ISCORE: Immunotherapy Sequencing in COlon and REctal Cancer
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ABSTRACT:
DISEASE(S): Metastatic Colorectal Cancer,Rectal Neoplasms,Metastatic Ras Wild-type Colorectal Cancer Which Has Previously Responded To Folfiri Chemotherapy And Cetuximab Treatment But Then Progressed
PROVIDER: 2299249 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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DOI: https://doi.org/10.1038/s41591-024-02965-0
PubMed: https://pubmed.ncbi.nlm.nih.gov/38689060/
Journal: https://www.nature.com/articles/s41591-024-02965-0
Abstract
Antibodies targeting the immune checkpoint molecules PD-1, PD-L1 and CTLA-4 administered alone or in combination with chemotherapy are standard of care in most patients with metastatic non-small cell lung cancers. When given prior to curative surgery, tumor responses and improved event-free survival are achieved. New antibody combinations may be more efficacious and tolerable. In an ongoing, open-label phase II study, 60 biomarker-unselected, treatment-naïve patients with resectable non-small cell lung cancer were randomized to receive two preoperative doses of nivolumab (anti-PD-1) with or without relatlimab (anti-LAG-3) antibody therapy. The primary study endpoint was feasibility of surgery within 43 days, which was met by all patients. Curative resection was achieved in 95% of patients. Secondary endpoints included pathological and radiographic response rates, pathologically complete resection rates, disease-free and overall survival rates, and safety. Major pathological (≤10% viable tumor cells) and objective radiographic responses were achieved in 27% and 10% (nivolumab), and 30% and 27% (nivolumab and relatlimab) of patients, respectively. In 100% (nivolumab) and 90% (nivolumab and relatlimab) of patients tumors and lymph nodes were pathologically completely resected. With 12 months median duration of follow-up, disease-free survival and overall survival rates at 12 months were 89% and 93% (nivolumab), and 93% and 100% (nivolumab and relatlimab). Both treatments were safe with grade ≥ 3 treatment-emergent adverse events reported in 10% and 13% of patients per study arm. Exploratory analyses provided insights into biological processes triggered by preoperative immunotherapy. This study establishes the feasibility and safety of dual targeting of PD-1 and LAG-3 prior to lung cancer surgery.
| EGAS00001007753 | EGA
Project description:Abstract: Purpose: We evaluated whether IDO-inhibitor BMS986205 (IDOi) + PD-1 inhibitor nivolumab enhanced T-cell activity and augmented immune-mediated antitumor responses in untreated, resectable HNSCC. We employed response-adaptive surgical timing to identify responders to immunotherapy and enhance their response. Patients and Methods: Patients with HNSCC were 3:1 randomized to receive nivolumab with or without BMS986205 PO daily (NCT03854032). In the combination arm, BMS986205 was initiated 7 days prior to nivolumab. Patients were stratified by HPV status. Response-adaptive surgical timing involved response assessment by radiographic criteria 4 weeks after nivolumab in both arms. Non-responders underwent surgical resection, while responders received 4 more weeks of randomized therapy before surgery. Biomarker analysis utilized pathologic treatment response (pTR) and RNA sequencing. Results: Forty-two patients were enrolled, and the addition of IDOi to nivolumab did not result in greater rate of radiographic response (p=0.909). Treatment was well-tolerated with only 2 (5%) patients experiencing grade 3 immune-related adverse events. The addition of IDO-inhibitor augmented rates of pTR in patients with high baseline IDO RNA expression (p<0.05). Response-adaptive surgical timing demonstrated reliability in differentiating pathologic responders versus non-responders (p=0.009). A pretreatment NK cell signature, PD-L1 status, and IFN-g expression in the HPV– cohort correlated with response. HPV+ cohort found B-cell and CAF signatures predictive of response/non-response. Conclusions: Response-adaptive surgical timing enhanced treatment response. IDO-inhibitor BMS986205 augmented pTR in patients with high IDO1-expression in baseline samples, indicating a need for identifying and targeting resistant nodes to immunotherapy. HPV-status-dependent signatures predicting response to immunotherapy in HNSCC warrant further study.
