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Study to Evaluate Efficacy and Safety of Selective Internal Radiation Therapy Plus Xelox, Bevacizumab and Atezolizumab (Immune Chekpoint Inhibitor) in Patients With Liver-dominant Metastatic Colorectal Cancer

ABSTRACT: The main objective of the SIRTCI study is to evaluate the safety and efficacy of the combination chemotherapy (XELOX: Capecitabine plus oxaliplatin), anti-angiogenic (Bevacizumab), SIRT (TheraSphere) and ICI (Atezolizumab) in patients with CRC with predominant liver metastases. SIRTCI is a single-arm, prospective, multi-centre phase II study. The main inclusion criteria are patients with MSS mRCC with predominantly non-operable liver metastases and measurable disease. Patients with extra-hepatic metastases can be included since the objective of the study is to induce local and abscopal effects of radiotherapy combined with ICI by stimulating the anti-tumour immune response to destroy both hepatic and extra-hepatic metastases.

DISEASE(S): Metastatic Colorectal Cancer,Pmmr,Internal Radiotherapy,Colorectal Neoplasms,Mss,Immune Checkpoint Inhibitor

PROVIDER: 2360050 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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SFRP2+ CAFs Hinder Abscopal Effect from Combined Radiotherapy and Immunotherapy by Forming a Hostile Perivascular Niche

Project description:Despite accumulating cases of radiotherapy-induced abscopal effect in the lung cancer with the introduction of immune checkpoint inhibitors (ICIs), the occurrence of this effect remains infrequent and unpredictable to be a therapeutic goal. Here, we showed that the combination of radiotherapy (8Gy*3F) and ICI alleviated the tumor burden at the irradiated site whereas no discernible benefit was observed in the abscopal tumors. RNA-sequencing data showed that extracellular structure organization pathways were enriched in the abscopal tumors after combined therapy, with Sfrp2 being identified as a central hub. SFRP2 expression was observed in cancer-associated fibroblasts (CAFs) and was elevated in abscopal tumors after combined therapy. Blockade of SFRP2 followed by combined radiotherapy and ICI reinvigorated infiltration and cytotoxicity of CD8+ T cells, and elicited regression of abscopal tumors, which was abrogated by CD8α depletion. Mechanistically, in vitro experiments demonstrated that SFRP2+ CAFs induced apoptosis of CD8+ T cells. The spatial transcriptome analysis showed that SFRP2+ CAFs were located in proximity to the vessels and surrounded by abundant macrophages and limited CD8Tex, thereby creating an immunosuppressive perivascular niche, which was validated in paraffin sections of human lung cancer. Lineage-tracing assays showed SFRP2+ CAFs were derived from pericytes. IGF-1 released by irradiated tumors facilitated the transition of pericytes into fibroblasts and stimulated the expression of SFRP2. In summary, SFRP2+ CAFs hijack the abscopal effect from combined radiotherapy and immunotherapy via inducing apoptosis of CD8+ T cells and orchestrating a hostile perivascular niche in the lung cancer. Targeting SFRP2+ CAF may recondition the TME and promote the abscopal effect.

2024-04-01 | GSE261799 | GEO

Impact of Diet and aPD1 on CD8 metabolism

Project description:Only a small fraction of patients with HCC benefit from immune checkpoint inhibitor (ICI) therapy. Recently published studies suggest that HCC in patients with NASH does not respond the ICI therapy. Indeed, we demonstrate that anti-PD1 therapy is not working in several murine NASH models. CD8+ T cells were identified as the effector of anti-PD1 therapy. We observed a proinflammatory phenotype if hepatic CD8+ T cells that does not explain the inefficacy of anti-PD1 therapy in NASH. However, our study revealed an impairment of intratumoral CD8+ T cells movement abilities in NASH. Additionally, a broad reduction of metabolic fitness was observed in hepatic CD8+ T cells NASH. This was restored by metformin treatment. The combination treatment of anti-PD1 and metformin reduced intrahepatic tumor burden in NASH, a finding with important implications for NASH patients. This GEO submission contains raw files for the CD8 nsolver microarray analyses.

2022-03-31 | GSE184231 | GEO

Melanoma cell intrinsic GABAA receptor enhancement potentiates radiation and immune checkpoint inhibitor response by promoting direct and T cell-mediated anti-tumor activity

Project description:Most metastatic melanoma patients show variable responses to radiotherapy and do not benefit from immune checkpoint inhibitors (ICIs). Improved strategies for combination therapy that leverage potential benefits from radiotherapy and ICI are critical. Genes coding for subunits of GABAARs express functional GABAARs in melanoma cells. By enhancing GABAAR mediated anion transport, benzodiazepines depolarize melanoma cells and impair their viability. In vivo, benzodiazepine alone reduces tumor growth and potentiates radiotherapy and α-PD-L1 anti-tumor activity. Combination of benzodiazepine, radiotherapy, and α-PD-L1 results in near complete regression of treated tumors and a potent abscopal effect, mediated by increased infiltration of polyfunctional CD8+ T cells. Treated tumors show expression of cytokine:cytokine receptor interactions and overrepresentation of p53 signaling. This study identifies an anti-tumor strategy combining radiation and/or immune checkpoint inhibitor with modulation of GABAARs in melanoma using a benzodiazepine.

