Cited by 1,192Cancer Immunotherapy and BiomarkersImmunotherapy and Immune ResponsesCancer Genomics and Diagnostics

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The Challenges of Tumor Mutational Burden as an Immunotherapy Biomarker

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Jardim, Denis L., Goodman, Aaron, de Melo Gagliato, Debora, Kurzrock, Razelle·2021·Cancer Cell

DOI 10.1016/j.ccell.2020.10.001PMC PMC7878292

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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.

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First-line nivolumab plus ipilimumab in advanced non-small-cell lung cancer (CheckMate 568): outcomes by programmed death ligand 1 and tumor mutational burden as biomarkers
Ready, N., Hellmann, M. D., Awad, M. M., Otterson, G. A., Gutierrez, M., Gainor, J. F., Borghaei, H., Jolivet, J., Horn, L., Mates, M., et al. (2019) · Journal of Clinical Oncology · doi:10.1200/jco.18.01042 · Cited by 581
MHC proteins confer differential sensitivity to CTLA-4 and PD-1 blockade in untreated metastatic melanoma
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PD-L1 expression and tumor mutational burden are independent biomarkers in most cancers
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Alterations in DNA damage response and repair genes as potential marker of clinical benefit from PD-1/PD-L1 blockade in advanced urothelial cancers
Teo, M. Y., Seier, K., Ostrovnaya, I., Regazzi, A. M., Kania, B. E., Moran, M. M., Cipolla, C. K., Bluth, M. J., Chaim, J., Al-Ahmadie, H., et al. (2018) · Journal of Clinical Oncology · doi:10.1200/jco.2017.75.7740 · Cited by 544
Biomarker: Predictive or Prognostic?
Ballman, K. V. (2015) · Journal of Clinical Oncology · doi:10.1200/jco.2015.63.3651 · Cited by 520 · cited 1×
“(Ballman, 2015).”
Mutational and putative neoantigen load predict clinical benefit of adoptive T cell therapy in melanoma
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Targeted Next Generation Sequencing Identifies Markers of Response to PD-1 Blockade
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Assessment of blood tumor mutational burden as a potential biomarker for immunotherapy in patients with non-small cell lung cancer with use of a next-generation sequencing cancer gene panel
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MHC-I Genotype Restricts the Oncogenic Mutational Landscape
Marty, R., Kaabinejadian, S., Rossell, D., Slifker, M. J., van de Haar, J., Engin, H. B., de Prisco, N., Ideker, T., Hildebrand, W. H., Font-Burgada, J., et al. (2017) · Cell · doi:10.1016/j.cell.2017.09.050 · Cited by 356
Contribution of systemic and somatic factors to clinical response and resistance to PD-L1 blockade in urothelial cancer: An exploratory multi-omic analysis
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Implementing TMB measurement in clinical practice: considerations on assay requirements
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Tumor mutational burden quantification from targeted gene panels: major advancements and challenges
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Dynamics of Tumor and Immune Responses during Immune Checkpoint Blockade in Non–Small Cell Lung Cancer
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Immune Cell PD-L1 Colocalizes with Macrophages and Is Associated with Outcome in PD-1 Pathway Blockade Therapy
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Microsatellite-Stable Tumors with High Mutational Burden Benefit from Immunotherapy
