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A Randomized Trial of Combined PD-L1 and CTLA-4 Inhibition with Targeted Low-Dose or Hypofractionated Radiation for Patients with Metastatic Colorectal Cancer

ABSTRACT: A Randomized Trial of Combined PD-L1 and CTLA-4 Inhibition with Targeted Low-Dose or Hypofractionated Radiation for Patients with Metastatic Colorectal Cancer

PROVIDER: PRJNA970492 | ENA |

REPOSITORIES: ENA

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A Randomized Trial of Combined PD-L1 and CTLA-4 Inhibition with Targeted Low-Dose or Hypofractionated Radiation for Patients with Metastatic Colorectal Cancer

Project description:A Randomized Trial of Combined PD-L1 and CTLA-4 Inhibition with Targeted Low-Dose or Hypofractionated Radiation for Patients with Metastatic Colorectal Cancer

| PRJNA970493 | ENA

A Randomized Trial of Combined PD-L1 and CTLA-4 Inhibition with Targeted Low-Dose or Hypofractionated Radiation for Patients with Metastatic Colorectal Cancer.

Project description:PurposeProspective human data are lacking regarding safety, efficacy, and immunologic impacts of different radiation doses administered with combined PD-L1/CTLA-4 blockade.Patients and methodsWe performed a multicenter phase II study randomly assigning patients with metastatic microsatellite stable colorectal cancer to repeated low-dose fractionated radiation (LDFRT) or hypofractionated radiation (HFRT) with PD-L1/CTLA-4 inhibition. The primary endpoint was response outside the radiation field. Correlative samples were analyzed using multiplex immunofluorescence (IF), IHC, RNA/T-cell receptor (TCR) sequencing, cytometry by time-of-flight (CyTOF), and Olink.ResultsEighteen patients were evaluable for response. Median lines of prior therapy were four (range, 1-7). Sixteen patients demonstrated toxicity potentially related to treatment (84%), and 8 patients had grade 3-4 toxicity (42%). Best response was stable disease in 1 patient with out-of-field tumor shrinkage. Median overall survival was 3.8 months (90% confidence interval, 2.3-5.7 months). Correlative IF and RNA sequencing (RNA-seq) revealed increased infiltration of CD8+ and CD8+/PD-1+/Ki-67+ T cells in the radiation field after HFRT. LDFRT increased foci of micronuclei/primary nuclear rupture in two subjects. CyTOF and RNA-seq demonstrated significant declines in multiple circulating immune populations, particularly in patients receiving HFRT. TCR sequencing revealed treatment-associated changes in T-cell repertoire in the tumor and peripheral blood.ConclusionsWe demonstrate the feasibility and safety of adding LDFRT and HFRT to PD-L1/CTLA-4 blockade. Although the best response of stable disease does not support the use of concurrent PD-L1/CTLA-4 inhibition with HFRT or LDFRT in this population, biomarkers provide support that both LDFRT and HFRT impact the local immune microenvironment and systemic immunogenicity that can help guide future studies.

| S-EPMC8102320 | biostudies-literature

Boosting effect of high-dose influenza vaccination on innate immunity among elderly: a randomized-control trial

Project description:This study is a phase IV, randomized (1:1 ratio, blocks of various size, electronic allocation), open-label, active-controlled, multi-center trial enrolling adults aged sixty-five years or older to evaluate the different mechanisms of the immunological action of QIV-HD (Efluelda®) compared to QIV-SD (InfluvacTetra®). For transcriptomic analysis, 2.5 ml whole blood was collected in PAXgene tubes (Qiagen) from each subject before vaccination (D-7and D0) and 24 hours after (D1). Total RNA was extracted from blood according to the handbook of the PAXgene Blood RNA Kit. Purity and integrity of the RNA was assessed on the Agilent 2100 Bioanalyzer with the RNA 6000 Nano LabChip reagent set. One V2 sample (#02-066-FB) of QIV-SD group without good RNA quantity was removed for transcriptomic analyze. Sample preparation for microarray hybridization was carried out as described in the Applied BiosystemsTM GeneChipTM Whole Transcript (WT) PLUS Reagent Kit User Guide (Thermo Fisher Scientific, Waltham, MA, USA), and were hybridized to Applied BiosystemsTM GeneChipTM Clariom S human arrays. The fluorescent signals were measured with an Applied BiosystemsTM GeneChipTM GeneChip Scanner 3000 7G System, and controlled by the Applied BiosystemsTM GeneChipTM Command Console v5.0 software. Affymetrix’ Guanine Cytosine Count Normalization algorithm and Affymetrix’ Signal Space Transformation algorithm were used to normalized raw data by using Affymetrix Power Tools software v2.11.4. One V2 sample (#02-066-FB) of QIV-SD group without good RNA quantity was removed.