2020-10-23 | GSE159829 | GEO

Single cell transcriptomes of hepatic immune cells from mice with and without colorectal cancer liver metastasis

Project description:Metastasis is the primary cause of cancer mortality. Cancer frequently metastasizes to the liver. We report that liver metastases diminish immunotherapy efficacy systemically in patients and preclinical models. Mechanistically, liver metastases siphon activated CD8+ T cells from systemic circulation. Within the liver, activated antigen-specific Fas+CD8+ T cells undergo apoptosis following their interaction with FasL+CD11b+F4/80+ monocyte-derived macrophages. Consequently, liver metastases create a systemic immune desert in both preclinical models and patients. Liver-directed radiotherapy eliminates immunosuppressive hepatic macrophages, increases hepatic T-cell survival, and reduces hepatic siphoning. Thus, liver metastases co-opt host peripheral tolerance mechanisms to cause acquired immunotherapy resistance through CD8+ T-cell deletion and the combination of liver-directed radiotherapy and immunotherapy is a novel therapeutic strategy to promote systemic anti-tumour immunity.

2020-10-02 | GSE157600 | GEO

Hepatic transcriptomics of squalene in male Apoe-deficient mice on Western diet

Project description:Background and Purpose: Squalene is the main hydrocarbon present in extra virgin olive oil and it has been reported to have anti-steatotic properties in different animal models. The aims of this study were to investigate its effects on liver transcriptomics in Male C57BL/6J Apoe-deficient mice. Experimental Approaches: Male C57BL/6J Apoe-deficient mice were fed a purified Western diet with or without squalene during 11 weeks and hepatic squalene content was assessed. Hepatic transcriptomic changes were studied and confirmed by RT-qPCR. Key Results: Squalene supplementation increased its hepatic content. The Cyp2b10 and Cyp2c55 gene expressions were significantly up-regulated by the squalene intake in all animal models, with independence of sex, sexual hormones, dietary fat content, genetic background and dose, and were strongly associated with antioxidant defense capacity and with lipid content and composition. Conclusions and Implications: hepatic squalene exerts its activity through overexpression of these cytochromes and their changes in virgin olive oil diets may be due to squalene.

2021-04-30 | GSE145343 | GEO

Anti-PD-L1 antibody direct activation of macrophages contributes to an abscopal response in murine brain tumors

Project description:Immunotherapy approaches for glioblastoma multiforme have been thus far largely unsuccessful, suggesting unappreciated complexity in glioma biology and immunology. The intra-tumoral heterogeneity of these intrinsic brain tumors results in therapies killing only a subset of the tumor cells; therefore, therapeutic success will require achieving and optimizing an “abscopal effect” where tumor cells not specifically targeted are recognized and attacked as bystanders by the immune system. We have modified an immune-competent, genetically-driven mouse glioma model where a portion of the tumor burden is treated and another untreated portion is used as a readout of therapeutic efficacy. We find that following radiation of one lesion, anti-PD-L1 therapy enhances the abscopal response (macrophages and T-cells) to the un-irradiated lesion. In gliomas with few baseline T-cells, the anti-PD-L1-enhanced abscopal response occurs as an anti-PD-L1-driven, macrophage-mediated, and ERK-dependent increase in phagocytosis of tumor cells. Our results indicate that combined radiation and anti-PD-L1 therapy for gliomas results in peripherally-derived macrophages being responders in tumors with few baseline T-cells in the microenvironment.

2019-10-01 | GSE111806 | GEO

Innate immune checkpoint inhibitor resistance is associated with melanoma sub-types exhibiting invasive and de-differentiated gene expression signatures

Project description:Melanoma is a highly aggressive skin cancer, which, although highly immunogenic, frequently escapes the body’s immune defences. Immune checkpoint inhibitors (ICI), such as anti-PD1, anti-PDL1, and anti-CTLA4 antibodies lead to reactivation of immune pathways, promoting rejection of melanoma. However, the benefits of ICI therapy remain limited to a relatively small proportion of patients who do not exhibit ICI resistance. Moreover, the precise mechanisms underlying innate and acquired ICI resistance remain unclear. Here, we have investigated differences in melanoma tissues in responder and non-responder patients to anti-PD1 therapy in terms of tumour and immune cell gene-associated signatures.

2022-09-15 | GSE213145 | GEO

Combined Resection of Colorectal Metastases

Project description:This is a Phase II study of combined surgical resection for patients with both intra- and extra-hepatic metastases from colorectal cancer. The primary objective is to determine the two-year disease free survival (DFS) of patients who undergo surgical resection of both intra- and extra-hepatic metastases from colorectal cancer. The secondary objectives are to determine the overall survival rate (OS), patterns of treatment failure, treatment efficacy (R0 resection rate), peri-operative morbidity and mortality rates, health related quality of life, and hospital length of stay.

| 2049976 | ecrin-mdr-crc

Prospective study in patients with cancer of the colon or rectum with liver metastasis, of the efficacy and toxicity of standard therapy (chemotherapy + targeted therapy) combined with immunotherapy and internal radiotherapy targeting the liver

Project description:Primary objectives: Evaluate the progression-free survival at 9 months (according to RECIST 1.1) according to the investigator. Primary endpoints: Progression-free survival at 9 months: percentage of patients alive and without a radiological progression (whatever the type of radiological progression: hepatic or extra-hepatic) 9 months after inclusion (using RECIST v1.1 criteria) according to the investigator

| 2539311 | ecrin-mdr-crc

DNA methylation in sarcoma patients

Project description:We retrospectively identified adult patients who had received anti-PD-1 ICI therapy for recurrent sarcoma and performed DNA methylation profiling using Infinium MethylationEPIC microarrays. Response to anti-PD-1 ICI therapy was correlated with DNA methylation profiles.

2021-04-21 | GSE172468 | GEO

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