Stereotactic body radiation therapy (SBRT) combined with PD1 inhibitor for the treatment of colorectal cancer liver metastasis: a prospective, multicenter, phase II clinical study
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ABSTRACT:
DISEASE(S): Colorectal Cancer With Liver Metastasis
PROVIDER: 113557 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:Purpose: Stereotactic body radiotherapy (SBRT) is an emerging treatment modality for pancreatic ductal adenocarcinoma (PDAC) that can effectively prime cytotoxic T cells by inducing immunogenic tumor cell death in preclinical models. SBRT effects on human PDAC have yet to be thoroughly investigated, therefore, this study aimed to characterize immunomodulation in the human PDAC tumor microenvironment following therapy. Experimental Design: Tumor samples were obtained from patients with resectable PDAC. Radiotherapy was delivered a median of seven days prior to surgical resection, and sections were analyzed by multiplex IHC (mIHC), RNA-Seq, and T cell receptor sequencing (TCR-Seq). Results: Analysis of SBRT-treated tumor tissue indicated reduced tumor cell density and increased immunogenic cell death relative to untreated controls. Radiotherapy promoted collagen deposition, however, vasculature was unaffected and spatial analyses lacked evidence of T cell sequestration. Conversely, SBRT resulted in fewer tertiary lymphoid structures and failed to lessen or reprogram abundant immune suppressor populations. Higher percentages of PD-1+ T cells were observed following SBRT, and a subset of tumors displayed more clonal T cell repertoires. Conclusions: These findings suggest that SBRT augmentation of antitumor immunogenicity may be dampened by an overabundance of refractory immunosuppressive populations, and support the continued development of SBRT/immunotherapy combination for human PDAC.
2021-10-08 | GSE185311 | GEO
Project description:Five year survival rates for pancreatic cancer remain low, around 11%. We assessed differential gene expression between SBRT responders and non-responders as well as expression pre and post SBRT. Samples were obtained from the University of Colorado biorepository. All patients had borderline resectable pancreatic cancer, treated with neoadjuvant chemotherapy followed by restaging, and treatment with 30–33.6 Gy SBRT to pancreatic tumors, followed by pancreaticoduodenectomy and adjuvant chemotherapy. We observed increases in PDL1, PD1, CD25, and a decrease in CD122 expression following RT. Furthermore, we found that responders to SBRT exhibit decrased CD25 expression with increased CD122 and CD132 expression compared to non-responders. Using GSEA of responders vs. non-responders, we found responders to SBRT exhibit enrichment of inflammatory response, IFN signaling, and IL2/STAT5 signaling.
2023-04-20 | GSE225767 | GEO
Project description:Immune checkpoint inhibitors have a poor effect on MSS colorectal cancer. Studies have shown that SBRT, chemotherapy and anti-vascular therapy can enhance the anti-tumor effect of PD-1 antibody. This is a prospective, single-arm study to explore the efficacy and safety of SBRT Sequential CapeOX Regimen Chemotherapy Combined With Bevacizumab and Sintilimab in treatment with patients with initially unresectable advanced colorectal cancer.
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Project description:Metastatic colorectal cancer is one of the common malignant tumors and the overall prognosis is poor. The introduction of immune-checkpoint inhibition (ICI) has led to a paradigm shift in the treatment of patients with metastatic cancer. Stereotactic body radiation therapy (SBRT) delivers a large dose of radiation to the tumor target with high precision while sparing irradiation of the surrounding normal tissues. It is suggested that SBRT could be the most appropriate radiotherapy modality to be combined with immunotherapy since it induces the expression of a series of cytokines and new tumour-associated antigens (TAAs) and is more likely to cause intense immune response and exert an abscopal effect than conventional radiotherapy.
Thus, this study is to explore the use of SBRT in combination with ICI in colorectal cancer patients with oligometastasis, in order to get better local and systemic tumor control and improve progress-free survival (PFS).
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Project description:Background & Aims: Immune checkpoint inhibitors combined with anti-angiogenic agents produces benefits in the treatment of advanced hepatocellular carcinoma (HCC). We investigated the efficacy and immunomodulatory activity of cabozantinib alone and combined with anti-PD1 in experimental models of HCC, and explored the potential target population that might benefit from this combination. Approach & Results: C57BL/6J mice bearing subcutaneous Hepa1-6 or Hep53.4 tumours received cabozantinib, anti-PD1, their combination or placebo. Tumour and blood samples were analysed by flow cytometry, immunohistochemistry, transcriptome and cytokine profiling. Cabozantinib-related effects were validated in a colorectal cancer PDX model. Transcriptomic data from three human HCC cohorts (Cohort 1: n=167, Cohort 2: n=57, TCGA: n=319) were used to cluster patients according to neutrophil features, and assess their impact on survival. The combination of cabozantinib and anti-PD1 showed increased anti-tumour efficacy compared to monotherapy and placebo (P<0.05). Cabozantinib alone significantly increased neutrophil infiltration and reduced CD8+PD1+ T cell proportions in the tumour, while the combination with anti-PD1 further stimulated both effects and significantly decreased T regulatory cell infiltration (all P<0.05). In blood, cabozantinib and especially combination increased the proportions of overall T cells (P<0.01) and memory/effector T cells (P<0.05), while lowering the neutrophil-to-lymphocyte ratio (P<0.001 for combination). Unsupervised clustering of human HCCs revealed that high tumour enrichment in neutrophil features observed with the treatment combination was linked to less proliferative phenotypes, and well-differentiated HCC with better prognosis. Neutrophil recruitment in both humans and mice was linked to CXCR2 ligands and CXCL12 (P<0.05). Conclusions: Cabozantinib in combination with anti-PD1 enhanced anti-tumour immunity by bringing together innate neutrophil-driven and adaptive immune responses, a mechanism of action which favours this approach for the treatment of HCC.
