The Challenges of Tumor Mutational Burden as an Immunotherapy Biomarker

Jardim, Denis Leonardo Fontes; Goodman, Aaron M.; Gagliato, Débora De Melo; Kurzrock, Razelle

doi:10.1016/j.ccell.2020.10.001

Cited by 707 publications

(565 citation statements)

References 151 publications

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“…It is worth noting that TMB does not always correlate with ICI responsiveness and its applicability should be considered with caution due to important limitations as a predictive biomarker, especially when used in isolation. Major challenges for TMB utility and its limitations have been reported and critically discussed in excellent recent studies and review articles [29,[37][38][39][40]. A composite predictor that also includes other critical variables, such as PD-L1 IHC, immune-related mutational and epigenetic landscapes as well as gene expression signatures, MHC and T cell receptor repertoire, clonality of neoantigens and tumor heterogeneity, is urgently needed [33,38].…”

Section: Response Evaluation and Biomarker Development For Icimentioning

confidence: 99%

Immune-Related Mutational Landscape and Gene Signatures: Prognostic Value and Therapeutic Impact for Head and Neck Cancer

Feng

Heß

2021

Cancers

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Immunotherapy by immune checkpoint inhibition has become a main pillar in the armamentarium to treat head and neck cancer and is based on the premise that the host immune system can be reactivated to successfully eliminate cancer cells. However, the response rate remains low and only a small subset of head and neck cancer patients achieves a durable clinical benefit. The availability of multi-omics data and emerging computational technologies facilitate not only a deeper understanding of the cellular composition in the tumor immune microenvironment but also enables the study of molecular principles in the complex regulation of immune surveillance versus tolerance. These knowledges will pave the way to apply immunotherapy more precisely and effectively. This review aims to provide a holistic view on how the immune landscape dictates the tumor fate and vice versa, and how integrative analysis of multi-omics data contribute to our current knowledge on the accuracy of predictive biomarkers and on a broad range of factors influencing the response to immunotherapy in head and neck cancer.

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Section: Response Evaluation and Biomarker Development For Icimentioning

confidence: 99%

Immune-Related Mutational Landscape and Gene Signatures: Prognostic Value and Therapeutic Impact for Head and Neck Cancer

Feng

Heß

2021

Cancers

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“…58 Fourth, at least some assumptions on the utility of TMB are based on results from retrospective studies which need to be validated in prospective studies. 58 All these taken together highlight limitations of TMB as a predictive biomarker, particularly when used in isolation. Mechanistically, MSI-H/dMMR tumors are a specific type of high TMB tumor that generates a high mutation associated neo-antigen (MANA) load due to defective genomic repair machinery.…”

Section: Challenges In Immune Checkpoint Inhibitionmentioning

confidence: 99%

The Association Between Inflammation and Immunosuppression: Implications for ICI Biomarker Development

Sacdalan

Lucero

2021

OTT

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Evasion of immune destruction is considered one of the hallmarks of cancer. Chronic inflammation can enable immune escape by suppressing immune surveillance and permitting the development of tumors and creating a tumor microenvironment that sustains cancer. This includes generating mechanisms that prevent the effectiveness of anti-tumor treatment including immune checkpoint inhibitor therapy. In this review, we explore the interplay of inflammation and immunosuppression, their effects on the tumor microenvironment, and their implications for immune checkpoint inhibitor therapy particularly in the context of predictive biomarkers for their use.

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“…Indeed, pembrolizumab has just been approved by FDA for the treatment of adult and pediatric patients with unresectable or metastatic tumor with high TMB based on cohorts with ten tumor types from the phase 2 KEYNOTE-158 study 59 . However, TMB alone is not a perfect predictor for patient response and survival 24 .…”

Section: Resultsmentioning

confidence: 99%

“…In addition, recently FDA has approved pembrolizumab for several other cancer types with high TMB 59 . Nevertheless, TMB alone is not a perfect predictor for patient response 24 . We found that the fraction of older patients who show response to immunotherapy is much higher than younger ones under the same level of TMB.…”

Section: Discussionmentioning

confidence: 99%

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Imprints of tumor mutation burden on chromosomes and relation to cancer risk in humans: A pan-cancer analysis

Thirumalai

2020

Preprint

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Cancers, resulting in uncontrolled cell proliferation, are driven by accumulation of somatic mutations. Whole-genome sequencing has produced a catalogue of millions of somatic mutations, which contain the evolutionary history of the cancers. However, the connection between the extent and rate of mutation accumulation and disease development and risks are poorly understood. We analyzed data from 5,000 cancer patients with more than 1,200,000 mutations for 16 cancer types using The Cancer Genome Atlas (TCGA) database to unearth markers of tumor evolution. A strong correlation between Tumor Mutation Burden (TMB) and the Patient Age at Diagnosis (PAD) for cancers with low TMB (mean value less than 3 mutations per million base pairs) is absent in cancers with high TMB. The finding, demarcating cancers according to the TMB, resolves controversies relating the dynamics of mutation accumulation and disease risks for different cancers. We also find that the differences in cancer risk between the sexes are mainly driven by the disparity in mutation burden.A simple model, explaining these results, also show that immunotherapy could work well for elderly melanoma patients. 1 otareva. Thyroid cancer in children and adolescents of Bryansk and Kaluga Regions. Age, 4(10-14):15-19, 1996. 31 Dmitriy I Podolskiy, Alexei V Lobanov, Gregory V Kryukov, and Vadim N Gladyshev. Analysis of cancer genomes reveals basic features of human aging and its role in cancer development.

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The Challenges of Tumor Mutational Burden as an Immunotherapy Biomarker

Cited by 707 publications

References 151 publications

Immune-Related Mutational Landscape and Gene Signatures: Prognostic Value and Therapeutic Impact for Head and Neck Cancer

Immune-Related Mutational Landscape and Gene Signatures: Prognostic Value and Therapeutic Impact for Head and Neck Cancer

The Association Between Inflammation and Immunosuppression: Implications for ICI Biomarker Development

Imprints of tumor mutation burden on chromosomes and relation to cancer risk in humans: A pan-cancer analysis

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