The Challenges of Tumor Mutational Burden as an Immunotherapy Biomarker

Tumor mutational burden (TMB) reflects cancer mutation quantity. Mutations are processed to neo-antigens and presented by major histocompatibility complex (MHC) proteins to T cells. To evade immune eradication, cancers exploit checkpoints that dampen T cell reactivity. Immune checkpoint inhibitors (...

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Published in	Cancer cell Vol. 39; no. 2; pp. 154 - 173
Main Authors	Jardim, Denis L., Goodman, Aaron, de Melo Gagliato, Debora, Kurzrock, Razelle
Format	Journal Article
Language	English
Published	United States Elsevier Inc 08.02.2021
Subjects	biomarker Biomarkers, Tumor - genetics Biomarkers, Tumor - immunology cancer therapy genetics Humans Immune Checkpoint Inhibitors - pharmacology immunotherapy Immunotherapy - methods Major Histocompatibility Complex - genetics Major Histocompatibility Complex - immunology Mutation - genetics Mutation - immunology mutattional load Neoplasms - genetics Neoplasms - immunology Neoplasms - therapy T-Lymphocytes - immunology cancer therapy mutattional load genetics biomarker immunotherapy
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Abstract	Tumor mutational burden (TMB) reflects cancer mutation quantity. Mutations are processed to neo-antigens and presented by major histocompatibility complex (MHC) proteins to T cells. To evade immune eradication, cancers exploit checkpoints that dampen T cell reactivity. Immune checkpoint inhibitors (ICIs) have transformed cancer treatment by enabling T cell reactivation; however, response biomarkers are required, as most patients do not benefit. Higher TMB results in more neo-antigens, increasing chances for T cell recognition, and clinically correlates with better ICI outcomes. Nevertheless, TMB is an imperfect response biomarker. A composite predictor that also includes critical variables, such as MHC and T cell receptor repertoire, is needed. Tumor mutational burden (TMB) reflects cancer mutation quantity. Mutations are processed to neo-antigens and presented by major histocompatibility complex (MHC) proteins to T cells. To evade immune eradication, cancers exploit checkpoints that dampen T cell reactivity. Immune checkpoint inhibitors (ICIs) have transformed cancer treatment by enabling T cell reactivation; however, response biomarkers are required, as most patients do not benefit. Higher TMB results in more neo-antigens, increasing chances for T cell recognition, and clinically correlates with better ICI outcomes. Nevertheless, TMB is an imperfect response biomarker. A composite predictor that also includes critical variables, such as MHC and T cell receptor repertoire, is needed.
AbstractList	Tumor mutational burden (TMB) reflects cancer mutation quantity. Mutations are processed to neo-antigens and presented by major histocompatibility complex (MHC) proteins to T cells. To evade immune eradication, cancers exploit checkpoints that dampen T cell reactivity. Immune checkpoint inhibitors (ICIs) have transformed cancer treatment by enabling T cell reactivation; however, response biomarkers are required, as most patients do not benefit. Higher TMB results in more neo-antigens, increasing chances for T cell recognition, and clinically correlates with better ICI outcomes. Nevertheless, TMB is an imperfect response biomarker. A composite predictor that also includes critical variables, such as MHC and T cell receptor repertoire, is needed.Tumor mutational burden (TMB) reflects cancer mutation quantity. Mutations are processed to neo-antigens and presented by major histocompatibility complex (MHC) proteins to T cells. To evade immune eradication, cancers exploit checkpoints that dampen T cell reactivity. Immune checkpoint inhibitors (ICIs) have transformed cancer treatment by enabling T cell reactivation; however, response biomarkers are required, as most patients do not benefit. Higher TMB results in more neo-antigens, increasing chances for T cell recognition, and clinically correlates with better ICI outcomes. Nevertheless, TMB is an imperfect response biomarker. A composite predictor that also includes critical variables, such as MHC and T cell receptor repertoire, is needed. Tumor mutational burden (TMB) reflects cancer mutation quantity. Mutations are processed to neo-antigens and presented by major histocompatibility complex (MHC) proteins to T-cells. To evade immune eradication, cancers exploit checkpoints that dampen T-cell reactivity. Immune checkpoint inhibitors (ICIs) have transformed cancer treatment by enabling T-cell reactivation; however, response biomarkers are required, as most patients do not benefit. Higher TMB results in more neo-antigens, increasing chances for T-cell recognition, and clinically correlates with better ICI outcomes. Nevertheless, TMB is an imperfect response biomarker. A composite predictor that also includes critical variables, such