@article {Smith40, author = {Kellie N. Smith and Nicolas J. Llosa and Tricia R. Cottrell and Nicholas Siegel and Hongni Fan and Prerna Suri and Hok Yee Chan and Haidan Guo and Teniola Oke and Anas H. Awan and Franco Verde and Ludmila Danilova and Valsamo Anagnostou and Ada J. Tam and Brandon S. Luber and Bjarne R. Bartlett and Laveet K. Aulakh and John-William Sidhom and Qingfeng Zhu and Cynthia L. Sears and Leslie Cope and William H. Sharfman and Elizabeth D. Thompson and Joanne Riemer and Kristen A. Marrone and Jarushka Naidoo and Victor E. Velculescu and Patrick M. Forde and Bert Vogelstein and Kenneth W. Kinzler and Nickolas Papadopoulos and Jennifer N. Durham and Hao Wang and Dung T. Le and Sune Justesen and Janis M. Taube and Luis A. Diaz, Jr and Julie R. Brahmer and Drew M. Pardoll and Robert A. Anders and Franck Housseau}, title = {Persistent mutant oncogene specific T cells in two patients benefitting from anti-PD-1}, volume = {7}, number = {1}, elocation-id = {40}, year = {2019}, doi = {10.1186/s40425-018-0492-x}, publisher = {BMJ Specialist Journals}, 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 {\textendash} BRAF-N581I in the NSCLC and AKT1-E17K in the CRC {\textendash} 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}, URL = {https://jitc.bmj.com/content/7/1/40}, eprint = {https://jitc.bmj.com/content/7/1/40.full.pdf}, journal = {Journal for ImmunoTherapy of Cancer} }