Goodman, A. M., Sokol, E. S., Frampton, G. M., Lippman, S. M., & Kurzrock, R. (2019) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-19-0149 · Cited by 310
Self-citation
Safety and tolerability of pembrolizumab in patients with relapsed/refractory primary mediastinal large B-cell lymphoma
Zinzani, P. L., Ribrag, V., Moskowitz, C. H., Michot, J., Kuruvilla, J. G., Balakumaran, A., Zhang, Y., Chlosta, S., Shipp, M. A., & Armand, P. A. (2017) · Blood · doi:10.1182/blood-2016-12-758383 · Cited by 290
The Superior Efficacy of Anti-PD-1/PD-L1 Immunotherapy in KRAS-Mutant Non-Small Cell Lung Cancer that Correlates with an Inflammatory Phenotype and Increased Immunogenicity
Liu, C., Zheng, S., Jin, R., Wang, X., Wang, F., Zang, R., Xu, H., Lu, Z., Huang, J., Lei, Y., et al. (2019) · Cancer Letters · doi:10.1016/j.canlet.2019.10.027 · Cited by 288
Prevalence ofPDL1Amplification and Preliminary Response to Immune Checkpoint Blockade in Solid Tumors
Goodman, A. M., Piccioni, D. E., Kato, S., Boichard, A., Wang, H., Frampton, G. M., Lippman, S. M., Connelly, C. F., Fabrizio, D. A., Miller, V. A., et al. (2018) · JAMA Oncology · doi:10.1001/jamaoncol.2018.1701 · Cited by 250
Self-citation
Mutational Landscape and Sensitivity to Immune Checkpoint Blockers
Chabanon, R. M., Pedrero, M., Lefèbvre, C., Marabelle, A., Soria, J., & Postel-Vinay, S. C. (2016) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-16-0903 · Cited by 236
T cell receptor repertoire features associated with survival in immunotherapy-treated pancreatic ductal adenocarcinoma
Hopkins, A. C., Yarchoan, M., Durham, J. N., Yusko, E. C., Rytlewski, J. A., Robins, H. S., Laheru, D. A., Le, D. T., Lutz, E. R., & Jaffee, E. M. (2018) · JCI Insight · doi:10.1172/jci.insight.122092 · Cited by 233
Comprehensive cancer-gene panels can be used to estimate mutational load and predict clinical benefit to PD-1 blockade in clinical practice
Campesato, L. F., Barroso‐Sousa, R., Jimenez, L., Corrêa, B., Sabbaga, J., Hoff, P. M., Reis, L. F. L., Galante, P. A. F., & Camargo, A. A. (2015) · Oncotarget · doi:10.18632/oncotarget.5950 · Cited by 224
Immune gene signatures for predicting durable clinical benefit of anti-PD-1 immunotherapy in patients with non-small cell lung cancer
Hwang, S., Kwon, A.-Y., Jeong, J.-Y., Kim, S., Kang, H., Park, J., Kim, J.-H., Han, O. J., Lim, S. M., & An, H. J. (2020) · Scientific Reports · doi:10.1038/s41598-019-57218-9 · Cited by 215
The path to a better biomarker: application of a risk management framework for the implementation of PD‐L1 and TILs as immuno‐oncology biomarkers in breast cancer clinical trials and daily practice
Ericsson, P. I. G., Stovgaard, E. S., Sua, L. F., Reisenbichler, E., Kos, Z., Carter, J. M., Michiels, S., Quesne, J. P. C. L., Nielsen, T. O., Lænkholm, A., et al. (2020) · The Journal of Pathology · doi:10.1002/path.5406 · Cited by 215
Evolutionary Pressure against MHC Class II Binding Cancer Mutations
Pyke, R. M., Thompson, W. K., Salem, R. M., Font-Burgada, J., Zanetti, M., & Carter, H. K. (2018) · Cell · doi:10.1016/j.cell.2018.08.048 · Cited by 212
Hypermutated Circulating Tumor DNA: Correlation with Response to Checkpoint Inhibitor–Based Immunotherapy
Khagi, Y., Goodman, A. M., Daniels, G. A., Patel, S. P., Sacco, A. G., Randall, J. M., Bazhenova, L. A., & Kurzrock, R. (2017) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-17-1439 · Cited by 203
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ARID1A alterations function as a biomarker for longer progression-free survival after anti-PD-1/PD-L1 immunotherapy
Okamura, R., Kato, S., Lee, S., Jimenez, R. E., Sicklick, J. K., & Kurzrock, R. (2020) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2019-000438 · Cited by 189
