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Myeloid mimicry mediates hyperprogression in patients with renal medullary carcinoma treated with nivolumab plus ipilimumab

ABSTRACT: Myeloid mimicry mediates hyperprogression in patients with renal medullary carcinoma treated with nivolumab plus ipilimumab

PROVIDER: PRJNA1079196 | ENA |

REPOSITORIES: ENA

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Myeloid mimicry mediates hyperprogression in patients with renal medullary carcinoma treated with nivolumab plus ipilimumab

Project description:Renal medullary carcinoma (RMC) is a rare but highly aggressive malignancy that mainly afflicts young individuals of African descent and has few treatment options. Despite the approval of combination immune checkpoint therapy (ICT) for other kidney cancers, its efficacy against RMC remains elusive. We conducted a prospective clinical trial of nivolumab plus ipilimumab in patients with RMC. Enrollment was halted for futility after a prespecified interim analysis revealed that all 10 patients experienced rapid disease progression with 5/10 meeting radiological criteria for hyperprogression. Median progression-free survival was only 1.38 months (95% confidence interval (CI): 1.28, 1.60). To elucidate the underlying mechanisms, we analyzed high-quality single-cell RNA sequencing data from RMC patients before and after nivolumab plus ipilimumab treatment. Our analysis suggested that ICT-triggered interferon gamma upregulation induces RMC tumor cells to activate key myeloid regulators such as the CEBPB / p300 complex that promote tumor cell proliferation leading to hyperprogression. Using an immunocompetent somatic mosaic genetically engineered mouse model of RMC, we confirmed that combination ICT induced hyperprogression of primary and metastatic tumors compared with IgG control by hijacking myeloid-affiliated transcriptional circuits. Blocking of this “myeloid mimicry” adaptive mechanism using a selective inhibitor of p300 induced sensitivity to combination ICT in our animal model of RMC. These findings provide novel insights into RMC adaptation to ICT and demonstrate that inhibiting master myeloid regulators can elicit antitumor responses to ICT thus informing the next generation of immunotherapy strategies targeting hyperprogression.

2025-06-30 | GSE256326 | GEO

Sitravatinib in combination with nivolumab plus ipilimumab in patients with advanced clear cell renal cell carcinoma: a phase 1 trial

Project description:Sitravatinib is an immunomodulatory tyrosine kinase inhibitor that can improve responses when combined with immune checkpoint therapy (ICT). We conducted a phase I trial to determine the optimal dose of triplet therapy with sitravatinib plus nivolumab plus ipilimumab in 22 previously untreated patients with advanced clear cell renal cell carcinoma (ccRCC). The primary endpoint was safety. The addition of even a low sitravatinib dose of 35 mg daily to nivolumab 3 mg/kg and ipilimumab 1 mg/kg resulted in high frequency of immune-related adverse events (irAEs). Subsequent dose reduction of ipilimumab to 0.7 mg/kg in combination with nivolumab 3 mg/kg allowed safe escalation of sitravatinib up to 100 mg daily. Key secondary endpoints were objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Overall, the triplet combination in the dose-finding setting achieved an ORR of 45.5%, DCR of 86.4%, and a median PFS of 14.5 months with 72.7% of patients alive after a median follow-up of 15.7 months. Single-cell RNA-seq performed in longitudinally collected tumor biopsies from 12 patients treated with the triplet therapy identified a tumor cell-specific epithelial-mesenchymal transition (EMT)-like program associated with treatment resistance and poor outcomes in patients of this trial and in patients of the TCGA ccRCC cohort. Within the tumor microenvironment (TME), the emergence of treatment resistance was characterized by a transition from cytotoxic to exhausted T cell state and enrichment for M2-like myeloid cells. The observed changes in gene expression dynamics and cellular states in tumor cell and TME may help inform future strategies to optimize ICT efficacy.

2024-11-26 | GSE264586 | GEO

Biopsy analysis of trial S1616: Ipilimumab plus nivolumab versus ipilimumab alone in patients with anti-PD-1-refractory melanoma

Project description:Biopsy analysis of trial S1616: Ipilimumab plus nivolumab versus ipilimumab alone in patients with anti-PD-1-refractory melanoma

| PRJNA1263050 | ENA

Biopsy analysis of trial S1616: Ipilimumab plus nivolumab versus ipilimumab alone in patients with anti-PD-1-refractory melanoma

Project description:Biopsy analysis of trial S1616: Ipilimumab plus nivolumab versus ipilimumab alone in patients with anti-PD-1-refractory melanoma

| PRJNA1263048 | ENA

Pilot Trial of Arginine Deprivation plus Nivolumab and Ipilimumab in Patients with Metastatic Uveal Melanoma

