Ex Vivo Profiling of PD-1 Blockade Using Organotypic Tumor Spheroids

Cancer Discov. 2018 Feb;8(2):196-215. doi: 10.1158/2159-8290.CD-17-0833.

Russell W Jenkins ¹ ², Amir R Aref ¹ ³, Patrick H Lizotte ¹ ³, Elena Ivanova ¹ ³, Susanna Stinson ⁴, Chensheng W Zhou ¹ ⁵, Michaela Bowden ¹ ⁵, Jiehui Deng ¹, Hongye Liu ¹ ³ ⁶, Diana Miao ¹ ⁷, Meng Xiao He ¹ ⁷ ⁸, William Walker ¹ ³, Gao Zhang ⁹, Tian Tian ¹⁰, Chaoran Cheng ¹⁰, Zhi Wei ¹⁰, Sangeetha Palakurthi ¹ ³, Mark Bittinger ¹ ³, Hans Vitzthum ², Jong Wook Kim ¹ ⁷, Ashley Merlino ¹, Max Quinn ¹, Chandrasekar Venkataramani ⁴, Joshua A Kaplan ⁴, Andrew Portell ¹ ³, Prafulla C Gokhale ¹ ³, Bart Phillips ⁴, Alicia Smart ¹ ⁷, Asaf Rotem ¹, Robert E Jones ¹ ³, Lauren Keogh ¹ ³, Maria Anguiano ¹¹, Lance Stapleton ⁴, Zhiheng Jia ⁴, Michal Barzily-Rokni ², Israel Cañadas ¹, Tran C Thai ¹, Marc R Hammond ², Raven Vlahos ¹ ⁵, Eric S Wang ¹², Hua Zhang ¹, Shuai Li ¹, Glenn J Hanna ¹, Wei Huang ¹ ³, Mai P Hoang ¹³, Adriano Piris ¹⁴, Jean-Pierre Eliane ¹³, Anat O Stemmer-Rachamimov ¹³, Lisa Cameron ¹⁵, Mei-Ju Su ¹, Parin Shah ¹, Benjamin Izar ¹ ⁷, Manisha Thakuria ¹ ¹⁶, Nicole R LeBoeuf ¹ ¹⁶, Guilherme Rabinowits ¹, Viswanath Gunda ¹⁷, Sareh Parangi ¹⁷, James M Cleary ¹, Brian C Miller ¹, Shunsuke Kitajima ¹, Rohit Thummalapalli ¹, Benchun Miao ², Thanh U Barbie ¹⁸, Vivek Sivathanu ¹⁹, Joshua Wong ¹, William G Richards ²⁰, Raphael Bueno ²⁰, Charles H Yoon ¹⁸, Juan Miret ¹ ³, Meenhard Herlyn ⁹, Levi A Garraway ¹, Eliezer M Van Allen ¹ ⁷, Gordon J Freeman ¹, Paul T Kirschmeier ¹ ³, Jochen H Lorch ¹, Patrick A Ott ¹, F Stephen Hodi ¹, Keith T Flaherty ², Roger D Kamm ¹⁹ ²¹, Genevieve M Boland ¹⁷, Kwok-Kin Wong ¹ ³, David Dornan ²², Cloud Peter Paweletz ²³ ³, David A Barbie ²³

Affiliations

1 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
2 Division of Medical Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
3 Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts.
4 Gilead Sciences, Foster City, California.
5 Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts.
6 Laboratory of Systems Pharmacology, Harvard Medical School, Boston, Massachusetts.
7 Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
8 Harvard Graduate Program in Biophysics, Boston, Massachusetts.
9 Melanoma Research Center and Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, Pennsylvania.
10 Department of Computer Science, New Jersey Institute of Technology, Newark, New Jersey.
11 Center for Applied Medical Research, University of Navarra, Pamplona, Spain.
12 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
13 Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
14 Department of Pathology, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts.
15 Confocal and Light Microscopy Core Facility, Dana-Farber Cancer Institute, Boston, Massachusetts.
16 Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
17 Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
18 Department of Surgical Oncology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
19 Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts.
20 Division of Thoracic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
21 Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts.
22 Gilead Sciences, Foster City, California. dbarbie@partners.org CloudP_Paweletz@dfci.harvard.edu David.Dornan@gilead.com.
23 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. dbarbie@partners.org CloudP_Paweletz@dfci.harvard.edu David.Dornan@gilead.com.

PMID: 29101162 DOI: 10.1158/2159-8290.CD-17-0833

Abstract

Ex vivo systems that incorporate features of the tumor microenvironment and model the dynamic response to Immune Checkpoint blockade (ICB) may facilitate efforts in precision immuno-oncology and the development of effective combination therapies. Here, we demonstrate the ability to interrogate ex vivo response to ICB using murine- and patient-derived organotypic tumor spheroids (MDOTS/PDOTS). MDOTS/PDOTS isolated from mouse and human tumors retain autologous lymphoid and myeloid cell populations and respond to ICB in short-term three-dimensional microfluidic culture. Response and resistance to ICB was recapitulated using MDOTS derived from established immunocompetent mouse tumor models. MDOTS profiling demonstrated that TBK1/IKKε inhibition enhanced response to PD-1 blockade, which effectively predicted tumor response in vivo Systematic profiling of secreted cytokines in PDOTS captured key features associated with response and resistance to PD-1 blockade. Thus, MDOTS/PDOTS profiling represents a novel platform to evaluate ICB using established murine models as well as clinically relevant patient specimens.Significance: Resistance to PD-1 blockade remains a challenge for many patients, and biomarkers to guide treatment are lacking. Here, we demonstrate feasibility of ex vivo profiling of PD-1 blockade to interrogate the tumor immune microenvironment, develop therapeutic combinations, and facilitate precision immuno-oncology efforts. Cancer Discov; 8(2); 196-215. ©2017 AACR.See related commentary by Balko and Sosman, p. 143See related article by Deng et al., p. 216This article is highlighted in the In This Issue feature, p. 127.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-128679

TBK1/IKKε-IN-5

99.58%, TBK1/IKKε Inhibitor

IKK

Cancer

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