Adoptive Transfer of Tumor-Infiltrating Lymphocytes in Patients with Metastatic Melanoma: Intent-to-Treat Analysis and Efficacy after Failure to Prior Immunotherapies
Michal J. Besser,Ronnie Shapira-Frommer,Orit Itzhaki,Avraham J. Treves,Douglas Zippel,Daphna Levy,Adva Kubi,Noa Shoshani,Dragoslav Zikich,Yaara Ohayon,Daniel Ohayon,Bruria Shalmon,Gal Markel,Gal Markel,Ronit Yerushalmi,Sara Apter,Alon Ben-Nun,Eytan Ben-Ami,Avichai Shimoni,Arnon Nagler,Jacob Schachter +20 more
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Adoptive transfer of TIL can yield durable and complete responses in patients with refractory melanoma, even when other immunotherapies have failed.Abstract:
Purpose: Adoptive cell transfer (ACT) using autologous tumor-infiltrating lymphocytes (TIL) was reported to yield objective responses in about 50% of metastatic patients with melanoma. Here, we present the intent-to-treat analysis of TIL ACT and analyze parameters predictive to response as well as the impact of other immunotherapies. Experimental Design: Eighty patients with stage IV melanoma were enrolled, of which 57 were treated with unselected/young TIL and high-dose interleukin-2 (IL-2) following nonmyeloablative lymphodepleting conditioning. Results: TIL cultures were established from 72 of 80 enrolled patients. Altogether 23 patients were withdrawn from the study mainly due to clinical deterioration during TIL preparation. The overall response rate and median survival was 29% and 9.8 months for enrolled patients and 40% and 15.2 months for treated patients. Five patients achieved complete and 18 partial remission. All complete responders are on unmaintained remission after a median follow-up of 28 months and the 3-year survival of responding patients was 78%. Multivariate analysis revealed blood lactate-dehydrogenase levels, gender, days of TIL in culture, and the total number of infused CD8 + cells as independent predictive markers for clinical outcome. Thirty-two patients received the CTLA-4-blocking antibody ipilimumab prior or post TIL infusion. Retrospective analysis revealed that nonresponders to ipilimumab or IL-2 based therapy had the same overall response rate to ACT as other patients receiving TIL. No additional toxicities to TIL therapy occurred following ipilimumab treatment. Conclusion: Adoptive transfer of TIL can yield durable and complete responses in patients with refractory melanoma, even when other immunotherapies have failed. Clin Cancer Res; 19(17); 4792–800. ©2013 AACR .read more
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Journal ArticleDOI
Adoptive cell transfer as personalized immunotherapy for human cancer.
TL;DR: The ability to genetically engineer lymphocytes to express conventional T cell receptors or chimeric antigen receptors has further extended the successful application of ACT for cancer treatment.
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IL-2: The First Effective Immunotherapy for Human Cancer
TL;DR: The genetic modification of T cells with genes encoding αβ TCRs or chimeric Ag receptors and the administration of these cells after expansion in IL-2 have extended effective cell transfer therapy to other cancer types.
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Binding of the Fap2 protein of Fusobacterium nucleatum to human inhibitory receptor TIGIT protects tumors from immune cell attack.
Chamutal Gur,Yara Ibrahim,Batya Isaacson,Rachel Yamin,Jawad Abed,Moriya Gamliel,Jonatan Enk,Yotam Bar-On,Noah Stanietsky-Kaynan,Shunit Coppenhagen-Glazer,Noam Shussman,Gideon Almogy,Angelica Cuapio,Erhard Hofer,Dror Mevorach,Adi Tabib,Rona Ortenberg,Gal Markel,Karmela Miklić,Stipan Jonjić,Caitlin A. Brennan,Wendy S. Garrett,Gilad Bachrach,Ofer Mandelboim +23 more
TL;DR: This work has shown that natural killer cell killing of various tumors is inhibited in the presence of various F. nucleatum strains, and identified a bacterium-dependent, tumor-immune evasion mechanism in which tumors exploit the Fap2 protein of F. nucleus to inhibit immune cell activity via TIGIT.
