Tumor mutation burden, DNA mismatch repair status and checkpoint immunotherapy markers in primary and relapsed malignant rhabdoid tumors

Abro, Brooj; Kaushal, Madhurima; Chen, Ling; Wu, Robert; Dehner, Louis P.; Pfeifer, John D.; He, Mai

doi:10.1016/j.prp.2019.03.023

Cited by 24 publications

(20 citation statements)

References 40 publications

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“…The presence of PD-L1/PD-1 and CTLA-4 expression and response to immune checkpoint inhibitor therapy has, in lung cancer and melanoma, been correlated with high TMB (33,34). INI1-deficient cancers in children have, of all cancers, amongst the lowest mutational burden (30,35,36). Importantly, patients with PD-L1 expressing tumors of multiple histologies have improved responses and survival with immune checkpoint inhibition compared to patients with PD-L1 negative tumors (37).…”

Section: Patients Treated With Immune Checkpoint Inhibitionmentioning

confidence: 99%

Genomic and Immunologic Characterization of INI1-Deficient Pediatric Cancers

Forrest

Al‐Ibraheemi

Doan

et al. 2020

Clinical Cancer Research

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The prognosis for patients with INI1-deficient pediatric cancers is poor and therapeutic options, particularly in the relapsed or refractory setting, are limited. We sought to characterize the association between SMARCB1 genetic variants identified by next-generation sequencing and INI1 protein expression and to evaluate PD-L1 and CD8 expression in INI1-deficient tumors. Available evidence suggests a low rate of PD-L1 expression and response to immune checkpoint blockade in pediatric cancers. INI1-negative pediatric cancers may represent an important exception to this despite remarkably low tumor mutational burden. Our findings provide evidence supporting a novel strategy for treating INI1-deficient cancers. This study contributes to emerging data that immune checkpoint blockade either as monotherapy or in combination with other agents may be an effective treatment approach for these aggressive cancers. Research.

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Section: Patients Treated With Immune Checkpoint Inhibitionmentioning

confidence: 99%

Genomic and Immunologic Characterization of INI1-Deficient Pediatric Cancers

Forrest

Al‐Ibraheemi

Doan

et al. 2020

Clinical Cancer Research

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“…H Yasui et al tumours and metastatic relapses [16]. Our results suggest that in the setting of progression under therapy, TMB increases through private mutations in metastatic tumours.…”

mentioning

confidence: 51%

A dynamic mutational landscape associated with an inter‐regionally diverse immune response in malignant rhabdoid tumour

Yasui

Valind

Karlsson

et al. 2020

The Journal of Pathology

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Malignant rhabdoid tumour (MRT) is a childhood neoplasm of high malignancy characterised by biallelic mutation and/or loss of the epigenetic master regulator SMARCB1, accompanied by no or few other oncogenic drivers. In spite of their generally low mutational burden, an intratumoural T‐cell response has been reported in a subset of MRTs, indicating that immune checkpoint inhibition may be considered a viable therapy option for some patients. We assess here the evolution over time and space of predicted neoantigens and indicators of immune checkpoint status in two MRT patients who progressed under treatment. Both patients showed an accumulation of novel clonal and subclonal mutations, including predicted neoantigens, in metastases compared to their inferred ancestral clones in the primary tumours. The first patient had peritoneal metastases from an MRT of the liver. Clonal deconvolution revealed polyclonal seeding from the primary tumour to a single metastatic site, followed by a local subclonal burst of mutations. The second patient had a renal MRT with multiple pulmonary metastases, each of which could be traced back to a single genetically unique founder cell, with formation of novel subclones in two metastases. Both patients showed a regionally heterogeneous landscape of predicted neoantigens and of tumour‐infiltrating lymphocytes expressing CD8 and PD1. In both patients, some tumour regions fulfilled established criteria for PD‐L1 positivity (> 1% of tumour cells), while others did not. This suggests that even in a tumour type like MRT, with a single driver mutation, there can be heterogeneity in neoantigen repertoire, immune response, and biomarkers for checkpoint blockade among sampled locations. This must be taken into account when assessing progressed MRT patients for checkpoint inhibition therapy. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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“…However, we recently provided evidence of an active, ongoing intratumor T‐cell response in specific subgroups of RT patients and in a mouse SMARCB1‐deficient RT model 9 . Furthermore, we and others have reported in vivo responses to ICB for such tumors both in mice 9 and in humans 10‐12 . Importantly, no differences in TMB were identified between PD‐L1–positive and PD‐L1–negative SMARCB1‐deficient tumors in an independent cohort of pediatric patients 13 .…”

Section: Swi/snf Mutations Can Evoke a Targetable Immune Response In mentioning

confidence: 74%