Leronlimab in Combination With Regorafenib in Patients With CCR5+, Metastatic Colorectal Cancer
Ontology highlight
ABSTRACT:
DISEASE(S): Colorectal Cancer,Colorectal Neoplasms,Microsatellite Stable,Metastatic,Ccr5
PROVIDER: 8540 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:Microsatellite-stable metastatic colorectal cancer (MSS mCRC) remains resistant to conventional immunotherapies, yet in a phase I trial the combination of regorafenib, ipilimumab, and nivolumab (RIN) demonstrated a 27.6% overall response rate and a median overall survival of 20 months, particularly benefiting patients without liver metastases. Correlative studies of tumor biopsies from eight patients and peripheral blood samples from 29 patients revealed that good responders had a more immunogenic tumor microenvironment (TME) at baseline, with enhanced cellular proliferation, active DNA repair pathways, and elevated STING pathway expression, along with a Th1-skewed cytokine profile in peripheral blood. Poor responders exhibited dysregulated inflammation, vascular remodeling, and T cells showing pathogen-response gene signatures indicative of chronic inflammation; in those with liver metastases, T cells showed immune senescence and metabolic hyperactivation. After RIN therapy, good responders displayed increased TME immune cell infiltration, upregulation of immune-related genes, marked expansion of previously low-frequency TCR clones in CD8 T cells, heightened naive T cell proliferation, and activation of immune and metabolic pathways. Poor responders initially showed transient increases in bulk CD8 T cells, NK cells, Th1 cytokine production, and reduced exhaustion markers but did not sustain meaningful TCR repertoire expansion. These findings underscore the potential of RIN to reshape the immunological landscape of MSS mCRC by modulating both TME and systemic immunity, highlighting the importance of predictive biomarkers to guide personalized therapeutic strategies, particularly for overcoming resistance in liver metastases.
2026-02-01 | GSE289583 | GEO
Project description:Microsatellite-stable metastatic colorectal cancer (MSS mCRC) remains resistant to conventional immunotherapies, yet in a phase I trial the combination of regorafenib, ipilimumab, and nivolumab (RIN) demonstrated a 27.6% overall response rate and a median overall survival of 20 months, particularly benefiting patients without liver metastases. Correlative studies of tumor biopsies from eight patients and peripheral blood samples from 29 patients revealed that good responders had a more immunogenic tumor microenvironment (TME) at baseline, with enhanced cellular proliferation, active DNA repair pathways, and elevated STING pathway expression, along with a Th1-skewed cytokine profile in peripheral blood. Poor responders exhibited dysregulated inflammation, vascular remodeling, and T cells showing pathogen-response gene signatures indicative of chronic inflammation; in those with liver metastases, T cells showed immune senescence and metabolic hyperactivation. After RIN therapy, good responders displayed increased TME immune cell infiltration, upregulation of immune-related genes, marked expansion of previously low-frequency TCR clones in CD8 T cells, heightened naive T cell proliferation, and activation of immune and metabolic pathways. Poor responders initially showed transient increases in bulk CD8 T cells, NK cells, Th1 cytokine production, and reduced exhaustion markers but did not sustain meaningful TCR repertoire expansion. These findings underscore the potential of RIN to reshape the immunological landscape of MSS mCRC by modulating both TME and systemic immunity, highlighting the importance of predictive biomarkers to guide personalized therapeutic strategies, particularly for overcoming resistance in liver metastases.
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Project description:The BRAF inhibitor encorafenib and anti-EGFR antibody cetuximab modestly improve survival for patients with microsatellite stable (MSS) BRAFV600E metastatic colorectal cancer (mCRC), characterized by higher immune activation than MSS BRAFwild-type CRC. In this phase I/II study (NCT04017650) of 26 participants with MSS BRAFV600E mCRC who received encorafenib, cetuximab, and anti-PD-1 antibody nivolumab, we report an overall response rate of 50% (95% confidence interval (CI) 29-71) and median progression-free survival of 7.4 months (95% CI, 5.6-9.6). Transcriptomic profiling of pretreatment biopsies and extracellular vesicle RNA (evRNA) isolated from plasma show enrichment of non-canonical MAP kinase signaling and immune activation signatures for responders. Complement pathway activation enriches in non-responder biopsies. On serial evRNA profiling, decreased MAPK signature and increased interferon gamma response signature associate with sustained treatment benefit. MSS BRAFV600E mCRC with baseline MAP kinase activation and immune activation signatures may benefit from the triple combination but not with complement pathway activation.
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Project description:While patients with microsatellite instable, metastatic colorectal cancer (CRC) benefit from immune checkpoint blockade, chemotherapy with targeted therapies remains the only therapeutic option for microsatellite stable (MSS) tumors. The single arm, phase IB/II MEDITREME trial evaluates safety and efficacy of durvalumab plus tremelimumab in combination with mFOLFOX6 chemotherapy in first line, in 57 patients with RAS-mutant unresectable mCRC. Safety was primary objective of phase IB and no safety issue was observed. The primary objective of phase II was efficacy in terms of 3-month PFS in MSS patients, which was met with a 3 month PFS of 90.7% [95% CI: 79.2-96%]. For secondary objective, response rate was 64.5%, median PFS was 8.2 months [95% CI: 5.9–8.6] and overall survival was not reached in MSS patients. Higher tumor mutational burden and a lower degree of genomic instability in responder patients. Integrated transcriptomic analysis underlined that high immune signature, and low epithelio-mesenchymal transition were associated with better outcome. Immunomonitoring showed induction of neoantigen and NY-ESO1 and TERT blood tumor specific T cell response associated with better PFS. The combination of durvalumab-tremelimumab with mFOLFOX6 was tolerable with promising clinical activity in MSS mCRC.
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Project description:MicroRNA profiling was performed on baseline bloods using the NanoString nCounter platform in a serial liquid biopsies obtained at baseline in chemo-refractory mCRC patients treated with regorafenib in a phase II clinical trial (PROSPECT-R n=40; NCT03010722).
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