Tumor Mutational Burden and Other Biomarkers Help to Assess the Efficacy of Immunotherapies

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Immunotherapy has revolutionized the treatment of many types of cancer by taking advantage of the immune system’s ability to fight cancer cells. In the last few years, a growing number of immunotherapy-based clinical trials were launched to increase success rates further. Specific biomarkers help to stratify patients for the best treatment choice, and also to support the promising development of new immunotherapy combinations.

The center for Dermatooncology at the University hospital Tübingen conducted a prospective biomarker study (Forschner 2019) in cooperation with CeGaT GmbH. This study aimed to identify reliable biomarkers, which predict the patient’s response to anti-CTLA-4 and anti-PD-1 immunotherapy.

Tumor mutational burden (TMB) is a biomarker that has been described as particularly useful for immunotherapy and was thus assessed as part of this study. TMB refers to the number of mutations present in a cancer patients’ tumor and is quantified as mutations per million base pairs (mut/Mbp). Furthermore, repetitive liquid biopsies were collected to determine the concentration of circulating tumor DNA (ctDNA) during treatment. Several studies have shown that ctDNA levels are associated with treatment response and prognosis and could therefore serve as non-invasive predictive markers.

Within this study, we demonstrated that patients with a high TMB (>23.1) showed a significantly better response to therapy and, consequently, a better outcome compared to patients with TMB-low or TMB-intermediate tumors. Similarly, undetectable levels of ctDNA, or a >50% decrease of the cell-free DNA (cfDNA) concentration at the time of first follow-up (3w post treatment initiation) was significantly associated with therapy response and better overall survival.

The results of this study strengthen the increasing importance of the analysis of biomarkers such as TMB, ctDNA, or cfDNA in the prediction and early assessment of the effectiveness of immunotherapies.

 

CeGaT Research and Pharma Solution offers different methods of TMB analysis to meet the most diverse study requirements

 

At CeGaT, the TMB score can be evaluated based on different sequencing approaches. The best choice for a specific project depends on the underlaying scientific question and availability of patient material. Typically, the TMB score is assessed through whole-exome sequencing of the tumor tissue, as well as the corresponding normal tissue (e.g. blood sample). By comparing the variants detected in both samples, we can discriminate between tumor specific (somatic) mutations, and mutations present in every tissue of the patient.

However, recent studies have shown that the TMB score can also be effectively estimated if only a panel of genes gets sequenced, provided the sequencing panel covers a genomic region of at least 1,5 Mb (Buchhalter 2018). Thus, for many cases, it is not only sufficient but even more expedient to analyze a selected panel of genes. Therefore, we make use of our CeGaT somatic tumor panel which comprises more than 700 selected, cancer-related genes.

Clinical samples are very precious material and availability is often limited. A comparison of tumor and normal tissue might not always be possible. To meet this challenge, CeGaT uses the solution provided by Illumina, in which TMB score is evaluated based on tumor tissue analysis only: TruSight Oncology 500 (TSO500) comprises the next-generation sequencing based analysis of 523 cancer-relevant genes and their standardized bioinformatic assessment. No normal tissue is required.

For the most comprehensive results, CeGaT’s customers always receive information about the tumor’s microsatellite instability (MSI) in addition to TMB analysis – regardless of whether it is based on TSO500, whole-exome sequencing, or CeGaT somatic tumor panel sequencing. Besides TMB, MSI is another important biomarker for the patient’s response to immunotherapy.

Contact us in order to find out which TMB product is the best choice for your study.

 

Combine your TMB analysis with the following services offered by CeGaT Research and Pharma Solutions:

  • Detection and sequencing of certain immune subpopulations (e.g. CD4+, CD8+, PD-1+ T cells)
  • Detection of (neo)antigen-specific T cells
  • Microbiome analysis
  • T cell receptor (TCR) sequencing
  • Human leukocyte antigen (HLA) analysis
  • Transcriptome sequencing

Further information can be found here.

 

Forschner A, Battke F, Hadaschik D, Schulze M, Weißgraeber S, Han CT, Kopp M, Frick M, Klumpp B, Tietze N, Amaral T, Martus P, Sinnberg T, Eigentler T, Keim U, Garbe C, Döcker D, Biskup S. Tumor mutation burden and circulating tumor DNA in combined CTLA-4 and PD-1 antibody therapy in metastatic melanoma – results of a prospective biomarker study.
J Immunother Cancer. 2019 Jul 12;7(1):180. doi: 10.1186/s40425-019-0659-0.

Buchhalter I, Rempel E, Endris V, Allgäuer M, Neumann O, Volckmar AL, Kirchner M, Leichsenring J, Lier A, von Winterfeld M, Penzel R, Christopoulos P, Thomas M, Fröhling S, Schirmacher P, Budczies J, Stenzinger A. Size matters: Dissecting key parameters for panel-based tumor mutational burden analysis. Int J Cancer. 2019. Feb 15; 144(4):848-858. doi: 10.1002/ijc.31878.