Jelena Levi1, Samuel Goth2, Lyna Huynh2, Tina Lam2, Tony L Huynh3, Brailee Schulte3, Juliet A Packiasamy2. 1. CellSight Technologies Incorporated, San Francisco, California; and jlevi@cellsighttech.com. 2. CellSight Technologies Incorporated, San Francisco, California; and. 3. Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California.
Abstract
Most clinical trials exploring various combinations of chemo- and immunotherapy rely on serial biopsy to provide information on immune response. The aim of this study was to assess the value of 18F-arabinosyl guanine (18F-AraG) as a noninvasive tool that profiles tumors on the basis of the key player in adaptive antitumor response, CD8+ cells, and evaluates the immunomodulatory effects of chemotherapy. Methods: To evaluate the ability of 18F-AraG to report on the presence of CD8+ cells within the tumor microenvironment, we imaged a panel of syngeneic tumor models (MC38, CT26, LLC, A9F1, 4T1, and B16F10) and correlated the signal intensity with the number of lymphocytes found in the tumors. The capacity of 18F-AraG to detect immunomodulatory effects of chemotherapy was determined by longitudinal imaging of tumor-bearing mice (MC38 and A9F1) undergoing 2 types of chemotherapy: oxaliplatin/cyclophosphamide, shown to induce immunogenic cell death, and paclitaxel/carboplatin, reported to cause immunogenically silent tumor cell death. Results: In the tumor panel, 18F-AraG revealed strikingly different uptake patterns resembling cancer-immune phenotypes observed in the clinic. A statistically significant correlation was found between the 18F-AraG signal and the number of PD-1-positive CD8+ cells isolated from the tumors (r 2 = 0.528, P < 0.0001). In the MC38 model, paclitaxel/carboplatin did not result in an appreciable change in signal after therapy (1.69 ± 0.25 vs. 1.50 ± 0.33 percentage injected dose per gram), but oxaliplatin/cyclophosphamide treatment led to close to a 2.4-fold higher 18F-AraG signal (1.20 ± 0.31 vs. 2.84 ± 0.93 percentage injected dose per gram). The statistically significant increase in signal after oxaliplatin/cyclophosphamide was also observed in the A9F1 model (0.95 ± 0.36 vs. 1.99 ± 0.54 percentage injected dose per gram). Conclusion: The ability of 18F-AraG PET to assess the location and function of CD8+ cells, as well immune activity within tumors after immune priming therapy, warrants further investigation into its utility for patient selection, evaluation of optimal time to deliver immunotherapies, and assessment of combinatorial therapies.
Most clinical trials exploring various combinations of chemo- and immunotherapy rely on serial biopsy to provide information on immune response. The aim of this study was to assess the value of 18F-arabinosyl guanine (18F-AraG) as a noninvasive tool that profiles tumors on the basis of the key player in adaptive antitumor response, CD8+ cells, and evaluates the immunomodulatory effects of chemotherapy. Methods: To evaluate the ability of 18F-AraG to report on the presence of CD8+ cells within the tumor microenvironment, we imaged a panel of syngeneic tumor models (MC38, CT26, LLC, A9F1, 4T1, and B16F10) and correlated the signal intensity with the number of lymphocytes found in the tumors. The capacity of 18F-AraG to detect immunomodulatory effects of chemotherapy was determined by longitudinal imaging of tumor-bearing mice (MC38 and A9F1) undergoing 2 types of chemotherapy: oxaliplatin/cyclophosphamide, shown to induce immunogenic cell death, and paclitaxel/carboplatin, reported to cause immunogenically silent tumor cell death. Results: In the tumor panel, 18F-AraG revealed strikingly different uptake patterns resembling cancer-immune phenotypes observed in the clinic. A statistically significant correlation was found between the 18F-AraG signal and the number of PD-1-positive CD8+ cells isolated from the tumors (r 2 = 0.528, P < 0.0001). In the MC38 model, paclitaxel/carboplatin did not result in an appreciable change in signal after therapy (1.69 ± 0.25 vs. 1.50 ± 0.33 percentage injected dose per gram), but oxaliplatin/cyclophosphamide treatment led to close to a 2.4-fold higher 18F-AraG signal (1.20 ± 0.31 vs. 2.84 ± 0.93 percentage injected dose per gram). The statistically significant increase in signal after oxaliplatin/cyclophosphamide was also observed in the A9F1 model (0.95 ± 0.36 vs. 1.99 ± 0.54 percentage injected dose per gram). Conclusion: The ability of 18F-AraG PET to assess the location and function of CD8+ cells, as well immune activity within tumors after immune priming therapy, warrants further investigation into its utility for patient selection, evaluation of optimal time to deliver immunotherapies, and assessment of combinatorial therapies.