2022-06-15 | GSE174570 | GEO
Project description:Background & Aims: Immune checkpoint inhibitors combined with anti-angiogenic agents produces benefits in the treatment of advanced hepatocellular carcinoma (HCC). We investigated the efficacy and immunomodulatory activity of cabozantinib alone and combined with anti-PD1 in experimental models of HCC, and explored the potential target population that might benefit from this combination. Approach & Results: C57BL/6J mice bearing subcutaneous Hepa1-6 or Hep53.4 tumours received cabozantinib, anti-PD1, their combination or placebo. Tumour and blood samples were analysed by flow cytometry, immunohistochemistry, transcriptome and cytokine profiling. Cabozantinib-related effects were validated in a colorectal cancer PDX model. Transcriptomic data from three human HCC cohorts (Cohort 1: n=167, Cohort 2: n=57, TCGA: n=319) were used to cluster patients according to neutrophil features, and assess their impact on survival. The combination of cabozantinib and anti-PD1 showed increased anti-tumour efficacy compared to monotherapy and placebo (P<0.05). Cabozantinib alone significantly increased neutrophil infiltration and reduced CD8+PD1+ T cell proportions in the tumour, while the combination with anti-PD1 further stimulated both effects and significantly decreased T regulatory cell infiltration (all P<0.05). In blood, cabozantinib and especially combination increased the proportions of overall T cells (P<0.01) and memory/effector T cells (P<0.05), while lowering the neutrophil-to-lymphocyte ratio (P<0.001 for combination). Unsupervised clustering of human HCCs revealed that high tumour enrichment in neutrophil features observed with the treatment combination was linked to less proliferative phenotypes, and well-differentiated HCC with better prognosis. Neutrophil recruitment in both humans and mice was linked to CXCR2 ligands and CXCL12 (P<0.05). Conclusions: Cabozantinib in combination with anti-PD1 enhanced anti-tumour immunity by bringing together innate neutrophil-driven and adaptive immune responses, a mechanism of action which favours this approach for the treatment of HCC.
2022-06-15 | GSE174770 | GEO
Project description:This study is designed to see whether stereotactic body radiation therapy (SBRT) can reduce tumour size, slow progression of the disease, prolong life and improve quality of life. SBRT is concentrated focused radiation therapy delivered very precisely to the liver tumour.
Presently, the treatment for unresectable liver metastases from colorectal cancer is most often chemotherapy or novel targeted therapy. These treatments may improve survival, but not control the metastases permanently; so new treatments are needed to control metastases. It is hoped that knowledge obtained from this study will improve our ability to treat patients with liver tumours that cannot be treated with surgery and other methods, and that SBRT may prove to be a treatment that can lead to long-term and permanent control of liver tumours for some patients.
| 2073283 | ecrin-mdr-crc
Project description:Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of unresectable hepatocellular carcinoma (HCC), but their impressive efficacy is seen in a fraction of patients. One key mechanism of immunotherapy resistance is the paucity of dendritic cells (DCs) in liver malignancies. Here, we tested the combined blockade of programmed death receptor 1 (PD1) and CXCR4, a receptor for CXCL12, a pleiotropic factor that mediates immunosuppression in tumors. Using orthotopic grafted and autochthonous HCC models with underlying liver damage, we evaluated treatment feasibility and efficacy.
2024-11-03 | GSE280861 | GEO
Project description:This is a Phase II study to determine the efficacy of SBRT to treat liver metastases in patients with Colorectal Adenocarcinoma, Carcinoma of the Anal Canal and Gastrointestinal Neuroendocrine Tumors that are not amenable to surgery. Patients should have no evidence of extra-hepatic disease or have disease that is planned to be treated with curative intent.
Therefore, SBRT is being considered as a potentially curative procedure.
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Project description:While immune checkpoint blockade therapy (ICBT) benefits cancer patients, many fail to maintain their response due to adaptive resistance mechanisms. IFNγ is critical for cellular immunity, but also promotes adaptive resistance to ICBT. We have established a role for PARP14 in mediating IFNγ-induced adaptive resistance. We confirm that chronic pre-treatment of tumour cells with IFNγ confers resistance to α-PD-1 antibodies in syngeneic mouse tumour models. We identified that PARP14 was consistently upregulated in cancer cells treated chronically with IFNγ as well as in IFNγ-high melanoma samples. Further, we showed that PARP14 knockdown or pharmacological inhibition restores sensitivity to α-PD-1 antibodies accompanied by increased immune cell infiltration into tumours but the decreased presence of regulatory T cells. RNA sequencing analysis of tumours and cultured cells treated with PARP14 inhibitor showed an upregulation of inflammatory-related pathways. In conclusion, PARP14 is an actionable target for reversing IFNγ-driven adaptive resistance to ICBT.
2023-08-08 | E-MTAB-12195 | biostudies-arrayexpress