Immune responses in genomically simple SWI/SNF–deficient cancers

Leruste, Amaury; Chauvin, Céline; Pouponnot, Célio; Bourdeaut, Franck; Waterfall, Joshua J.; Piaggio, Eliane

doi:10.1002/cncr.33172

Cited by 7 publications

(5 citation statements)

References 56 publications

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“…Such efforts will enhance the discovery and understanding of novel targets and combinational strategies with ICIs for tumors with appropriate immune, genetic, or mutational profiles, with the ultimate goal of improving patient outcomes. 38 , 50 …”

Section: Resultsmentioning

confidence: 99%

Nivolumab with or without ipilimumab in pediatric patients with high-grade CNS malignancies: Safety, efficacy, biomarker, and pharmacokinetics—CheckMate 908

et al. 2023

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Background Therapeutic options are limited in pediatric CNS malignancies. CheckMate 908 (NCT03130959) is an open-label, sequential-arm, phase 1b/2 study investigating nivolumab (NIVO) and NIVO+ipilimumab (IPI) in pediatric patients with high-grade CNS malignancies. Methods Patients (N=166) in 5 cohorts received NIVO 3 mg/kg every 2 weeks (Q2W) or NIVO 3 mg/kg+IPI 1 mg/kg every 3 weeks (4 doses) followed by NIVO 3 mg/kg Q2W. Primary endpoints included overall survival (OS; newly diagnosed diffuse intrinsic pontine glioma [DIPG]) and progression-free survival (PFS; other recurrent/progressive or relapsed/resistant CNS cohorts). Secondary endpoints included other efficacy metrics and safety. Exploratory endpoints included pharmacokinetics and biomarker analyses. Results As of January 13, 2021, median OS (80% CI) was 11.7 (10.3-16.5) and 10.8 (9.1-15.8) months with NIVO and NIVO+IPI, respectively, in newly diagnosed DIPG. Median PFS (80% CI) with NIVO and NIVO+IPI was 1.7 (1.4-2.7) and 1.3 (1.2-1.5) months, respectively, in recurrent/progressive high-grade glioma; 1.4 (1.2-1.4) and 2.8 (1.5-4.5) months in relapsed/resistant medulloblastoma; and 1.4 (1.4-2.6) and 4.6 (1.4-5.4) months in relapsed/resistant ependymoma. In patients with other recurrent/progressive CNS tumors, median PFS (95% CI) was 1.2 (1.1-1.3) and 1.6 (1.3-3.5) months, respectively. Grade 3/4 treatment-related adverse-event rates were 14.1% (NIVO) and 27.2% (NIVO+IPI). NIVO and IPI first-dose trough concentrations were lower in youngest and lowest-weight patients. Baseline tumor programmed death ligand 1 expression was not associated with survival. Conclusions NIVO±IPI did not demonstrate clinical benefit relative to historical data. The overall safety profiles were manageable with no new safety signals.

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Section: Resultsmentioning

confidence: 99%

Nivolumab with or without ipilimumab in pediatric patients with high-grade CNS malignancies: Safety, efficacy, biomarker, and pharmacokinetics—CheckMate 908

et al. 2023

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“…Current findings help to define future strategies for immune checkpoint inhibitors either by focusing research on specific disease subpopulations (eg, ATRT-MYC, extracranial MRT), or by providing the means to identify therapeutic combination partners that augment T-cell infiltration and proliferation in “immune cold” tumor microenvironments. 119 …”

Section: Potential Targeted Therapeutic Approaches To Extracranial Mrtmentioning

confidence: 99%

Current and Emerging Therapeutic Approaches for Extracranial Malignant Rhabdoid Tumors

Nemes

Johann²,

Tüchert³

et al. 2022

CMAR

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“…However, several recent observations argue to the contrary, as many malignancies driven primarily by SWI/SNF deficiency were found to harbor a simple genotype and frequently lack any additional genomic abnormalities other than the primary SWI/SNF mutation in the sense of a “single-gene disease.”24 Accordingly, many of these aggressive undifferentiated malignancies do not show increased TMB. Nevertheless, seminal observations have pointed out a significant response to ICI therapy in these apparently “cold tumors.”11,25,26 These observations indicate a role for the SWI/SNF complex in the regulation of tumor immunity and have challenged the “TMB dogma” as being a universal (entity-independent) predictive biomarker for ICI response 27,28…”

Section: Major Classes Of Switch/sucrose Nonfermentable -Deficient Ma...mentioning

confidence: 99%

“…Nevertheless, seminal observations have pointed out a significant response to ICI therapy in these apparently "cold tumors." 11,25,26 These observations indicate a role for the SWI/SNF complex in the regulation of tumor immunity and have challenged the "TMB dogma" as being a universal (entity-independent) predictive biomarker for ICI response. 27,28 Lack of higher genomic instability in these single-gene diseases lead to speculate that the cancer immunogenicity might not be related to somatic variants within coding genes only, but noncoding sequences may play a role as well in these gnomically simple (stable) still highly immunogenic malignancies.…”

Section: Major Classes Of Switch/sucrose Nonfermentable -Deficient Ma...mentioning

confidence: 99%

SWI/SNF-deficient Malignancies: Optimal Candidates for Immune-oncological Therapy?

Agaimy

2022

Advances in Anatomic Pathology

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Inactivation of different subunits of the SWItch/sucrose nonfermentable (SWI/SNF) chromatin remodeling complex has emerged as one of the most frequent genetic pathways driving a variety of neoplasms of diverse histogenesis, originating in different organs. With few exceptions, most SWI/SNF-deficient malignancies pursue a highly aggressive clinical course resulting in widespread disease dissemination either at or soon after diagnosis, ultimately causing patients’ death soon after diagnosis, despite the apparently curative treatment intention. To date, no satisfactorily effective systemic chemotherapy has been established for treating these diseases. This disappointing finding underlines the urgent need for an effective systemic therapy that would enable sufficient intermediate to long-term disease control. Recently, SWI/SNF-deficiency has increasingly emerged as pivotal in cancer immunogenicity and hence a promising biomarker predicting response to immune-checkpoint inhibition therapy utilizing several recently established drugs. This review summarizes the most recent literature on this topic with emphasis on the entities that most likely represent suitable candidates for immune therapy.

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Immune responses in genomically simple SWI/SNF–deficient cancers

Abstract: Switch/sucrose nonfermentable–deficient cancers may respond to immune checkpoint blockade. Combinations with epidrugs or radiation therapies can offer new specific therapeutic vulnerabilities.

Cited by 7 publications

References 56 publications

Nivolumab with or without ipilimumab in pediatric patients with high-grade CNS malignancies: Safety, efficacy, biomarker, and pharmacokinetics—CheckMate 908

Nivolumab with or without ipilimumab in pediatric patients with high-grade CNS malignancies: Safety, efficacy, biomarker, and pharmacokinetics—CheckMate 908

Current and Emerging Therapeutic Approaches for Extracranial Malignant Rhabdoid Tumors

SWI/SNF-deficient Malignancies: Optimal Candidates for Immune-oncological Therapy?

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