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Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy

  • Author(s): Cristescu, R
  • Mogg, R
  • Ayers, M
  • Albright, A
  • Murphy, E
  • Yearley, J
  • Sher, X
  • Liu, XQ
  • Lu, H
  • Nebozhyn, M
  • Zhang, C
  • Lunceford, J
  • Joe, A
  • Cheng, J
  • Webber, AL
  • Ibrahim, N
  • Plimack, ER
  • Ott, PA
  • Seiwert, T
  • Ribas, A
  • McClanahan, TK
  • Tomassini, JE
  • Loboda, A
  • Kaufman, D
  • et al.
Abstract

Programmed cell death protein-1 (PD-1) and programmed cell death ligand-1 (PD-L1) checkpoint blockade immunotherapy elicits durable antitumor effects in multiple cancers, yet not all patients respond. We report the evaluation of >300 patient samples across 22 tumor types from four KEYNOTE clinical trials. Tumor mutational burden (TMB) and a T cell-inflamed gene expression profile (GEP) exhibited joint predictive utility in identifying responders and nonresponders to the PD-1 antibody pembrolizumab. TMB and GEP were independently predictive of response and demonstrated low correlation, suggesting that they capture distinct features of neoantigenicity and T cell activation. Analysis of The Cancer Genome Atlas database showed TMB and GEP to have a low correlation, and analysis by joint stratification revealed biomarker-defined patterns of targetable-resistance biology. These biomarkers may have utility in clinical trial design by guiding rational selection of anti-PD-1 monotherapy and combination immunotherapy regimens.

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