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Persistent mutant oncogene specific T cells in two patients benefitting from anti-PD-1.
Smith, Kellie N; Llosa, Nicolas J; Cottrell, Tricia R; Siegel, Nicholas; Fan, Hongni; Suri, Prerna; Chan, Hok Yee; Guo, Haidan; Oke, Teniola; Awan, Anas H; Verde, Franco; Danilova, Ludmila; Anagnostou, Valsamo; Tam, Ada J; Luber, Brandon S; Bartlett, Bjarne R; Aulakh, Laveet K; Sidhom, John-William; Zhu, Qingfeng; Sears, Cynthia L; Cope, Leslie; Sharfman, William H; Thompson, Elizabeth D; Riemer, Joanne; Marrone, Kristen A; Naidoo, Jarushka; Velculescu, Victor E; Forde, Patrick M; Vogelstein, Bert; Kinzler, Kenneth W; Papadopoulos, Nickolas; Durham, Jennifer N; Wang, Hao; Le, Dung T; Justesen, Sune; Taube, Janis M; Diaz, Luis A; Brahmer, Julie R; Pardoll, Drew M; Anders, Robert A; Housseau, Franck.
Afiliación
  • Smith KN; Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, MD, USA.
  • Llosa NJ; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.
  • Cottrell TR; Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, MD, USA.
  • Siegel N; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.
  • Fan H; Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, MD, USA.
  • Suri P; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.
  • Chan HY; Department of Pathology, Johns Hopkins University, Baltimore, MD, USA.
  • Guo H; Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, MD, USA.
  • Oke T; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.
  • Awan AH; Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, MD, USA.
  • Verde F; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.
  • Danilova L; Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, MD, USA.
  • Anagnostou V; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.
  • Tam AJ; Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, MD, USA.
  • Luber BS; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.
  • Bartlett BR; Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, MD, USA.
  • Aulakh LK; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.
  • Sidhom JW; Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, MD, USA.
  • Zhu Q; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.
  • Sears CL; Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, MD, USA.
  • Cope L; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.
  • Sharfman WH; Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, MD, USA.
  • Thompson ED; Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, MD, USA.
  • Riemer J; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.
  • Marrone KA; Division of Biostatistics and Bioinformatics, Johns Hopkins University, Baltimore, MD, USA.
  • Naidoo J; Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, MD, USA.
  • Velculescu VE; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.
  • Forde PM; Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, MD, USA.
  • Vogelstein B; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.
  • Kinzler KW; Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, MD, USA.
  • Papadopoulos N; Division of Biostatistics and Bioinformatics, Johns Hopkins University, Baltimore, MD, USA.
  • Durham JN; Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, MD, USA.
  • Wang H; The Swim Across America Laboratory, John Hopkins University, Baltimore, MD, USA.
  • Le DT; Ludwig Center and Howard Hughes Medical Institute, Johns Hopkins University, Baltimore, MD, USA.
  • Justesen S; Present address: B.R.B.,Bioinformatics Core, Department of Complementary & Integrative Medicine, University of Hawaii John A. Burns School of Medicine, Honolulu, HI, 96813, USA.
  • Taube JM; Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, MD, USA.
  • Diaz LA; The Swim Across America Laboratory, John Hopkins University, Baltimore, MD, USA.
  • Brahmer JR; Ludwig Center and Howard Hughes Medical Institute, Johns Hopkins University, Baltimore, MD, USA.
  • Pardoll DM; Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, MD, USA.
  • Anders RA; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.
  • Housseau F; Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, MD, USA.
J Immunother Cancer ; 7(1): 40, 2019 02 11.
Article en En | MEDLINE | ID: mdl-30744692
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.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Linfocitos T / Neoplasias Colorrectales / Carcinoma de Pulmón de Células no Pequeñas / Antígeno B7-H1 / Antineoplásicos Inmunológicos / Nivolumab / Neoplasias Pulmonares Tipo de estudio: Prognostic_studies Límite: Aged / Female / Humans Idioma: En Revista: J Immunother Cancer Año: 2019 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Linfocitos T / Neoplasias Colorrectales / Carcinoma de Pulmón de Células no Pequeñas / Antígeno B7-H1 / Antineoplásicos Inmunológicos / Nivolumab / Neoplasias Pulmonares Tipo de estudio: Prognostic_studies Límite: Aged / Female / Humans Idioma: En Revista: J Immunother Cancer Año: 2019 Tipo del documento: Article País de afiliación: Estados Unidos