2025-02-25 | E-MTAB-14109 | biostudies-arrayexpress

Transcriptome of YTN16 tumor tissues after treatment with anti-PD-L1 or anti-CTLA-4

Project description:A murine gastric cancer YTN16 is sensitive to anti-CTLA-4, but resistant to anti-PD-L1. To investigate tumor microenvironments after treatment of these mAbs, we performed RNA-Seq analyses.

2022-01-19 | GSE184092 | GEO

The PRIMAL Randomized Clinical Trial

Project description:Bifidobacterium and Lactobacillus Probiotics and Gut Dysbiosis in Preterm Infants: The PRIMAL Randomized Clinical Trial

| PRJEB85277 | ENA

The PRIMAL Randomized Clinical Trial

Project description:Bifidobacterium and Lactobacillus Probiotics and Gut Dysbiosis in Preterm Infants: The PRIMAL Randomized Clinical Trial

| PRJEB85138 | ENA

In vivo gene expression data from wild type and CTLA-4 KO 5C.C7 T cells

Project description:CTLA-4 is thought to inhibit effector T cells both intrinsically, by competing with CD28 for B7 ligands, and extrinsically, through the action of regulatory T cells. We studied in vivo responses of normal and CTLA-4-deficient antigen-specific murine effector CD4+ T cells. In order to do these studies in a physiological model of immunity to foreign antigen, we transferred small numbers of congenically marked RAG2-deficient 5C.C7 T cells with either a normal or knockout allele of CTLA-4 into normal syngeneic B10.A recipient mice. The T cells were then activated by immunization with MCC peptide and LPS. To look for transcriptional signatures of negative regulation of T cell responses by CTLA-4, we used microarray analysis to compare transcripts in wild type and CTLA-4 KO 5C.C7 T cells four days after immunization. This is the first instance in which differences are observed in extent of accumulation of wild type and CTLA-4 KO 5C.C7 T cells. To compare the gene expression profile between wild type and CTLA-4 KO adoptively transferred T cells 4 days after immunization.

2012-09-05 | E-GEOD-37563 | biostudies-arrayexpress

Single-cell RNA sequencing reveals recruitment of the M2-like CCL8high macrophages in Lewis lung carcinoma-bearing mice following hypofractionated radiotherapy

Project description:Tumor-associated macrophages (TAMs) are a crucial factor in reprogramming the tumor microenvironment following radiotherapy. The mechanisms underlying this process remain to be elucidated. We used single cell RNA sequencing (scRNA-seq) to investigate the effects of hypofractionated radiotherapy on macrophages dynamics in a subcutaneous Lewis lung carcinoma (LLC) murine model.

2024-04-03 | GSE256051 | GEO

RNAseq of tumor samples from CT26 syngeneic mouse treated with a PD-L1 and CTLA-4 immunotherapy combination

Project description:The ability to modulate immune-inhibitory pathways using checkpoint blockade antibodies such as PD-1, PD-L1, and CTLA-4 represents a significant breakthrough in cancer therapy in recent years. This has driven interest in identifying small-molecule-immunotherapy combinations to increase the proportion of responses. Murine syngeneic models, which have a functional immune system, represent an essential tool for pre-clinical evaluation of new immunotherapies. However, immune response varies widely between models and the translational relevance of each model is not fully understood, making selection of an appropriate pre-clinical model for drug target validation challenging. Utilizing RNAseq transcriptomic profiling, we have characterised the changes in gene regulatory pathways and immune populations in CT26 mice after treatment with the combination of anti-PD-L1 and anti-CTLA-4 antibodies. At day 7 post tumor implant, the pathways analysis of differentially expressed genes indicated an enrichment for migration of leukocytes in response to inflammation and communication between innate and adaptive immune cells. Similarly, analysis of upstream regulators suggested that lipopolysaccharide, IL-1B, TNF, IFNG, and NFKB1A pathways associated with inflammation were activated. At day 14, pathways related T-helper cell signalling pathways were upregulated. In addition, upstream regulators of the lipopolysaccharide and IFNG pathway, as well STAT1 and IL21 pathway were enriched, indicative of innate and adaptive immune response to inflammation.

2020-04-16 | E-MTAB-7777 | biostudies-arrayexpress

Early Biomarkers of Tumor Response in High Dose Hypofractionated Radiotherapy Word Package 3 : Immune Response

Project description:This study will follow-up immune cell populations, secreted factors and released nanovesicles in the blood before, during and after high dose radiation therapy which should give new information of the efficacy of the hypofractionated high dose radiation therapy and a rationale for adjuvant immunotherapy.

| 2189624 | ecrin-mdr-crc

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