as MHC and T-cell receptor repertoire, is needed. Tumor mutational burden (TMB) reflects cancer mutation quantity. Mutations are processed to neo-antigens and presented by major histocompatibility complex (MHC) proteins to T cells. To evade immune eradication, cancers exploit checkpoints that dampen T cell reactivity. Immune checkpoint inhibitors (ICIs) have transformed cancer treatment by enabling T cell reactivation; however, response biomarkers are required, as most patients do not benefit. Higher TMB results in more neo-antigens, increasing chances for T cell recognition, and clinically correlates with better ICI outcomes. Nevertheless, TMB is an imperfect response biomarker. A composite predictor that also includes critical variables, such as MHC and T cell receptor repertoire, is needed. Tumor mutational burden (TMB) reflects cancer mutation quantity. Mutations are processed to neo-antigens and presented by major histocompatibility complex (MHC) proteins to T cells. To evade immune eradication, cancers exploit checkpoints that dampen T cell reactivity. Immune checkpoint inhibitors (ICIs) have transformed cancer treatment by enabling T cell reactivation; however, response biomarkers are required, as most patients do not benefit. Higher TMB results in more neo-antigens, increasing chances for T cell recognition, and clinically correlates with better ICI outcomes. Nevertheless, TMB is an imperfect response biomarker. A composite predictor that also includes critical variables, such as MHC and T cell receptor repertoire, is needed. Tumor mutational burden (TMB) reflects cancer mutation quantity. Mutations are processed to neo-antigens and presented by major histocompatibility complex (MHC) proteins to T cells. To evade immune eradication, cancers exploit checkpoints that dampen T cell reactivity. Immune checkpoint inhibitors (ICIs) have transformed cancer treatment by enabling T cell reactivation; however, response biomarkers are required, as most patients do not benefit. Higher TMB results in more neo-antigens, increasing chances for T cell recognition, and clinically correlates with better ICI outcomes. Nevertheless, TMB is an imperfect response biomarker. A composite predictor that also includes critical variables, such as MHC and T cell receptor repertoire, is needed.
Author	Goodman, Aaron de Melo Gagliato, Debora Jardim, Denis L. Kurzrock, Razelle
AuthorAffiliation	2 Center for Personalized Cancer Therapy and Division of Hematology and Oncology, University of California, San Diego, CA, USA 1 Centro de Oncologia Hospital Sírio Libanês – São Paulo, Brazil 3 Hospital; Beneficiência Portuguesa, Department of Medical Oncology, São Paulo, Brazil
AuthorAffiliation_xml	– name: 1 Centro de Oncologia Hospital Sírio Libanês – São Paulo, Brazil – name: 3 Hospital; Beneficiência Portuguesa, Department of Medical Oncology, São Paulo, Brazil – name: 2 Center for Personalized Cancer Therapy and Division of Hematology and Oncology, University of California, San Diego, CA, USA
Author_xml	– sequence: 1 givenname: Denis L. surname: Jardim fullname: Jardim, Denis L. organization: Centro de Oncologia Hospital Sírio Libanês–São Paulo, São Paulo, Brazil – sequence: 2 givenname: Aaron surname: Goodman fullname: Goodman, Aaron organization: Center for Personalized Cancer Therapy and Division of Hematology and Oncology, University of California, San Diego, CA, USA – sequence: 3 givenname: Debora surname: de Melo Gagliato fullname: de Melo Gagliato, Debora organization: Hospital Beneficência Portuguesa, Department of Medical Oncology, São Paulo, Brazil – sequence: 4 givenname: Razelle surname: Kurzrock fullname: Kurzrock, Razelle email: rkurzrock@ucsd.edu organization: Center for Personalized Cancer Therapy and Division of Hematology and Oncology, University of California, San Diego, CA, USA
BackLink	https://www.ncbi.nlm.nih.gov/pubmed/33125859$$D View this record in MEDLINE/PubMed
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Snippet	Tumor mutational burden (TMB) reflects cancer mutation quantity. Mutations are processed to neo-antigens and presented by major histocompatibility complex...
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SubjectTerms	biomarker Biomarkers, Tumor - genetics Biomarkers, Tumor - immunology cancer therapy genetics Humans Immune Checkpoint Inhibitors - pharmacology immunotherapy Immunotherapy - methods Major Histocompatibility Complex - genetics Major Histocompatibility Complex - immunology Mutation - genetics Mutation - immunology mutattional load Neoplasms - genetics Neoplasms - immunology Neoplasms - therapy T-Lymphocytes - immunology
Title	The Challenges of Tumor Mutational Burden as an Immunotherapy Biomarker
URI	https://dx.doi.org/10.1016/j.ccell.2020.10.001 https://www.ncbi.nlm.nih.gov/pubmed/33125859 https://www.proquest.com/docview/2456410660 https://pubmed.ncbi.nlm.nih.gov/PMC7878292
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