Authors: Jelena Levi; Tina Lam; Samuel R Goth; Shahriar Yaghoubi; Jennifer Bates; Gang Ren; Salma Jivan; Tony L Huynh; Joseph E Blecha; Roli Khattri; Karl F Schmidt; Dominique Jennings; Henry VanBrocklin Journal: Cancer Res Date: 2019-05-07 Impact factor: 12.701
Authors: Benjamin M Larimer; Eric Wehrenberg-Klee; Frank Dubois; Anila Mehta; Taylor Kalomeris; Keith Flaherty; Genevieve Boland; Umar Mahmood Journal: Cancer Res Date: 2017-05-01 Impact factor: 12.701
Authors: Franck Pagès; Bernhard Mlecnik; Florence Marliot; Gabriela Bindea; Fang-Shu Ou; Carlo Bifulco; Alessandro Lugli; Inti Zlobec; Tilman T Rau; Martin D Berger; Iris D Nagtegaal; Elisa Vink-Börger; Arndt Hartmann; Carol Geppert; Julie Kolwelter; Susanne Merkel; Robert Grützmann; Marc Van den Eynde; Anne Jouret-Mourin; Alex Kartheuser; Daniel Léonard; Christophe Remue; Julia Y Wang; Prashant Bavi; Michael H A Roehrl; Pamela S Ohashi; Linh T Nguyen; SeongJun Han; Heather L MacGregor; Sara Hafezi-Bakhtiari; Bradly G Wouters; Giuseppe V Masucci; Emilia K Andersson; Eva Zavadova; Michal Vocka; Jan Spacek; Lubos Petruzelka; Bohuslav Konopasek; Pavel Dundr; Helena Skalova; Kristyna Nemejcova; Gerardo Botti; Fabiana Tatangelo; Paolo Delrio; Gennaro Ciliberto; Michele Maio; Luigi Laghi; Fabio Grizzi; Tessa Fredriksen; Bénédicte Buttard; Mihaela Angelova; Angela Vasaturo; Pauline Maby; Sarah E Church; Helen K Angell; Lucie Lafontaine; Daniela Bruni; Carine El Sissy; Nacilla Haicheur; Amos Kirilovsky; Anne Berger; Christine Lagorce; Jeffrey P Meyers; Christopher Paustian; Zipei Feng; Carmen Ballesteros-Merino; Jeroen Dijkstra; Carlijn van de Water; Shannon van Lent-van Vliet; Nikki Knijn; Ana-Maria Mușină; Dragos-Viorel Scripcariu; Boryana Popivanova; Mingli Xu; Tomonobu Fujita; Shoichi Hazama; Nobuaki Suzuki; Hiroaki Nagano; Kiyotaka Okuno; Toshihiko Torigoe; Noriyuki Sato; Tomohisa Furuhata; Ichiro Takemasa; Kyogo Itoh; Prabhu S Patel; Hemangini H Vora; Birva Shah; Jayendrakumar B Patel; Kruti N Rajvik; Shashank J Pandya; Shilin N Shukla; Yili Wang; Guanjun Zhang; Yutaka Kawakami; Francesco M Marincola; Paolo A Ascierto; Daniel J Sargent; Bernard A Fox; Jérôme Galon Journal: Lancet Date: 2018-05-10 Impact factor: 79.321
Authors: Michael D Buck; David O'Sullivan; Ramon I Klein Geltink; Jonathan D Curtis; Chih-Hao Chang; David E Sanin; Jing Qiu; Oliver Kretz; Daniel Braas; Gerritje J W van der Windt; Qiongyu Chen; Stanley Ching-Cheng Huang; Christina M O'Neill; Brian T Edelson; Edward J Pearce; Hiromi Sesaki; Tobias B Huber; Angelika S Rambold; Erika L Pearce Journal: Cell Date: 2016-06-09 Impact factor: 41.582
Authors: Leonie Voorwerk; Maarten Slagter; Hugo M Horlings; Karolina Sikorska; Koen K van de Vijver; Michiel de Maaker; Iris Nederlof; Roelof J C Kluin; Sarah Warren; SuFey Ong; Terry G Wiersma; Nicola S Russell; Ferry Lalezari; Philip C Schouten; Noor A M Bakker; Steven L C Ketelaars; Dennis Peters; Charlotte A H Lange; Erik van Werkhoven; Harm van Tinteren; Ingrid A M Mandjes; Inge Kemper; Suzanne Onderwater; Myriam Chalabi; Sofie Wilgenhof; John B A G Haanen; Roberto Salgado; Karin E de Visser; Gabe S Sonke; Lodewyk F A Wessels; Sabine C Linn; Ton N Schumacher; Christian U Blank; Marleen Kok Journal: Nat Med Date: 2019-05-13 Impact factor: 53.440
Authors: Benjamin L Franc; Sam Goth; John MacKenzie; Xiaojuan Li; Joseph Blecha; Tina Lam; Salma Jivan; Randall A Hawkins; Henry VanBrocklin Journal: Mol Imaging Date: 2017-01-01 Impact factor: 4.488
Authors: Caroline Guglielmetti; Jelena Levi; Tony L Huynh; Brice Tiret; Joseph Blecha; Ryan Tang; Henry VanBrocklin; Myriam M Chaumeil Journal: J Nucl Med Date: 2021-04-09 Impact factor: 11.082
Authors: Fiona Hegi-Johnson; Stacey Rudd; Rodney J Hicks; Dirk De Ruysscher; Joseph A Trapani; Thomas John; Paul Donnelly; Benjamin Blyth; Gerard Hanna; Sarah Everitt; Peter Roselt; Michael P MacManus Journal: NPJ Precis Oncol Date: 2022-04-07