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Small-Cell Carcinoma of the Ovary, Hypercalcemic Type–Genetics, New Treatment Targets, and Current Management Guidelines
Tischkowitz, M. D., Huang, S., Banerjee, S. N., Hague, J., Hendricks, W. P. D., Huntsman, D. D., Lang, J. D., Orlando, K. A., Oza, A. M., Pautier, P., et al. (2020) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-19-3797 · Cited by 174
Peripheral Blood TCR Repertoire Profiling May Facilitate Patient Stratification for Immunotherapy against Melanoma
Hogan, S. A., Courtier, A., Cheng, P. F., Jaberg-Bentele, N. F., Goldinger, S. M., Manuel, M., Perez, S., Plantier, N., Mouret, J.-F., Nguyen‐Kim, T. D. L., et al. (2018) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-18-0136 · Cited by 155
Recurrent SERPINB3 and SERPINB4 mutations in patients who respond to anti-CTLA4 immunotherapy
Riaz, N., Havel, J. J., Kendall, S. M., Makarov, V., Walsh, L. A., Desrichard, A., Weinhold, N., & Chan, T. A.-T. (2016) · Nature Genetics · doi:10.1038/ng.3677 · Cited by 151
Hyperprogressive disease in early‐phase immunotherapy trials: Clinical predictors and association with immune‐related toxicities
Kanjanapan, Y., Day, D., Wang, L. E., Al‐Sawaihey, H., Abbas, E., Namini, A., Siu, L. L., Hansen, A. R., Razak, A. A., Spreafico, A., et al. (2019) · Cancer · doi:10.1002/cncr.31999 · Cited by 141
Adverse Events Associated with Immune Checkpoint Blockade
Tervaert, J.-W. C., Ye, C., & Yacyshyn, E. (2018) · New England Journal of Medicine · doi:10.1056/nejmc1801663 · Cited by 134
Metastatic basal cell carcinoma with amplification of PD-L1: exceptional response to anti-PD1 therapy
Ikeda, S., Goodman, A. M., Cohen, P. R., Jensen, T. J., Ellison, C. K., Frampton, G. M., Miller, V. A., Patel, S. P., & Kurzrock, R. (2016) · npj Genomic Medicine · doi:10.1038/npjgenmed.2016.37 · Cited by 130
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Successful Treatment of HIV-Associated Kaposi Sarcoma with Immune Checkpoint Blockade
Galanina, N., Goodman, A. M., Cohen, P. R., Frampton, G. M., & Kurzrock, R. (2018) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-18-0121 · Cited by 126
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Neoantigens and genome instability: impact on immunogenomic phenotypes and immunotherapy response
Mardis, E. R. (2019) · Genome Medicine · doi:10.1186/s13073-019-0684-0 · Cited by 124 · cited 1×
“(Mardis, 2019) In fact, about 83% of MSI-H tumors also present TMB-H (≥20 mutations/Mb) (Chalmers et al., 2017).”
Background
Novel algorithmic approach predicts tumor mutation load and correlates with immunotherapy clinical outcomes using a defined gene mutation set
Roszik, J., Haydu, L. E., Hess, K. R., Oba, J., Joon, A. Y., Siroy, A. E., Karpinets, T. V., Stingo, F. C., Baladandayuthapani, V., Tetzlaff, M. T., et al. (2016) · BMC Medicine · doi:10.1186/s12916-016-0705-4 · Cited by 115
Harmonization of Tumor Mutational Burden Quantification and Association With Response to Immune Checkpoint Blockade in Non–Small-Cell Lung Cancer
Vokes, N. I., Liu, D., Ricciuti, B., Jimenez-Aguilar, E., Rizvi, H. A., Dietlein, F., He, M., Margolis, C. A., Elmarakeby, H., Girshman, J., et al. (2019) · JCO Precision Oncology · doi:10.1200/po.19.00171 · Cited by 112
MHC-I genotype and tumor mutational burden predict response to immunotherapy
Goodman, A. M., Castro, A., Pyke, R. M., Okamura, R., Kato, S., Riviere, P. J., Frampton, G. M., Sokol, E. S., Zhang, X., Ball, E. D., et al. (2020) · Genome Medicine · doi:10.1186/s13073-020-00743-4 · Cited by 112
Self-citation
