Analysis of Immune Signatures in Longitudinal Tumor Samples Yields Insight into Biomarkers of Response and Mechanisms of Resistance to Immune Checkpoint Blockade

被引：824

作者：

Chen, Pei-Ling ^{[1
,2
]}

Roh, Whijae ^{[1
]}

Reuben, Alexandre ^{[3
]}

Cooper, Zachary A. ^{[1
,3
,12
]}

Spencer, Christine N. ^{[1
]}

Prieto, Peter A. ^{[3
]}

Miller, John P. ^{[1
]}

Bassett, Roland L. ^{[4
]}

Gopalakrishnan, Vancheswaran ^{[3
]}

Wani, Khalida ^{[5
]}

De Macedo, Mariana Petaccia ^{[5
]}

Austin-Breneman, Jacob L. ^{[3
]}

Jiang, Hong ^{[3
]}

Chang, Qing ^{[1
]}

Reddy, Sangeetha M. ^{[6
]}

Chen, Wei-Shen ^{[1
,2
]}

Tetzlaff, Michael T. ^{[2
]}

Broaddus, Russell J. ^{[2
]}

Davies, Michael A. ^{[7
]}

Gershenwald, Jeffrey E. ^{[3
]}

Haydu, Lauren ^{[3
]}

Lazar, Alexander J. ^{[2
,5
]}

Patel, Sapna P. ^{[7
]}

Hwu, Patrick ^{[7
]}

Hwu, Wen-Jen ^{[7
]}

Diab, Adi ^{[7
]}

Glitza, Isabella C. ^{[7
]}

Woodman, Scott E. ^{[7
]}

Vence, Luis M. ^{[8
]}

Wistuba, Ignacio I. ^{[5
]}

Amaria, Rodabe N. ^{[7
]}

Kwong, Lawrence N. ^{[5
]}

Prieto, Victor ^{[2
]}

Davis, R. Eric ^{[9
]}

Ma, Wencai ^{[9
]}

Overwijk, Willem W. ^{[7
]}

Sharpe, Arlene H. ^{[10
]}

Hu, Jianhua ^{[4
]}

Futreal, P. Andrew ^{[1
]}

Blando, Jorge ^{[5
]}

Sharma, Padmanee ^{[8
,11
]}

Allison, James P. ^{[8
]}

Chin, Lynda ^{[1
]}

Wargo, Jennifer A. ^{[1
,3
]}

机构：

[1] Univ Texas MD Anderson Canc Ctr, Dept Genom Med, Houston, TX 77030 USA

[2] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA

[3] Univ Texas MD Anderson Canc Ctr, Dept Surg Oncol, Houston, TX 77030 USA

[4] Univ Texas MD Anderson Canc Ctr, Dept Biostat, Houston, TX 77030 USA

[5] Univ Texas MD Anderson Canc Ctr, Dept Translat Mol Pathol, Houston, TX 77030 USA

[6] Univ Texas MD Anderson Canc Ctr, Dept Canc Med, Houston, TX 77030 USA

[7] Univ Texas MD Anderson Canc Ctr, Dept Melanoma Med Oncol, Houston, TX 77030 USA

[8] Univ Texas MD Anderson Canc Ctr, Dept Immunol, Houston, TX 77030 USA

[9] Univ Texas MD Anderson Canc Ctr, Dept Lymphoma Myeloma, Houston, TX 77030 USA

[10] Harvard Med Sch, Dept Microbiol & Immunobiol, Boston, MA USA

[11] Univ Texas MD Anderson Canc Ctr, Genitourinary Med Oncol, Houston, TX 77030 USA

[12] MedImmune, Gaithersburg, MD USA

来源：

CANCER DISCOVERY | 2016年 / 6卷 / 08期

关键词：

ENDOTHELIAL GROWTH-FACTOR; PD-1; BLOCKADE; COMBINATION THERAPY; METASTATIC MELANOMA; CLINICAL-RESPONSE; CTLA-4; PLUS IPILIMUMAB; PHASE-II; SURVIVAL; SAFETY;

