RT Journal Article
SR Electronic
T1 Persistent mutant oncogene specific T cells in two patients benefitting from anti-PD-1
JF Journal for ImmunoTherapy of Cancer
JO J Immunother Cancer
FD BMJ Publishing Group Ltd
SP 40
DO 10.1186/s40425-018-0492-x
VO 7
IS 1
A1 Kellie N. Smith
A1 Nicolas J. Llosa
A1 Tricia R. Cottrell
A1 Nicholas Siegel
A1 Hongni Fan
A1 Prerna Suri
A1 Hok Yee Chan
A1 Haidan Guo
A1 Teniola Oke
A1 Anas H. Awan
A1 Franco Verde
A1 Ludmila Danilova
A1 Valsamo Anagnostou
A1 Ada J. Tam
A1 Brandon S. Luber
A1 Bjarne R. Bartlett
A1 Laveet K. Aulakh
A1 John-William Sidhom
A1 Qingfeng Zhu
A1 Cynthia L. Sears
A1 Leslie Cope
A1 William H. Sharfman
A1 Elizabeth D. Thompson
A1 Joanne Riemer
A1 Kristen A. Marrone
A1 Jarushka Naidoo
A1 Victor E. Velculescu
A1 Patrick M. Forde
A1 Bert Vogelstein
A1 Kenneth W. Kinzler
A1 Nickolas Papadopoulos
A1 Jennifer N. Durham
A1 Hao Wang
A1 Dung T. Le
A1 Sune Justesen
A1 Janis M. Taube
A1 Luis A. Diaz, Jr
A1 Julie R. Brahmer
A1 Drew M. Pardoll
A1 Robert A. Anders
A1 Franck Housseau
YR 2019
UL http://jitc.bmj.com/content/7/1/40.abstract
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.Kellie N. Smith and Nicolas J. Llosa contributed equally to this work.A correction to this article is available online at https://doi.org/10.1186/s40425-019-0547-7.Abbreviations:NSCLCNon-small cell lung cancerCRCColorectal cancerPD-1Programmed death 1PD-L1Programmed death ligand 1TMBTumor mutational burdenMMRdMismatch repair deficientMSI-HMicrosatellite instabibility highMMRpMismatch repair proficientMSSMicrosatellite stableECOGEastern Cooperative Oncology GroupFFPEFormalin fixed, paraffin embeddedCD8Cluster of differentiation 8WESWhole exome sequencingTCGAThe Cancer Genome AtlasMANAFESTMutation associated neoantigen functional expansion of specific T cellsTCRseqT cell receptor sequencingDNADeoxyribonucleic acidHLAHuman leukocyte antigenTCRVβT cell receptor variable gene, β chainMHCMajor histocompatibility complex