The emerging role of immune checkpoint inhibition in malignant lymphoma
Hude, I., Sasse, S., Engert, A., & Bröckelmann, P. J. (2016) · Haematologica · doi:10.3324/haematol.2016.150656 · Cited by 109
Association of tumour mutational burden with outcomes in patients with select advanced solid tumours treated with pembrolizumab in KEYNOTE-158
Marabelle, A., Fakih, M. G., Lopez, J., Shah, M., Shapira-Frommer, R., Nakagawa, K., Chung, H. C., Kindler, H. L., Lopez-Martin, J. A., Miller, W., et al. (2019) · Annals of Oncology · doi:10.1093/annonc/mdz253.018 · Cited by 104
Pembrolizumab (pembro) plus platinum-based chemotherapy (chemo) for metastatic NSCLC: Tissue TMB (tTMB) and outcomes in KEYNOTE-021, 189, and 407
Paz-Ares, L. G., Langer, C. J., Novello, S., Halmos, B., Cheng, Y., Gadgeel, S. M., Hui, R., Sugawara, S., Borghaei, H., Cristescu, R., et al. (2019) · Annals of Oncology · doi:10.1093/annonc/mdz394.078 · Cited by 104
Baseline Plasma Tumor Mutation Burden Predicts Response to Pembrolizumab-based Therapy in Patients with Metastatic Non–Small Cell Lung Cancer
Aggarwal, C., Thompson, J. C., Chien, A. L., Quinn, K., Hwang, W., Black, T. A., Yee, S. S., Christensen, T. E., Lariviere, M. J., Silva, B. A., et al. (2020) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-19-3663 · Cited by 103
High Tumor Mutational Burden Correlates with Longer Survival in Immunotherapy-Naïve Patients with Diverse Cancers
Riviere, P. J., Goodman, A. M., Okamura, R., Barkauskas, D. A., Whitchurch, T. J., Lee, S., Khalid, N. K., Collier, R., Mareboina, M., Frampton, G. M., et al. (2020) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-20-0161 · Cited by 96
Self-citation
Burden of tumor mutations, neoepitopes, and other variants are weak predictors of cancer immunotherapy response and overall survival
Wood, M. A., Weeder, B. R., David, J. K., Nellore, A., & Thompson, R. F. (2020) · Genome Medicine · doi:10.1186/s13073-020-00729-2 · Cited by 94
APOBEC-related mutagenesis and neo-peptide hydrophobicity: implications for response to immunotherapy
Boichard, A., Pham, T. V., Yeerna, H., Goodman, A. M., Tamayo, P., Lippman, S. M., Frampton, G. M., Tsigelny, I. F., & Kurzrock, R. (2018) · OncoImmunology · doi:10.1080/2162402x.2018.1550341 · Cited by 90
Self-citation
Initial results from a phase II study of nivolumab (NIVO) plus ipilimumab (IPI) for the treatment of metastatic castration-resistant prostate cancer (mCRPC; CheckMate 650).
Sharma, P., Pachynski, R. K., Narayan, V., Fléchon, A., Gravis, G., Galsky, M. D., Mahammedi, H., Patnaik, A., Subudhi, S. K., Ciprotti, M., et al. (2019) · Journal of Clinical Oncology · doi:10.1200/jco.2019.37.7_suppl.142 · Cited by 88
OA20.01 Tumor Mutation Burden (TMB) is Associated with Improved Efficacy of Atezolizumab in 1L and 2L+ NSCLC Patients
Kowanetz, M., Zou, W., Shames, D. S., Cummings, C. A., Rizvi, N. A., Spira, A. I., Frampton, G. M., Lévêque, V., Flynn, S., Mocci, S., et al. (2017) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2016.11.343 · Cited by 86
Integrated analysis of the immunological and genetic status in and across cancer types: impact of mutational signatures beyond tumor mutational burden
Budczies, J., Seidel, A., Christopoulos, P., Endris, V., Kloor, M., Győrffy, B., Seliger, B., Schirmacher, P., Stenzinger, A., & Denkert, C. (2018) · OncoImmunology · doi:10.1080/2162402x.2018.1526613 · Cited by 80
Abstract CT074: Tumor mutational burden (TMB) as a biomarker of survival in metastatic non-small cell lung cancer (mNSCLC): Blood and tissue TMB analysis from MYSTIC, a Phase III study of first-line durvalumab ± tremelimumab vs chemotherapy.
