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

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Oncogenes
T-Lymphocytes
Biomarkers
DNA Mismatch Repair
Neoplasms
Tumor Burden
Mutation
Colorectal Neoplasms
Patient Selection
Therapeutics
Lung
Population
Turcot syndrome

Keywords

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

ASJC Scopus subject areas

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

Cite this

@article{ed370e40a0e649a7ad54ebcf1deb8d45,
title = "Persistent mutant oncogene specific T cells in two patients benefitting from anti-PD-1",
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.",
keywords = "Checkpoint blockade, Neoantigens, Oncogene, Predictive biomarkers, T cells",
author = "Smith, {Kellie N.} and Llosa, {Nicolas J.} and Cottrell, {Tricia R.} and Nicholas Siegel and Hongni Fan and Prerna Suri and Chan, {Hok Yee} and Haidan Guo and Teniola Oke and Awan, {Anas H.} and Franco Verde and Ludmila Danilova and Valsamo Anagnostou and Tam, {Ada J.} and Luber, {Brandon S.} and Bartlett, {Bjarne R.} and Aulakh, {Laveet K.} and Sidhom, {John William} and Qingfeng Zhu and Sears, {Cynthia L.} and Leslie Cope and Sharfman, {William H.} and Thompson, {Elizabeth D.} and Joanne Riemer and Marrone, {Kristen A.} and Jarushka Naidoo and Velculescu, {Victor E.} and Forde, {Patrick M.} and Bert Vogelstein and Kinzler, {Kenneth W.} and Nickolas Papadopoulos and Durham, {Jennifer N.} and Hao Wang and Le, {Dung T.} and Sune Justesen and Taube, {Janis M.} and Diaz, {Luis A.} and Brahmer, {Julie R.} and Pardoll, {Drew M.} and Anders, {Robert A.} and Franck Housseau",
year = "2019",
month = "2",
day = "11",
doi = "10.1186/s40425-018-0492-x",
language = "English (US)",
volume = "7",
journal = "Journal for ImmunoTherapy of Cancer",
issn = "2051-1426",
publisher = "BioMed Central",
number = "1",

}

TY - JOUR

T1 - Persistent mutant oncogene specific T cells in two patients benefitting from anti-PD-1

AU - Smith, Kellie N.

AU - Llosa, Nicolas J.

AU - Cottrell, Tricia R.

AU - Siegel, Nicholas

AU - Fan, Hongni

AU - Suri, Prerna

AU - Chan, Hok Yee

AU - Guo, Haidan

AU - Oke, Teniola

AU - Awan, Anas H.

AU - Verde, Franco

AU - Danilova, Ludmila

AU - Anagnostou, Valsamo

AU - Tam, Ada J.

AU - Luber, Brandon S.

AU - Bartlett, Bjarne R.

AU - Aulakh, Laveet K.

AU - Sidhom, John William

AU - Zhu, Qingfeng

AU - Sears, Cynthia L.

AU - Cope, Leslie

AU - Sharfman, William H.

AU - Thompson, Elizabeth D.

AU - Riemer, Joanne

AU - Marrone, Kristen A.

AU - Naidoo, Jarushka

AU - Velculescu, Victor E.

AU - Forde, Patrick M.

AU - Vogelstein, Bert

AU - Kinzler, Kenneth W.

AU - Papadopoulos, Nickolas

AU - Durham, Jennifer N.

AU - Wang, Hao

AU - Le, Dung T.

AU - Justesen, Sune

AU - Taube, Janis M.

AU - Diaz, Luis A.

AU - Brahmer, Julie R.

AU - Pardoll, Drew M.

AU - Anders, Robert A.

AU - Housseau, Franck

PY - 2019/2/11

Y1 - 2019/2/11

N2 - 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.

AB - 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.

KW - Checkpoint blockade

KW - Neoantigens

KW - Oncogene

KW - Predictive biomarkers

KW - T cells

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U2 - 10.1186/s40425-018-0492-x

DO - 10.1186/s40425-018-0492-x

M3 - Article

C2 - 30744692

AN - SCOPUS:85061365058

VL - 7

JO - Journal for ImmunoTherapy of Cancer

JF - Journal for ImmunoTherapy of Cancer

SN - 2051-1426

IS - 1

M1 - 40

ER -