2024-11-20 | GSE281729 | GEO
Project description:To identify critical tumor-secreting factors that may contribute to immunotherapy efficacy against HCC, we subjected tumor samples from 10 HCC patients to whole-transcriptome sequencing, and categorized the patients into two groups according to clinical response to nivolumab. We then performed gene expression profiling analysis using data obtained from RNA-seq of Nivolumab reponders and non-reponsers.
2023-12-06 | GSE215011 | GEO
Project description:The purpose of this study is to evaluate relatlimab in combination with nivolumab, administered as a fixed-dose combination (nivolumab-relatlimab FDC, also referred to as BMS-986213) for the treatment of non-microsatellite instability high (MSI-H)/deficient mismatch repair (dMMR) metastatic colorectal cancer (mCRC) participants who failed at least 1 but no more than 4 prior lines of therapy for metastatic disease.
| 2718797 | ecrin-mdr-crc
Project description:At present, the mechanisms underlying the association between gut microbiota metabolites and immunotherapy in CRC remain unknown. Here, we conducted a multiomics analysis of a cohort of patients with mCRC and found that F.nucleatum was more abundant in patients who did not respond to immunotherapy. We also found that F. nucleatum diminished the sensitivity to anti-PD-1 mAb through its metabolite succinic acid. Accordingly, patients with lower serum succinic acid levels achieved a better response to immunotherapy. Mechanistically, F.nucleatum-derived succinic acid suppressed the cGAS-interferon-β pathway, consequently dampening the antitumor response by limiting CD8+ T-cell trafficking to the tumor microenvironment in vivo. Treatment with metronidazole reduced intestinal F.nucleatum abundance and thereby decreased serum succinic acid levels, thus resensitizing the tumors to immunotherapy in vivo. Collectively, our findings indicate that F. nucleatum and its metabolite succinic acid induce tumor resistance to immunotherapy and offer new insights into microbiota-metabolite-immune crosstalk in CRC.
2023-12-01 | GSE209864 | GEO
Project description:At present, the mechanisms underlying the association between gut microbiota metabolites and immunotherapy in CRC remain unknown. Here, we conducted a multiomics analysis of a cohort of patients with mCRC and found that F.nucleatum was more abundant in patients who did not respond to immunotherapy. We also found that F. nucleatum diminished the sensitivity to anti-PD-1 mAb through its metabolite succinic acid. Accordingly, patients with lower serum succinic acid levels achieved a better response to immunotherapy. Mechanistically, F.nucleatum-derived succinic acid suppressed the cGAS-interferon-β pathway, consequently dampening the antitumor response by limiting CD8+ T-cell trafficking to the tumor microenvironment in vivo. Treatment with metronidazole reduced intestinal F.nucleatum abundance and thereby decreased serum succinic acid levels, thus resensitizing the tumors to immunotherapy in vivo. Collectively, our findings indicate that F. nucleatum and its metabolite succinic acid induce tumor resistance to immunotherapy and offer new insights into microbiota-metabolite-immune crosstalk in CRC.