Peters, S., Cho, B. C., Reinmuth, N., Lee, K. H., Luft, A. V., Ahn, M., Baas, P., Cobo, M., Smolin, A., Vicente, D., et al. (2019) · Cancer Research · doi:10.1158/1538-7445.am2019-ct074 · Cited by 78 · cited 1×
“(Gandara et al., 2018; Khagi et al., 2017; Kim et al., 2018; Peters et al., 2019; Wang et al., 2019) The use of blood-based TMB assessment may be especially important since a subgroup of patients (~15% in our experience) may not have tissue for TMB assessment, either because the tissue is…”
Method
High expression of PD-1 ligands is associated with kataegis mutational signature and APOBEC3 alterations
Boichard, A., Tsigelny, I. F., & Kurzrock, R. (2017) · OncoImmunology · doi:10.1080/2162402x.2017.1284719 · Cited by 75
Self-citation
Mutations in DNA repair genes are associated with increased neoantigen burden and a distinct immunophenotype in lung squamous cell carcinoma
Chae, Y. K., Anker, J. F., Oh, M. S., Bais, P., Namburi, S., Agte, S., Giles, F. J., & Chuang, J. H. (2019) · Scientific Reports · doi:10.1038/s41598-019-39594-4 · Cited by 75
Predictive biomarkers for hyper-progression (HP) in response to immune checkpoint inhibitors (ICI) – analysis of somatic alterations (SAs)
Singavi, A. K., Menon, S., Kilari, D., Alqwasmi, A., Ritch, P. S., Thomas, J. P., Martin, A. L., Oxencis, C. J., Ali, S. S., & George, B. (2017) · Annals of Oncology · doi:10.1093/annonc/mdx376.006 · Cited by 73
Increased diversity with reduced “diversity evenness” of tumor infiltrating T-cells for the successful cancer immunotherapy
Hosoi, A., Takeda, K., Nagaoka, K., Iino, T., Matsushita, H., Ueha, S., Aoki, S., Matsushima, K., Kubo, M., Morikawa, T., et al. (2018) · Scientific Reports · doi:10.1038/s41598-018-19548-y · Cited by 69
Expression of TIM3/VISTA checkpoints and the CD68 macrophage-associated marker correlates with anti-PD1/PDL1 resistance: implications of immunogram heterogeneity
Kato, S., Okamura, R., Kumaki, Y., Ikeda, S., Nikanjam, M., Eskander, R. N., Goodman, A. M., Lee, S., Glenn, S. T., Dressman, D. C., et al. (2020) · OncoImmunology · doi:10.1080/2162402x.2019.1708065 · Cited by 68
Self-citation
TCR repertoires of intratumoral T‐cell subsets
Linnemann, C., Mezzadra, R., & Schumacher, T. N. (2013) · Immunological Reviews · doi:10.1111/imr.12140 · Cited by 64
Pan-cancer analysis of KEAP1 mutations as biomarkers for immunotherapy outcomes
Chen, X., Su, C., Ren, S., Zhou, C., & Jiang, T. (2020) · Annals of Translational Medicine · doi:10.21037/atm.2019.11.52 · Cited by 64
Immune profiling of microsatellite instability-high and polymerase ε (POLE)-mutated metastatic colorectal tumors identifies predictors of response to anti-PD-1 therapy
Wang, C., Gong, J., Tu, T. Y., Lee, P. P., & Fakih, M. (2018) · Journal of Gastrointestinal Oncology · doi:10.21037/jgo.2018.01.09 · Cited by 62
Primary efficacy results from B-F1RST, a prospective phase II trial evaluating blood-based tumour mutational burden (bTMB) as a predictive biomarker for atezolizumab (atezo) in 1L non-small cell lung cancer (NSCLC)
Kim, E. S., Velcheti, V., Mekhail, T. M., Leal, T. A. B., Dowell, J. E., Tsai, M. L., Dakhil, C. S. R., Stella, P. J., Shen, V., Hu, S., et al. (2018) · Annals of Oncology · doi:10.1093/annonc/mdy424.067 · Cited by 62
The Peptide-Receptive Transition State of MHC Class I Molecules: Insight from Structure and Molecular Dynamics
Mage, M. G., Dolan, M. A., Wang, R. Y., Boyd, L. F., Revilleza, M. J., Robinson, H. H., Natarajan, K., Myers, N. B., Hansen, T. H., & Margulies, D. H. (2012) · The Journal of Immunology · doi:10.4049/jimmunol.1200831 · Cited by 59
