Dynamics of Tumor and Immune Responses during Immune Checkpoint Blockade in Non-Small Cell Lung Cancer

被引：277

作者：

Anagnostou, Valsamo ^{[1
,2
]}

Forde, Patrick M. ^{[1
,2
]}

White, James R. ^{[1
]}

Niknafs, Noushin ^{[1
]}

Hruban, Carolyn ^{[1
]}

Naidoo, Jarushka ^{[1
,2
]}

Marrone, Kristen ^{[1
,2
]}

Sivakumar, I. K. Ashok ^{[1
,3
,4
]}

Bruhm, Daniel C. ^{[1
]}

Rosner, Samuel ^{[5
]}

Phallen, Jillian ^{[1
]}

Leal, Alessandro ^{[1
]}

Adleff, Vilmos ^{[1
]}

Smith, Kellie N. ^{[1
,2
]}

Cottrell, Tricia R. ^{[1
,6
]}

Rhymee, Lamia ^{[1
]}

Palsgrove, Doreen N. ^{[1
]}

Hann, Christine L. ^{[1
]}

Levy, Benjamin ^{[1
]}

Feliciano, Josephine ^{[1
]}

Georgiades, Christos ^{[7
]}

Verde, Franco ^{[7
]}

Illei, Peter ^{[1
,2
,6
]}

Li, Qing Kay ^{[1
,6
]}

Gabrielson, Edward ^{[1
,6
]}

Brock, Malcolm V. ^{[8
]}

Isbell, James M. ^{[9
]}

Sauter, Jennifer L. ^{[10
]}

Taube, Janis ^{[1
,2
,6
]}

Scharpf, Robert B. ^{[1
]}

Karchin, Rachel ^{[1
,3
]}

Pardoll, Drew M. ^{[1
,2
]}

Chaft, Jamie E. ^{[11
,12
]}

Hellmann, Matthew D. ^{[11
,12
]}

Brahmer, Julie R. ^{[1
,2
]}

Velculescu, Victor E. ^{[1
,2
,3
]}

机构：

[1] Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr, 1550 Orleans St,CRB2,Room 544, Baltimore, MD 21287 USA

[2] Johns Hopkins Univ, Sch Med, Bloomberg Kimmel Inst Canc Immunotherapy, Baltimore, MD USA

[3] Johns Hopkins Univ, Inst Computat Med, Baltimore, MD USA

[4] Appl Phys Lab, Laurel, MD USA

[5] Johns Hopkins Bayview Med Ctr, Dept Internal Med, Baltimore, MD USA

[6] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA

[7] Johns Hopkins Univ, Sch Med, Dept Radiol, Baltimore, MD 21205 USA

[8] Johns Hopkins Univ, Sch Med, Dept Surg, Baltimore, MD 21205 USA

[9] Mem Sloan Kettering Canc Ctr, Dept Surg, Thorac Serv, 1275 York Ave, New York, NY 10021 USA

[10] Mem Sloan Kettering Canc Ctr, Dept Pathol, 1275 York Ave, New York, NY 10021 USA

[11] Mem Sloan Kettering Canc Ctr, Dept Med, Thorac Oncol Serv, 1275 York Ave, New York, NY 10021 USA

[12] Weill Cornell Med Coll, New York, NY USA

来源：

CANCER RESEARCH | 2019年 / 79卷 / 06期

基金：

美国国家卫生研究院;

关键词：

CLONAL HEMATOPOIESIS; DNA; RESISTANCE; EVOLUTION; NIVOLUMAB; CRITERIA; THERAPY;

D O I：

10.1158/0008-5472.CAN-18-1127

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

Despite the initial successes of immunotherapy, there is an urgent clinical need for molecular assays that identify patients more likely to respond. Here, we report that ultra-sensitive measures of circulating tumor DNA (ctDNA) and T-cell expansion can be used to assess responses to immune checkpoint blockade in metastatic lung cancer patients (N = 24). Patients with clinical response to therapy had a complete reduction in ctDNA levels after initiation of therapy, whereas nonresponders had no significant changes or an increase in ctDNA levels. Patients with initial response followed by acquired resistance to therapy had an initial drop followed by recrudescence in ctDNA levels. Patients without a molecular response had shorter progression-free and overall survival compared with molecular responders [5.2 vs. 14.5 and 8.4 vs. 18.7 months; HR 5.36; 95% confidence interval (CI), 1.57-18.35; P = 0.007 and HR 6.91; 95% CI, 1.37-34.97; P = 0.02, respectively], which was detected on average 8.7 weeks earlier and was more predictive of clinical benefit than CT imaging. Expansion of T cells, measured through increases of T-cell receptor productive frequencies, mirrored ctDNA reduction in response to therapy. We validated this approach in an independent cohort of patients with early-stage non-small cell lung cancer (N = 14), where the therapeutic effect was measured by pathologic assessment of residual tumor after anti-PD1 therapy. Consistent with our initial findings, early ctDNA dynamics predicted pathologic response to immune checkpoint blockade. These analyses provide an approach for rapid determination of therapeutic outcomes for patients treated with immune checkpoint inhibitors and have important implications for the development of personalized immune targeted strategies. Significance: Rapid and sensitive detection of circulating tumor DNA dynamic changes and T-cell expansion can be used to guide immune targeted therapy for patients with lung cancer. See related commentary by Zou and Meyerson, p. 1038

引用

页码：1214 / 1225

页数：12

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