Project description:Pilot Trial of Arginine Deprivation plus Nivolumab and Ipilimumab in Patients with Metastatic Uveal Melanoma

| PRJNA836946 | ENA

Pilot Trial of Arginine Deprivation plus Nivolumab and Ipilimumab in Patients with Metastatic Uveal Melanoma

Project description:Metastatic uveal melanoma (UM) remains challenging to treat, with objective response rates to immune checkpoint blockade (ICB) much lower than in primary cutaneous melanoma (CM). Besides a lower mutational burden, the overall immune-excluded tumor microenvironment of UM might contribute to the poor response rate. We therefore aimed at targeting deficiency in argininosuccinate synthase 1, which is a key metabolic feature of UM. This study aimed at investigating safety and tolerability of a triple combination consisting of ipilimumab and nivolumab immunotherapy and the metabolic therapy ADI-PEG 20. 9 patients were enrolled in this pilot study. The combination therapy was safe and tolerable with absence of immune related adverse events (irAE) of special interest but with 4 of 9 patients experiencing a CTCAE grade 3 AE. No objective responses were observed. All except one patient developed anti-drug antibodies (ADA) within a month of treatment initiation and therefore did not maintain arginine depletion. Further, an IFNg-dependent inflammatory signature was observed in metastatic lesions in patients pre-treated with ICB compared with patients with no pretreatment. Multiplex immunohistochemistry demonstrated variable presence of tumor infiltrating CD8 lymphocytes and PD-L1 expression at baseline in metastases.

2022-05-13 | GSE202687 | GEO

Biopsies from advanced melanoma before and/or after treatment with nivolumab

Project description:Expression profiling of tumor samples obtained during CA209-038 (ClinicalTrials.gov Identifier: NCT01621490). The purpose of this study is to evaluate pharmacodynamic changes of nivolumab and nivolumab in combination with ipilimumab treatment on the biomarkers measured in the peripheral blood and tumor tissues of subjects with advanced melanoma (unresectable or advanced). Samples are rumor core needle biopsies obtained at trial enrolment (i.e. Screen) and/or at Cycle 1 Day 29 (i.e.Week 4) from Subjects With Advanced Melanoma (Unresectable or Metastatic) treated with nivolumab (BMS-936558,MDX-1106) 3 mg/kg solution intravenously every 2 weeks on Bristol-Myers Squibb clinical trial protocol CA209-038 Part 1 . Cohort 2 patients have progressed on anti-CTLA4 (ipilimumab) monoclonal antibody therapy. Values are from an interim lock of the trial data in July 2014. Best overall response (BOR) was defined using RECIST 1.1 criteria: tumor assessments between date of first dose and the date of first objectively documented progression, or the date of non-missing subsequent anti-cancer therapy (whichever occurs first) were used to derive BOR. MPCT is Maximum reduction in tumor size (index lesions only) up to first progression, and is the value typically shown on a waterfall plot.

2022-01-01 | E-MTAB-4030 | biostudies-arrayexpress

Phase II Clinical and Immune Correlate Study of Adjuvant Nivolumab plus Ipilimumab for High-Risk Resected Melanoma

Project description:Phase II Clinical and Immune Correlate Study of Adjuvant Nivolumab plus Ipilimumab for High-Risk Resected Melanoma

| PRJNA907804 | ENA

Gene expression of prostate tumor tissues treated with leuprolide acetate plus ipilimumab

Project description:To study the immune response of the prostate tumor tissues after the leuprolide acetate plus ipilimumab, we compared the gene expression of 6 post-therapy with 3 pre-therapy samples. We identified 690 differential expressed genes (DEGs). Pathway analysis showed that these genes are associated with critical immune pathways such as CTLA4 signaling, antigen presenting etc.

2017-02-08 | GSE77910 | GEO

Correlative study in Protocol S1400I A PHASE III RANDOMIZED STUDY OF NIVOLUMAB PLUS IPILIMUMAB VERSUS NIVOLUMAB IN STAGE IV SQUAMOUS CELL LUNG CANCER (CIMAC-CIDC)

Project description:Correlative study in Protocol S1400I A PHASE III RANDOMIZED STUDY OF NIVOLUMAB PLUS IPILIMUMAB VERSUS NIVOLUMAB IN STAGE IV SQUAMOUS CELL LUNG CANCER (CIMAC-CIDC)

| PRJNA1014197 | ENA

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