2023-10-01 | GSE181337 | GEO
Project description:Purpose: Cancer-associated fibroblasts (CAF) have been implicated as potential mediators of checkpoint immunotherapy response. However, the extensive heterogeneity of these cells has precluded rigorous understanding of their immunoregulatory role in the tumor microenvironment Experimental Design: We performed high dimensional single-cell RNA sequencing (scRNA-Seq) on four patient tumors pre- and post-treatment from a neoadjuvant trial of advanced-stage head and neck squamous cell carcinoma (HNSCC) patients that were treated with the aPD-1 therapy, nivolumab. The head and neck CAF (HNCAF) protein activity profiles, derived from this cohort of paired scRNA-Seq, were used to perform protein activity enrichment analysis on the 28-patient parental cohort of clinically annotated bulk transcriptomic profiles. Ex vivo coculture assays were used to test functional relevance of HNCAF subtypes Results: Fourteen distinct cell types were identified with the fibroblast population showing significant changes in abundance following nivolumab treatment. Among the fibroblast subtypes, HNCAF-0/3 emerged as predictive of nivolumab response, while HNCAF-1 was associated with immunosuppression. Functionally, HNCAF-0/3 were found to reduce TGFβ-dependent PD-1+TIM-3+ exhaustion of CD8 T cells, increase CD103+NKG2A+ resident memory phenotypes, and enhance the overall cytolytic profile of T cells Conclusions: Our findings demonstrate the functional importance of distinct HNCAF subsets in modulating the immunoregulatory milieu of human HNSCC. Additionally, we have identified clinically actionable HNCAF subtypes that can be used as a biomarker of response and resistance in future clinical trials
2022-03-16 | GSE195832 | GEO
Project description:Background: The skeletal system ranks as the third most common site for cancer metastasis, often leading to pain with nociceptive and neuropathic features. PD-1-targeting therapeutic antibodies offer effective cancer treatment but can cause treatment-related acute pain. Understanding the mechanisms of this pain and identifying potential interventions is still a challenge. Methods: A murine model of bone cancer pain was established using Lewis lung carcinoma (LLC) cells, followed by intravenous administration of nivolumab, a human anti-PD-1 monoclonal antibody. Pain thresholds were measured, and micro-CT images of the skeletal system were obtained. High-throughput sequencing of the spinal cord/colon transcriptome during the acute phase of bone cancer pain and gut microbiota analysis were performed. Immunofluorescence staining and western blot experiments assessed spinal cord microglia activation and acute pain-associated molecules. Results: PD-1 inhibition with nivolumab protected against bone degradation initiated by LLC cell administration but consistently induced acute pain during nivolumab treatment. Spinal cord and colon transcriptomics revealed an immunopathological pattern during tumor progression and the acute pain phase, with notable changes in interleukin and S100 gene families. Gut microbiota analysis post-immunotherapy showed a decline in beneficial bacteria associated with SCFA production. Activation of spinal cord microglia and enhanced glycolytic metabolism were confirmed as key factors in inducing acute pain following immunotherapy. Conclusions: This study reveals that nivolumab induces acute pain by activating microglia and enhancing glycolytic metabolism in the treatment of bone cancer and uncovers connections between transcriptomic changes, gut microbiota, and acute pain following ICB treatment. It offers novel insights into the relationship between immune checkpoint blockade therapies and pain management.
2023-09-14 | GSE242789 | GEO
Project description:Pre-treatment tumor expression of PD-L1 has been shown to correlate with favorable clinical outcomes following PD-1 blocking therapies. However, the majority of patients with PD-L1+ tumors do not respond to treatment. With the goal of obtaining insights into the mechanisms underlying the response to anti-PD-1 targeted therapies in patients with renal cell carcinoma (RCC) with positive tumor expression of PD-L1, microarray expression data was obtained for pre-treatment tumors from patients with RCC who did or did not have a positive response to anti-PD-1 (nivolumab) therapy. Insight into these mechanisms may lead to improved rationally designed therapies, and biomarkers for selecting patients