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Clonal Neoantigen: Emerging "Mechanism-based" Biomarker of Immunotherapy Response

John Nemunaitis1, Laura Stanbery1, David Willoughby2

  • 1Gradalis, Inc., Dallas, TX 75225, USA.

Cancers
|December 9, 2023
PubMed

Insights

Clonal mutations drive cancer. High clonal tumor mutational burden (TMB) predicts better survival and response to checkpoint inhibitors, unlike subclonal TMB. Novel immunotherapies target these clonal neoantigens.

Area of Science:

  • Oncology
  • Genomics
  • Immunotherapy

Background:

  • Clonal mutations initiate cancer development.
  • Genomic sequencing aids in identifying biomarkers for targeted therapies.
  • Neoantigens derived from clonal mutations are crucial for immune response.

Purpose of the Study:

  • To investigate the predictive value of clonal versus subclonal neoantigens for checkpoint inhibitor therapy response.
  • To explore the association between tumor mutational burden (TMB) and clinical outcomes.
  • To review the mechanism of clonal neoantigen targeting and novel immunotherapies.

Main Methods:

  • Retrospective analysis of case examples and landmark trials.
  • Meta-analysis of over 1000 cancer patients from 12 trials.
  • Review of preclinical and clinical data on clonal neoantigens and autologous cellular immunotherapy (Vigil®).

Main Results:

  • High clonal TMB significantly correlates with better overall survival (p = 0.000000029).
  • High subclonal TMB showed no clinical benefit with checkpoint inhibitor therapy.
  • Vigil® demonstrated durable recurrence-free survival and overall survival in a subset of ovarian cancer patients with a homologous recombination proficient (HRP) profile.

Conclusions:

  • Clonal neoantigens are significant predictors of response to checkpoint inhibition.
  • Targeting clonal neoantigens holds promise for improving cancer treatment outcomes.
  • Autologous cellular immunotherapy like Vigil® shows potential for specific cancer patient populations.
Keywords:
Vigilbiomarkercancerclonal neoantigenimmunotherapy

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