Journal ArticleDOI
Classification of current anticancer immunotherapies
Lorenzo Galluzzi,Erika Vacchelli,José Manuel Bravo-San Pedro,Aitziber Buqué,Laura Senovilla,Elisa E. Baracco,Norma Bloy,Francesca Castoldi,Jean Pierre Abastado,Patrizia Agostinis,Ron N. Apte,Fernando Aranda,Maha Ayyoub,Philipp Beckhove,Jean-Yves Blay,Laura Bracci,Anne Caignard,Chiara Castelli,Federica Cavallo,Estaban Celis,Vincenzo Cerundolo,Aled Clayton,Mario P. Colombo,Lisa M. Coussens,Madhav V. Dhodapkar,Alexander M.M. Eggermont,Douglas T. Fearon,Wolf H. Fridman,Jitka Fucikova,Dmitry I. Gabrilovich,Jérôme Galon,Abhishek D. Garg,François Ghiringhelli,François Ghiringhelli,Giuseppe Giaccone,Giuseppe Giaccone,Eli Gilboa,Sacha Gnjatic,Axel Hoos,Anne Hosmalin,Anne Hosmalin,Anne Hosmalin,Dirk Jäger,Pawel Kalinski,Klas Kärre,Oliver Kepp,Rolf Kiessling,John M. Kirkwood,Eva Klein,Alexander Knuth,Claire E. Lewis,Roland S. Liblau,Roland S. Liblau,Roland S. Liblau,Michael T. Lotze,Enrico Lugli,Jean-Pierre Mach,Fabrizio Mattei,Domenico Mavilio,Ignacio Melero,Cornelis J. M. Melief,E. A. Mittendorf,Lorenzo Moretta,Adekunke Odunsi,Hideho Okada,Anna Karolina Palucka,Marcus E. Peter,Kenneth J. Pienta,Angel Porgador,George C. Prendergast,George C. Prendergast,Gabriel A. Rabinovich,Nicholas P. Restifo,Naiyer A. Rizvi,Catherine Sautès-Fridman,Hans Schreiber,Barbara Seliger,Hiroshi Shiku,Bruno Silva-Santos,Mark J. Smyth,Mark J. Smyth,Daniel E. Speiser,Daniel E. Speiser,Radek Spisek,Pramod K. Srivastava,James E. Talmadge,Eric Tartour,Sjoerd H. van der Burg,Benoît Van den Eynde,Benoît Van den Eynde,Richard G. Vile,Hermann Wagner,Jeffrey S. Weber,Theresa L. Whiteside,Jedd D. Wolchok,Jedd D. Wolchok,Laurence Zitvogel,Weiping Zou,Guido Kroemer +98 more
TL;DR: A critical, integrated classification of anticancer immunotherapies is proposed and the clinical relevance of these approaches is discussed.
Journal ArticleDOI
Randomized, Prospective Evaluation Comparing Intensity of Lymphodepletion Before Adoptive Transfer of Tumor-Infiltrating Lymphocytes for Patients With Metastatic Melanoma
Stephanie L. Goff,Mark E. Dudley,Deborah Citrin,Robert Somerville,John R. Wunderlich,David N. Danforth,Daniel Zlott,James Chih-Hsin Yang,Richard M. Sherry,Udai S. Kammula,Christopher A. Klebanoff,Michael S. Hughes,Nicholas P. Restifo,Michelle M. Langhan,Thomas E. Shelton,Lily Lu,Mei Li M. Kwong,Sadia Ilyas,Nicholas D. Klemen,Eden C. Payabyab,Kathleen E. Morton,Mary Ann Toomey,Seth M. Steinberg,Donald E. White,Steven A. Rosenberg +24 more
TL;DR: Adoptive cell transfer can mediate durable complete regressions in 24% of patients with metastatic melanoma, with median survival > 3 years.
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Journal ArticleDOI
Cancer Regression and Autoimmunity in Patients After Clonal Repopulation with Antitumor Lymphocytes
Mark E. Dudley,John R. Wunderlich,Paul F. Robbins,James Chih-Hsin Yang,Patrick Hwu,Douglas J. Schwartzentruber,Suzanne L. Topalian,Richard M. Sherry,Nicholas P. Restifo,Amy M. Hubicki,Michael R. Robinson,Mark Raffeld,Paul H. Duray,Claudia A. Seipp,Linda Rogers-Freezer,Kathleen E. Morton,Sharon Mavroukakis,Donald E. White,Steven A. Rosenberg +18 more
TL;DR: The adoptive transfer of highly selected tumor-reactive T cells directed against overexpressed self-derived differentiation antigens after a nonmyeloablative conditioning regimen resulted in the persistent clonal repopulation of T cells in cancer patients, leading to regression of the patients' metastatic melanoma as well as to the onset of autoimmune melanocyte destruction.
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