Persistent mutant oncogene specific T cells in two patients benefitting from anti-PD-1

Kellie N. Smith, Nicolas J. Llosa, Tricia R. Cottrell, Nicholas Siegel, Hongni Fan, Prerna Suri, Hok Yee Chan, Haidan Guo, Teniola Oke, Anas H. Awan, Franco Verde, Ludmila Danilova, Valsamo Anagnostou, Ada J. Tam, Brandon S. Luber, Bjarne R. Bartlett, Laveet K. Aulakh, John William Sidhom, Qingfeng Zhu, Cynthia L. SearsLeslie Cope, William H. Sharfman, Elizabeth D. Thompson, Joanne Riemer, Kristen A. Marrone, Jarushka Naidoo, Victor E. Velculescu, Patrick M. Forde, Bert Vogelstein, Kenneth W. Kinzler, Nickolas Papadopoulos, Jennifer N. Durham, Hao Wang, Dung T. Le, Sune Justesen, Janis M. Taube, Luis A. Diaz, Julie R. Brahmer, Drew M. Pardoll, Robert A. Anders, Franck Housseau

Research output: Contribution to journalArticle

Abstract

Background: Several predictive biomarkers are currently approved or are under investigation for the selection of patients for checkpoint blockade. Tumor PD-L1 expression is used for stratification of non-small cell lung (NSCLC) patients, with tumor mutational burden (TMB) also being explored with promising results, and mismatch-repair deficiency is approved for tumor site-agnostic disease. While tumors with high PD-L1 expression, high TMB, or mismatch repair deficiency respond well to checkpoint blockade, tumors with lower PD-L1 expression, lower mutational burdens, or mismatch repair proficiency respond much less frequently. Case presentation: We studied two patients with unexpected responses to checkpoint blockade monotherapy: a patient with PD-L1-negative and low mutational burden NSCLC and one with mismatch repair proficient colorectal cancer (CRC), both of whom lack the biomarkers associated with response to checkpoint blockade, yet achieved durable clinical benefit. Both maintained T-cell responses in peripheral blood to oncogenic driver mutations - BRAF-N581I in the NSCLC and AKT1-E17K in the CRC - years after treatment initiation. Mutation-specific T cells were also found in the primary tumor and underwent dynamic perturbations in the periphery upon treatment. Conclusions: These findings suggest that T cell responses to oncogenic driver mutations may be more prevalent than previously appreciated and could be harnessed in immunotherapeutic treatment, particularly for patients who lack the traditional biomarkers associated with response. Comprehensive studies are warranted to further delineate additional predictive biomarkers and populations of patients who may benefit from checkpoint blockade.

Original languageEnglish (US)
Article number40
JournalJournal for immunotherapy of cancer
Volume7
Issue number1
DOIs
StatePublished - Feb 11 2019

Keywords

  • Checkpoint blockade
  • Neoantigens
  • Oncogene
  • Predictive biomarkers
  • T cells

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

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