Association of Tumor Microenvironment T-cell Repertoire and Mutational Load with Clinical Outcome after Sequential Checkpoint Blockade in Melanoma
Yusko, E. C., Vignali, M., Wilson, R. K., Mardis, E. R., Hodi, F. S., Horak, C. E., Chang, H., Woods, D. M., Robins, H. S., & Weber, J. S. (2019) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-18-0226 · Cited by 59
Concordance between Comprehensive Cancer Genome Profiling in Plasma and Tumor Specimens
Müller, J. N., Falk, M., Talwar, J., Neemann, N., Mariotti, E., Bertrand, M., Zacherle, T., Lakis, S., Menon, R., Gloeckner, C., et al. (2017) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2017.07.014 · Cited by 57
Role of ultraviolet mutational signature versus tumor mutation burden in predicting response to immunotherapy
Pham, T. V., Boichard, A., Goodman, A. M., Riviere, P. J., Yeerna, H., Tamayo, P., & Kurzrock, R. (2020) · Molecular Oncology · doi:10.1002/1878-0261.12748 · Cited by 57
Self-citation
Impact of zumor mutation burden on nivolumab efficacy in second-line urothelial carcinoma patients: Exploratory analysis of the phase ii checkmate 275 study
Galsky, M. D., Saci, A., Szabó, P. M., Azrilevich, A., Horak, C. E., Lambert, A., Siefker-Radtke, A. O., Necchi, A., & Sharma, P. (2017) · Annals of Oncology · doi:10.1093/annonc/mdx371.003 · Cited by 56
Final efficacy results from B-F1RST, a prospective phase II trial evaluating blood-based tumour mutational burden (bTMB) as a predictive biomarker for atezolizumab (atezo) in 1L non-small cell lung cancer (NSCLC)
Socinski, M. A., Velcheti, V., Mekhail, T. M., Chae, Y. K., Leal, T. A. B., Dowell, J. E., Tsai, M. L., Dakhil, C. S. R., Stella, P. J., Shen, V., et al. (2019) · Annals of Oncology · doi:10.1093/annonc/mdz394.081 · Cited by 56
Analysis of Drug Development Paradigms for Immune Checkpoint Inhibitors
Jardim, D. L. F., Gagliato, D. D. M., Giles, F. J., & Kurzrock, R. (2017) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-17-1970 · Cited by 54
Self-citation
Comprehensive Genomic Profiling Reveals Diverse but Actionable Molecular Portfolios across Hematologic Malignancies: Implications for Next Generation Clinical Trials
Galanina, N., Bejar, R. L., Choi, M. Y., Goodman, A. M., Wieduwilt, M. J., Mulroney, C. M., Kim, L., Yeerna, H., Tamayo, P., Vergilio, J., et al. (2018) · Cancers · doi:10.3390/cancers11010011 · Cited by 54
Self-citation
Pembrolizumab (P) in patients (Pts) with colorectal cancer (CRC) with high tumor mutational burden (HTMB): Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) Study.
Meiri, E., Garrett-Mayer, E. S., Halabi, S., Mangat, P. K., Shrestha, S., Ahn, E. R., Osayameh, O., Perla, V., & Schilsky, R. L. (2020) · Journal of Clinical Oncology · doi:10.1200/jco.2020.38.4_suppl.133 · Cited by 52
Biomarkers predictive of response to pembrolizumab in head and neck cancer
Pfister, D. G., Haddad, R. I., Worden, F. P., Weiss, J., Mehra, R., Chow, L. Q. M., Liu, S. V., Kang, H., Saba, N. F., Wirth, L. J., et al. (2022) · Cancer Medicine · doi:10.1002/cam4.5434 · Cited by 51
Evolutionary Pressure against MHC Class II Binding Cancer Mutations
Pyke, R. M., Thompson, W. K., Salem, R. M., Font-Burgada, J., Zanetti, M., & Carter, H. K. (2018) · Cell · doi:10.1016/j.cell.2018.11.050 · Cited by 45
Atezolizumab (atezo) vs. chemotherapy (chemo) in platinum-treated locally advanced or metastatic urothelial carcinoma (mUC): Immune biomarkers, tumor mutational burden (TMB), and clinical outcomes from the phase III IMvigor211 study.
