Surufatinib With or Wothout Immunotherapy for Advanced Colorectal Cancer in Later Line
Ontology highlight
ABSTRACT:
DISEASE(S): Colorectal Neoplasms
PROVIDER: 2730034 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:Immune checkpoint blockade has revolutionized cancer therapy. In particular, inhibition of programmed cell death protein 1 (PD-1) is effective for the treatment of metastatic melanoma and other cancers. Despite a dramatic increase in progression-free survival, a large proportion of patients do not show durable response. Therefore, predictive biomarkers of clinical response are urgently needed. Here, we employed high-dimensional single cell mass cytometry and a bioinformatics pipeline for the in-depth characterization of the immune cell subsets in the peripheral blood of metastatic melanoma patients before and after anti-PD-1 immunotherapy. During therapy, we observed a clear treatment response to immunotherapy in the T cell compartment. However, prior to commending therapy a strong predictor of progression free and overall survival in response to anti-PD-1 immunotherapy was the frequency of CD14+CD16-HLA-DRhi monocytes. We could confirm this by conventional flow cytometry in an independent validation cohort and propose this as a novel predictive biomarker for therapy decisions in the clinic. In order to determine whether there are cell intrinsic changes in the monocyte signature, we performed RNA sequencing on sorted CD14+CD16-HLA-DRhi cells from HD, NR and R at baseline. Representative samples (n=4, each) of responders/non responders/ and healthy donors were selected from archival samples stored in the dermatology biobank according to the same clinical criteria used in the discovery and validation cohorts for CyTOF and FACS analysis. CD14+CD16-HLA-DRhiLin- (CD3, CD4, CD19, CD45RO) monocytes were sorted from frozen PBMC form blood samples from HD, R and NR at baseline.
2017-12-20 | E-MTAB-6214 | biostudies-arrayexpress
Project description:Increasing success is being achieved in the treatment of malignancies with stromal-targeted therapies, predominantly in anti-angiogenesis and immunotherapy, predominantly checkpoint inhibitors. Despite 15 years of clinical trials with anti-VEGF pathway inhibitors for cancer, we still find ourselves lacking reliable predictive biomarkers to select patients for anti-angiogenesis therapy. For the more recent immunotherapy agents, there are many approaches for patient selection under investigation. Notably, the predictive power of an Ad-VEGF-A164 mouse model to drive a stromal response with similarities to a wound healing response shows relevance for human cancer and was used to generate stromal signatures. We have developed gene signatures for 3 stromal states and leveraged the data from multiple large cohort bioinformatics studies of gastric cancer (TCGA, ACRG) to further understand how these relate to the dominant patient phenotypes identified by previous bioinformatics efforts. We have also designed multiplexed IHC assays that robustly represent the vascular and immune diversity in gastric cancer. Finally, we have used this methodology to arrive at a hypothesis of how angiogenesis and immunotherapy may fit into the experimental approaches for gastric cancer treatments. The Ad-VEGF-A164 angiogenesis model was performed as previously described. Animals were treated with various anti-VEGF Receptor antibodies via intraperitoneal injection at the doses (DC101 20 mpk or G6 10 mpk) and time points (day 0, day 5, day 20, day 60) to target all of the different populations of tumor-surrogate blood vessels, as they each develop at different time points. At least 5 animals, equally matched, were used per group. At the end of the experiment, angiogenic sites in flanks were photographed and tissues were taken for histology and RNA preparation.
2016-01-08 | E-GEOD-76628 | biostudies-arrayexpress
Project description:Immune checkpoint blockade (ICB) with PD1 or PDL1 antibodies has been approved for the treatment of non-small cell lung cancer (NSCLC). However, only a minority of the patients respond and sustained remissions are rare. Both chemotherapy and anti-angiogenic drugs may improve tumor response to ICB in mouse models and patients with cancer. Here, we used genetically engineered mouse models of KrasG12D/p53null NSCLC, including a mismatch repair-deficient variant (KrasG12D/p53null/Msh2null) with higher mutational burden, and longitudinal imaging to study tumor response and resistance to combinations of ICB, anti-angiogenic therapy, and chemotherapy. Anti-angiogenic blockade of VEGFA and angiopoietin-2 markedly slowed progression of established tumors but, contrary to findings in other mouse cancer models, addition of a PD1 or PDL1 antibody was not beneficial and even accelerated progression of some of the tumors. We found that anti-angiogenic treatment facilitated tumor infiltration by PD1+ regulatory T cells (T-regs), which were more efficiently targeted by the PD1 antibody than CD8+ T cells. Both tumor-associated macrophages (TAMs) of bone-marrow origin, which are CSF1R-dependent, and TAMs of alveolar origin, which are sensitive to cisplatin, contributed to establishing a TGFB-rich tumor microenvironment that supported PD1+ T-regs. Dual TAM targeting with a combination of cisplatin and a CSF1R inhibitor fully abated T-regs, redirected the PD1 antibody to CD8+ T cells, and improved the efficacy of anti-angiogenic immunotherapy, achieving regression of the majority of the tumors.
