Limited evidence of tumour mutational burden as a biomarker of response to immunotherapy

  title={Limited evidence of tumour mutational burden as a biomarker of response to immunotherapy},
  author={Carino Gurjao and Dina I Tsukrov and Maxim Imakaev and Lovelace J. Luquette and Leonid A. Mirny},
Cancer immunotherapy by immune checkpoint blockade (ICB) is effective for several cancer types 1, however, its clinical use is encumbered by a high variability in patient response. Several studies have suggested that Tumour Mutational Burden (TMB) correlates with patient response to ICB treatments 2–6, likely due to immunogenic neoantigens generated by novel mutations accumulated during cancer progression 7. Association of TMB and response to checkpoint inhibitors has become widespread in the… 

Improved prediction of immune checkpoint blockade efficacy across multiple cancer types.

A machine learning model is developed to predict ICB response by integrating genomic, molecular, demographic and clinical data from a comprehensively curated cohort with 1,479 patients treated with ICB across 16 different cancer types and significantly outperformed predictions based on tumor mutational burden.

Predicting immunotherapy response through genomics.

PBRM1 loss-of-function mutations and response to immune checkpoint blockade in clear cell renal cell carcinoma

This study provides further support for the biological association between PBRM1 LOF and favorable clinical outcomes on ICB in specific ccRCC clinical contexts and strongly caution against interpreting that this P BRM1 biological association, likely one of many modest mediators of tumor-immune-stromal interactions, achieves broadly generalizable predictive biomarker status forICB in diverse clinical contexts.

Mutation and Microsatellite Burden Predict Response to PD-1 Inhibition in Children with Germline DNA Replication Repair Deficiency

Improved survival is demonstrated for patients with tumours not previously known to respond to ICI, including CNS and synchronous cancers, and the dual roles of mutation burden and MS-indels in predicting sustained responses to immunotherapy are identified.

Identification of combinations of somatic mutations that predict cancer survival and immunotherapy benefit

CLICnet has the ability to systematically identify and catalogue combinations of mutations that predict cancer survival, unveiling intricate associations between mutations, survival, and immunotherapy benefit.

Intratumor Heterogeneity and Antitumor Immunity Shape One Another Bidirectionally

  • Y. WolfY. Samuels
  • Biology
    Clinical cancer research : an official journal of the American Association for Cancer Research
  • 2022
Key findings in the cancer immunogenomics literature are examined, deciphering the complex cross-talk between TMB, ITH, and antitumor immunity in human cancers and in vivo models, and the mutual influence of ITH and immunity are discussed.

Deconvolving clinically relevant cellular immune crosstalk from bulk gene expression using CODEFACS and LIRICS

CODEFACS and LIRICS identify a subset of ligand-receptor interactions in the melanoma TME that predict patient response to anti-PD1 therapy better than recently published transcriptomics-based methods.

Archetypes of checkpoint-responsive immunity.

Mismatch repair deficiency is not sufficient to increase tumor immunogenicity

It is demonstrated that immunosurveillance in MMRd tumors has no impact on TMB but shapes the clonal architecture of neoantigens by exacerbating ITH, which provides important context for understanding immune evasion in cancers with high TMB and have major implications for therapies aimed at increasing TMB.



Development of tumor mutation burden as an immunotherapy biomarker: utility for the oncology clinic

  • T. ChanM. Yarchoan S. Peters
  • Biology, Medicine
    Annals of oncology : official journal of the European Society for Medical Oncology
  • 2019
TMB, in concert with PD-L1 expression, has been demonstrated to be a useful biomarker for ICB selection across some cancer types; however, further prospective validation studies are required.

Tumor mutational load predicts survival after immunotherapy across multiple cancer types

Analysis of advanced cancer patients treated with immune-checkpoint inhibitors shows that tumor mutational burden, as assessed by targeted next-generation sequencing, predicts survival after immunotherapy across multiple cancer types.

Integrative molecular and clinical modeling of clinical outcomes to PD1 blockade in patients with metastatic melanoma

Analysis of fully clinically annotated and sequenced melanoma tumor samples collected before anti-PD1 treatment suggests that determinants of response differ on the basis of previous anti-CTLA4 therapy, and that tumor mutational burden may not be a strong predictor of response across melanoma subtypes.

Tumor mutational burden assessment as a predictive biomarker for immunotherapy in lung cancer patients: getting ready for prime-time or not?

The tumor mutation burden (TMB) or tumor mutation load (TML) emerged recently as a new predictive biomarker for immunotherapy response in NSCLC, however, this biomarker needs to be validated for routine clinical use and shares similar constraints with the PD-L1 IHC biomarker.

Intrinsic Resistance to Immune Checkpoint Blockade in a Mismatch Repair–Deficient Colorectal Cancer

Insight into resistance in MSI-H tumors is provided and immunotherapeutic strategies in additional genomic contexts of colorectal cancer are suggested.

Genomic correlates of response to CTLA-4 blockade in metastatic melanoma

Investigating the roles of tumor-specific neoantigens and alterations in the tumor microenvironment in the response to ipilimumab found no recurrent neoantigen peptide sequences predicted responder patient populations, suggesting detailed integrated molecular characterization of large patient cohorts may be needed to identify robust determinants of response and resistance to immune checkpoint inhibitors.

Genomic correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma

Clinical benefit was associated with loss-of-function mutations in the PBRM1 gene, which encodes a subunit of the PBAF switch-sucrose nonfermentable (SWI/SNF) chromatin remodeling complex, and may alter global tumor-cell expression profiles to influence responsiveness to immune checkpoint therapy.

Genomic correlates of response to immune checkpoint blockade in microsatellite-stable solid tumors

This study uniformly analyzed whole-exome sequencing of 249 tumors and matched normal tissue from patients with clinically annotated outcomes to immune checkpoint therapy across multiple cancer types to examine additional tumor genomic features that contribute to selective response.

Tumor Mutational Burden, Toxicity, and Response of Immune Checkpoint Inhibitors Targeting PD(L)1, CTLA-4, and Combination: A Meta-regression Analysis

There is a positive association between TMB and clinical response with anti-PD(L)1, anti-CTLA-4, and combination ICIs, but no association with toxicity in all treatment groups.