D O I：

10.1158/2159-8290.CD-15-1545

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

Immune checkpoint blockade represents a major breakthrough in cancer therapy; however, responses are not universal. Genomic and immune features in pretreatment tumor biopsies have been reported to correlate with response in patients with melanoma and other cancers, but robust biomarkers have not been identified. We studied a cohort of patients with metastatic melanoma initially treated with cytotoxic T-lymphocyte-associated antigen-4 (CTLA4) blockade (n = 53) followed by programmed death-1 (PD-1) blockade at progression (n = 46), and analyzed immune signatures in longitudinal tissue samples collected at multiple time points during therapy. In this study, we demonstrate that adaptive immune signatures in tumor biopsy samples obtained early during the course of treatment are highly predictive of response to immune checkpoint blockade and also demonstrate differential effects on the tumor microenvironment induced by CTLA4 and PD-1 blockade. Importantly, potential mechanisms of therapeutic resistance to immune checkpoint blockade were also identified. SIGNIFICANCE: These studies demonstrate that adaptive immune signatures in early on-treatment tumor biopsies are predictive of response to checkpoint blockade and yield insight into mechanisms of therapeutic resistance. These concepts have far-reaching implications in this age of precision medicine and should be explored in immune checkpoint blockade treatment across cancer types. Cancer Discov; 6( 8); 827-37. (C) 2016 AACR.

引用

页码：827 / 837

页数：11

共 43 条

[1]

Talimogene Laherparepvec Improves Durable Response Rate in Patients With Advanced Melanoma [J].

Andtbacka, Robert H. I. ;

Kaufman, Howard L. ;

Collichio, Frances ;

Amatruda, Thomas ;

Senzer, Neil ;

Chesney, Jason ;

Delman, Keith A. ;

Spitler, Lynn E. ;

Puzanov, Igor ;

Agarwala, Sanjiv S. ;

Milhem, Mohammed ;

Cranmer, Lee ;

Curti, Brendan ;

Lewis, Karl ;

Ross, Merrick ;

Guthrie, Troy ;

Linette, Gerald P. ;

Daniels, Gregory A. ;

Harrington, Kevin ;

Middleton, Mark R. ;

Miller, Wilson H., Jr. ;

Zager, Jonathan S. ;

Ye, Yining ;

Yao, Bin ;

Li, Ai ;

Doleman, Susan ;

VanderWalde, Ari ;

Gansert, Jennifer ;

Coffin, Robert S. .

JOURNAL OF CLINICAL ONCOLOGY, 2015, 33 (25) :2780-U98

[2]

Fitting Linear Mixed-Effects Models Using lme4 [J].

Bates, Douglas ;

Maechler, Martin ;

Bolker, Benjamin M. ;

Walker, Steven C. .

JOURNAL OF STATISTICAL SOFTWARE, 2015, 67 (01) :1-48

[3]

CONTROLLING THE FALSE DISCOVERY RATE - A PRACTICAL AND POWERFUL APPROACH TO MULTIPLE TESTING [J].

BENJAMINI, Y ;

HOCHBERG, Y .

JOURNAL OF THE ROYAL STATISTICAL SOCIETY SERIES B-STATISTICAL METHODOLOGY, 1995, 57 (01) :289-300

[4]

Safety and Activity of Anti-PD-L1 Antibody in Patients with Advanced Cancer [J].

Brahmer, Julie R. ;

Tykodi, Scott S. ;

Chow, Laura Q. M. ;

Hwu, Wen-Jen ;

Topalian, Suzanne L. ;

Hwu, Patrick ;

Drake, Charles G. ;

Camacho, Luis H. ;

Kauh, John ;

Odunsi, Kunle ;

Pitot, Henry C. ;

Hamid, Omid ;

Bhatia, Shailender ;

Martins, Renato ;

Eaton, Keith ;

Chen, Shuming ;

Salay, Theresa M. ;

Alaparthy, Suresh ;

Grosso, Joseph F. ;

Korman, Alan J. ;

Parker, Susan M. ;

Agrawal, Shruti ;

Goldberg, Stacie M. ;

Pardoll, Drew M. ;

Gupta, Ashok ;

Wigginton, Jon M. .