Powles, T. B., Loriot, Y., Ravaud, A., Vogelzang, N. J., Durán, I., Retz, M. M., Giorgi, U. D., Oudard, S. M., Bamias, A., Koeppen, H., et al. (2018) · Journal of Clinical Oncology · doi:10.1200/jco.2018.36.6_suppl.409 · Cited by 43
Immunotherapy with Checkpoint Blockade in the Treatment of Urothelial Carcinoma
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2 of the 151 references couldn’t be matched to a known paper.

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Galsky, 2017, Impact of tumormutation burden on nivolumab efficacy in secondline urothelial carcinoma patients: exploratory analysis of the phase II checkmate 275 study, Ann. Oncol., 28, v295, 10.1093/annonc/mdx371.003 · DOI

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Cold and hot tumors: from molecular mechanisms to targeted therapy
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“However, TMB relies on the replication components and processes of the immune system to achieve this effect.(238) Mutated processes of leucocyte and T cell proliferation regulation are identified as better interpretable genomic predictors than TMB.”
Background
Resistance Mechanisms to Anti-PD Cancer Immunotherapy
Vesely, M. D., Zhang, T., & Chen, L. (2022) · Annual Review of Immunology · doi:10.1146/annurev-immunol-070621-030155 · Cited by 468
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“In certain tumour types, the number of neoantigens in a tumour (or tumour mutational burden (TMB)) is correlated with responsiveness to ICIs 67,68 .”
Real-world application of tumor mutational burden-high (TMB-high) and microsatellite instability (MSI) confirms their utility as immunotherapy biomarkers
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“Furthermore, in other histologies, such as Kaposi sarcoma(18) and Merkel cell carcinoma, response to ICIs has been shown in the absence of TMB-H.(21) These findings of responsiveness or nonresponsiveness to ICI independent of TMB status highlight that other factors affecting ICI”
BackgroundInfluential

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Authors: Jardim, D. L., Goodman, A., de Melo Gagliato, D., & Kurzrock, R.
Affiliations: Hospital Sírio-Libanês (BR)
University of California San Diego (US)
Corresponding author: Kurzrock, Razelle
ORCID: Jardim, Denis L.
Goodman, Aaron
Kurzrock, Razelle
Venue: Cancer Cell
Publisher: Elsevier BV
Published: 2021-02
Volume: 39
Issue: 2
Pages: 154-173
ISSN: 1535-6108 (ISSN-L)
DOI: 10.1016/j.ccell.2020.10.001
PMC: PMC7878292
OpenAlex: W3097803258
Cited by: 1,192
References: 151
Citations by year: 2026: 134 · 2025: 263 · 2024: 294 · 2023: 276 · 2022: 171 · 2021: 53
FWCI: 13.60
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 372 d)
doi.org/10.15223/policy-017 (stm-asf)
doi.org/10.15223/policy-037 (stm-asf)
doi.org/10.15223/policy-012 (stm-asf)
doi.org/10.15223/policy-029 (stm-asf)
doi.org/10.15223/policy-004 (stm-asf)
Locations: Cancer Cell (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: Astellas Pharma US
National Cancer Institute (P30 CA023100)
Janssen Pharmaceuticals
AstraZeneca
Bristol-Myers Squibb
Genentech
Roche
EMD Serono
Pfizer
Meso Scale Diagnostics
Topics: Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
Keywords: tumor mutational burden, immunotherapy biomarkers, immune checkpoint inhibitors, neoantigens, MHC class I antigen presentation, T cell receptor repertoire, cancer immunotherapy response prediction
MeSH terms: Immune Checkpoint Inhibitors, Humans, Immunotherapy, Major Histocompatibility Complex, Mutation, Neoplasms, T-Lymphocytes, Biomarkers, Tumor

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The Challenges of Tumor Mutational Burden as an Immunotherapy Biomarker

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