who are more likely to benefit from these treatments. Gene expression profiling was performed on total RNA extracted from 11 formalin-fixed paraffin-embedded (FFPE) RCC specimens, 4 of which were from patients who had a positive response (objective tumor regression) to the anti-PD-1 (nivolumab) immunotherapy, and 7 of which were from patients who did not have a response. Details of the design, and the gene signatures found are given in the paper associated with this GEO Series: Maria Libera Ascierto, Tracee L. McMiller, Alan E. Berger, Ludmila Danilova, Robert A. Anders, George J. Netto, Haiying Xu, Theresa S. Pritchard, Jinshui Fan, Chris Cheadle, Leslie Cope, Charles G. Drake, Drew M. Pardoll, Janis M. Taube, and Suzanne L. Topalian, The Intratumoral Balance between Metabolic and Immunologic Gene Expression Is Associated with Antiâ??PD-1 Response in Patients with Renal Cell Carcinoma, published online in Cancer Immunology Research on 4 August 2016, doi: 10.1158/2326-6066.CIR-16-0072 http://cancerimmunolres.aacrjournals.org/content/early/2016/07/28/2326-6066.CIR-16-0072.full.pdf+html
2016-08-04 | E-GEOD-67501 | biostudies-arrayexpress
Project description:Immunotherapy has opened hitherto unknown possibilities to treat cancer. Whereas some cancer types (e.g. melanoma) can be efficiently treated, others lack measurable positive effects (e.g. PDAC). Moreover, stratification of responders/non-responders is only possible in some cancer types (e.g. melanoma). Hepatocellular carcinoma (HCC) has a dismal prognosis, limited treatment options and survival benefit, and represents a potential cancer entity for successful immunotherapy. Here, we investigated NASH-triggered HCC in the context PD-1-targeted immunotherapy. Using flow cytometry, single cell RNA sequencing, immunohistochemistry and mass spectrometric analyses, we found a progressive increase of CD8+PD-1+ effector T-cells with a unique profile of exhaustion and activation markers rising with murine and human NASH severity. Notably, late-stage HCC treatment with PD-1-targeted immunotherapy enhanced hepatic carcinogenesis in mice. Dissecting potential mechanisms of action during tumor-initiation and -progression we analyzed the effects of PD-1-targeted immunotherapy at HCC initiation. PD-1-targeted immunotherapy induced a pro-tumorigenic environment, enhanced necro-inflammation and increased NAFLD-activation score (NAS), leading to increased liver cancer incidence, tumor number and nodule size. In contrast, anti-CD8 or anti-CD8/anti-NK1.1 treatment reduced NAS and abrogated the development of liver cancer, thus identifying CD8+PD-1+ T-cells as drivers of liver cancer in NASH-triggered HCC. Increased apoptotic signaling, STAT3 phosphorylation and hepatic proliferation were detected in intra-tumoral liver tissue upon PD-1-targeted immunotherapy. In line, PD-1-/- mice challenged with a NASH diet displayed early onset of hepatocarcinogenesis, corroborating the pro-tumorigenic role of absent or reduced PD-1. Mechanistically PD-1-targeted immunotherapy mainly affected hepatic abundance of CD8+PD-1+ T-cells, instead of altering the quality of Tox+CXCR6+ expressing CD8+PD-1+TNF+CD39+Gzmb+ T-cells found in NASH livers, leading to an aggressive, pro-tumorigenic liver environment. Single-cell mapping of human NASH-, borderline NASH- or unaffected livers corroborated our preclinical NASH results. Moreover, in human NASH livers a correlation of hepatic CD8+, PD-1+, TNF+ T-cells with fibrosis and NASH severity was observed. Accordingly, HCC patients with NASH etiology display a sharp increase in intra- and peri-tumoral CD8+ PD-1+ T-cells. In a cohort of 65 patients recruited across 6 centers in Germany and Austria, patients with NAFLD/NASH-driven HCC responded worse to PD-1-targeted immunotherapy by Nivolumab or Pembrolizumab compared to non-NAFLD patients. This resulted in significant reduced overall survival, in trends of faster disease progression and reduced progression free survival. Histological analysis of livers derived from HCC patients treated with PD-1-targeted immunotherapy displayed high levels of intra and peri-tumoral CD8+ PD-1+ T-cells and Ki67+ hepatocytes. Taken together, these data indicate that PD-1-targeted immunotherapy induces immune-related adverse effects in NAFLD/NASH-driven HCC through CD8+PD-1+ T-cells. Our data call for stratification of HCC patients subjected to PD-1-targeted immunotherapy, with NAFLD being a negative predictor.
2021-03-03 | PXD017236 | Pride