NEW ENGLAND JOURNAL OF MEDICINE, 2012, 366 (26) :2455-2465

[5]

OX40 Is a Potent Immune-Stimulating Target in Late-Stage Cancer Patients [J].

Curti, Brendan D. ;

Kovacsovics-Bankowski, Magdalena ;

Morris, Nicholas ;

Walker, Edwin ;

Chisholm, Lana ;

Floyd, Kevin ;

Walker, Joshua ;

Gonzalez, Iliana ;

Meeuwsen, Tanisha ;

Fox, Bernard A. ;

Moudgil, Tarsem ;

Miller, William ;

Haley, Daniel ;

Coffey, Todd ;

Fisher, Brenda ;

Delanty-Miller, Laurie ;

Rymarchyk, Nicole ;

Kelly, Tracy ;

Crocenzi, Todd ;

Bernstein, Eric ;

Sanborn, Rachel ;

Urba, Walter J. ;

Weinberg, Andrew D. .

CANCER RESEARCH, 2013, 73 (24) :7189-7198

[6]

Combination Therapy with Anti-CTLA-4 and Anti-PD-1 Leads to Distinct Immunologic Changes In Vivo [J].

Das, Rituparna ;

Verma, Rakesh ;

Sznol, Mario ;

Boddupalli, Chandra Sekhar ;

Gettinger, Scott N. ;

Kluger, Harriet ;

Callahan, Margaret ;

Wolchok, Jedd D. ;

Halaban, Ruth ;

Dhodapkar, Madhav V. ;

Dhodapkar, Kavita M. .

JOURNAL OF IMMUNOLOGY, 2015, 194 (03) :950-959

[7]

Angiogenesis as a therapeutic target [J].

Ferrara, N ;

Kerbel, RS .

NATURE, 2005, 438 (7070) :967-974

[8]

Gabrilovich Dmitry, 1998, Blood, V92, P4150

[9]

Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens [J].

Gubin, Matthew M. ;

Zhang, Xiuli ;

Schuster, Heiko ;

Caron, Etienne ;

Ward, Jeffrey P. ;

Noguchi, Takuro ;

Ivanova, Yulia ;

Hundal, Jasreet ;

Arthur, Cora D. ;

Krebber, Willem-Jan ;

Mulder, Gwenn E. ;

Toebes, Mireille ;

Vesely, Matthew D. ;

Lam, Samuel S. K. ;

Korman, Alan J. ;

Allison, James P. ;

Freeman, Gordon J. ;

Sharpe, Arlene H. ;

Pearce, Erika L. ;

Schumacher, Ton N. ;

Aebersold, Ruedi ;

Rammensee, Hans-Georg ;

Melief, Cornelis J. M. ;

Mardis, Elaine R. ;

Gillanders, William E. ;

Artyomov, Maxim N. ;

Schreiber, Robert D. .

NATURE, 2014, 515 (7528) :577-+

[10]

Bevacizumab plus Ipilimumab in Patients with Metastatic Melanoma [J].

Hodi, F. Stephen ;

Lawrence, Donald ;

Lezcano, Cecilia ;

Wu, Xinqi ;

Zhou, Jun ;

Sasada, Tetsuro ;

Zeng, Wanyong ;

Giobbie-Hurder, Anita ;

Atkins, Michael B. ;

Ibrahim, Nageatte ;

Friedlander, Philip ;

Flaherty, Keith T. ;

Murphy, George F. ;

Rodig, Scott ;

Velazquez, Elsa F. ;

Mihm, Martin C., Jr. ;

Russell, Sara ;

DiPiro, Pamela J. ;

Yap, Jeffrey T. ;

Ramaiya, Nikhil ;

van den Abbeele, Annick D. ;

Gargano, Maria ;

McDermott, David .

CANCER IMMUNOLOGY RESEARCH, 2014, 2 (07) :632-642

← 1 2 3 4 5 →