME). A JAK inhibitor (JAKi) was introduced based on the pathway analysis results. Results Anti-PD1 and anti-CTLA4 combination treatment (dual ICI treatment) demonstrated therapeutic efficacy in certain mice, primarily mediated by CD8+ T cells. However, in mice resistant to dual ICI treatment, even with CD8+ T cell infiltration, most of the T cells exhibited exhaustion phenotype. Notably, resistant tumors displayed abnormal activation of the JAK-STAT pathway compared to the untreated group, with observed infiltration of macrophages, neutrophils, and Tregs in the TME. The concurrent administration of JAKi rescued CD8+ T cells function and reshaped the immunosuppressive TME, resulting in enhanced efficacy of the dual ICI treatment. Conclusion Dual ICI treatment exerts its anti-tumor effects by increasing tumor- specific CD8+ T cell infiltration, and the addition of JAKi further improves ICI resistant by reshaping the immunosuppressive TME.

2024-05-28 | GSE250238 | GEO

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