2021-08-15 | GSE169195 | GEO
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2021-08-15 | GSE169194 | GEO
Project description:Active immunotherapy is a promising strategy for anti-angiogenic cancer therapy. Recently, we have reported that a vaccine using human umbilical vein endothelial cells (HUVECs) induced specific anti-endothelial immune responses in the most of immunized patients, and resulted in tumor regression in some patients with recurrent malignant brain tumors, whereas not in colorectal cancer patients. In this study, we hypothesized that non-hypoxic perivascular tumor associated macrophages (TAMs) in colorectal cancer, but not in glioblastoma, might negatively alter the therapeutic efficacy of anti-angiogenic active immunotherapy. To test this hypothesis, we examined global gene expression profiles of non-hypoxic macrophages stimulated in vitro by soluble factors released from tumor cells of human glioblastoma U-87MG (‘brain TAMs’) or colorectal adenocarcinoma HT-29 (‘colon TAMs’).
2012-04-01 | GSE18804 | GEO
Project description:Active immunotherapy is a promising strategy for anti-angiogenic cancer therapy. Recently, we have reported that a vaccine using human umbilical vein endothelial cells (HUVECs) induced specific anti-endothelial immune responses in the most of immunized patients, and resulted in tumor regression in some patients with recurrent malignant brain tumors, whereas not in colorectal cancer patients. In this study, we hypothesized that non-hypoxic perivascular tumor associated macrophages (TAMs) in colorectal cancer, but not in glioblastoma, might negatively alter the therapeutic efficacy of anti-angiogenic active immunotherapy. To test this hypothesis, we examined global gene expression profiles of non-hypoxic macrophages stimulated in vitro by soluble factors released from tumor cells of human glioblastoma U-87MG (‘brain TAMs’) or colorectal adenocarcinoma HT-29 (‘colon TAMs’). Murine non-hypoxic TAMs were induced in vitro by incubation with soluble factors released from human cancer cell lines U-87MG ('brain TAMs') or HT-29 ('colon TAMs'), for RNA extraction and subsequent hybridization on Affymetrix microarrays. To evaluate homogeneous macrophage populations at different tumour developmental stages, RNA aliquots of control macrophages and TAMs obtained at five different time-points, i.e. 8h, 16h, 24h, 32h and 40h, were pooled and used for screening of differentially expressed genes. The experiments for TAMs as well as for control unstimulated macrophages were performed in triplicates.
2012-03-31 | E-GEOD-18804 | biostudies-arrayexpress
Project description:This model is based on:
Reinforcement learning-based control of tumor growth under anti-angiogenic therapy
Authors: Parisa Yazdjerdi, Nader Meskin, Mohammad Al-Naemi, Ala-Eddin Al Moustafa, Levente Kovacs
Abstract:
Background and objectives: In recent decades, cancer has become one of the most fatal and destructive diseases which is threatening humans life. Accordingly, different types of cancer treatment are studied with the main aim to have the best treatment with minimum side effects. Anti-angiogenic is a molecular targeted therapy which can be coupled with chemotherapy and radiotherapy. Although this method does not eliminate the whole tumor, but it can keep the tumor size in a given state by preventing the formation of new blood vessels. In this paper, a novel model-free method based on reinforcement learning (RL) framework is used to design a closed-loop control of anti-angiogenic drug dosing administration.
Methods: A Q-learning algorithm is developed for the drug dosing closed-loop control. This controller is designed using two different values of the maximum drug dosage to reduce the tumor volume up to a desired value. The mathematical model of tumor growth under anti-angiogenic inhibitor is used to simulate a real patient.
Results: The effectiveness of the proposed method is shown through in silico simulation and its robustness to patient parameters variation is demonstrated. It is demonstrated that the tumor reaches its minimal volume in 84 days with maximum drug inlet of 30 mg/kg/day. Also, it is shown that the designed controller is robust with respect to ± 20% of tumor growth parameters changes.
Conclusion: The proposed closed-loop reinforcement learning-based controller for cancer treatment using anti-angiogenic inhibitor provides an effective and novel result such that with a clinically valid and safe dosage of drug, the volume reduces up to 1mm3 in a reasonable short period compared to the literature.
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Project description:Anti-angiogenic therapy is commonly used for the treatment of CRC. Although patients derive some clinical benefit, treatment resistance inevitably occurs. The MET signaling pathway has been proposed to be a major contributor of resistance to anti-angiogenic therapy. MET is upregulated in response to VEGF pathway inhibition and plays an essential role in tumorigenesis and progression of tumors. In this study we set out to determine the efficacy of cabozantinib in a preclinical CRC PDTX model. We demonstrate potent inhibitory effects on tumor growth in 80% of tumors treated. The greatest antitumor effects were observed in tumors that possess a mutation in the PIK3CA gene. The underlying antitumor mechanisms of cabozantinib consisted of inhibition of angiogenesis and Akt activation and significantly decreased expression of genes involved in the PI3K pathway. These findings support further evaluation of cabozantinib in patients with CRC. PIK3CA mutation as a predictive biomarker of sensitivity is intriguing and warrants further elucidation. A clinical trial of cabozantinib in refractory metastatic CRC is being activated. CRC PDTX Model treated with cabozantinib
2014-08-30 | E-GEOD-60939 | biostudies-arrayexpress
Project description:Targeting metabolic symbiosis to overcome resistance to anti-angiogenic therapy
| PRJNA313284 | ENA