Concurrent PD-1 Blockade Negates the Effects of OX40 Agonist Antibody in Combination Immunotherapy through Inducing T-cell Apoptosis
Rajeev K. Shrimali,Shamim Ahmad,Vivek Verma,Peng Zeng,Sudha Ananth,Pankaj Gaur,Rachel M. Gittelman,Erik Yusko,Catherine Sanders,Harlan Robins,Scott A. Hammond,John Edward Janik,Mikayel Mkrtichyan,Seema Gupta,Samir N. Khleif +14 more
Reads0
Chats0
TLDR
Results indicate that anti–PD-1 added at the initiation of therapy exhibits a detrimental effect on the positive outcome of anti-OX40 agonist Ab, demonstrating the need to test treatment combination and sequencing before moving to the clinic.Abstract:
Combination therapies that depend on checkpoint inhibitor antibodies (Abs) such as for PD-1 or its ligand (PD-L1) together with immune stimulatory agonist Abs like anti-OX40 are being tested in the clinic to achieve improved antitumor effects. Here, we studied the potential therapeutic and immune effects of one such combination: Ab to PD-1 with agonist Ab to OX40/vaccine. We tested the antitumor effects of different treatment sequencing of this combination. We report that simultaneous addition of anti–PD-1 to anti-OX40 negated the antitumor effects of OX40 Ab. Antigen-specific CD8+ T-cell infiltration into the tumor was diminished, the resultant antitumor response weakened, and survival reduced. Although we observed an increase in IFNγ-producing E7-specifc CD8+ T cells in the spleens of mice treated with the combination of PD-1 blockade with anti-OX40/vaccine, these cells underwent apoptosis both in the periphery and the tumor. These results indicate that anti–PD-1 added at the initiation of therapy exhibits a detrimental effect on the positive outcome of anti-OX40 agonist Ab. These findings have important implications on the design of combination immunotherapy for cancer, demonstrating the need to test treatment combination and sequencing before moving to the clinic. Cancer Immunol Res; 5(9); 755–66. ©2017 AACR.read more
Citations
More filters
Journal ArticleDOI
Top 10 Challenges in Cancer Immunotherapy
Priti S. Hegde,Daniel S. Chen +1 more
TL;DR: Ten key challenges facing cancer immunotherapy are defined, which range from lack of confidence in translating pre-clinical findings to identifying optimal combinations of immune-based therapies for any given patient.
Journal ArticleDOI
Cancer immunoediting and resistance to T cell-based immunotherapy
Jake S. O’Donnell,Jake S. O’Donnell,Michele W.L. Teng,Michele W.L. Teng,Mark J. Smyth,Mark J. Smyth +5 more
TL;DR: How a deeper understanding of the mechanisms underlying the cancer immunoediting process can provide insight into the development of resistance to immunotherapies and the strategies that can be used to overcome such resistance is discussed.
Journal ArticleDOI
T Cell Dysfunction in Cancer.
TL;DR: The current understanding of T cell dysfunction in cancer, the value of novel technologies to dissect such dysfunction at the single cell level, and how the emerging understanding may be utilized to develop personalized strategies to restore antitumor immunity are discussed.
Journal ArticleDOI
Emerging Concepts for Immune Checkpoint Blockade-Based Combination Therapies
TL;DR: It is proposed that reducing tumor burden and increasing tumor immunogenicity are key factors to improve immunotherapy.
Journal ArticleDOI
Advances in cancer immunotherapy 2019 – latest trends
Stephan Kruger,Stephan Kruger,Matthias Ilmer,Matthias Ilmer,Sebastian Kobold,Bruno L. Cadilha,Stefan Endres,Steffen Ormanns,Gesa Schuebbe,Bernhard W. Renz,Bernhard W. Renz,Jan G. D’Haese,Hans Anton Schloesser,Volker Heinemann,Volker Heinemann,Marion Subklewe,Marion Subklewe,Stefan Boeck,Stefan Boeck,Jens Werner,Michael von Bergwelt-Baildon +20 more
TL;DR: This review summarizes seminal findings from clinical and translational studies recently presented or published at important meetings or in top-tier journals, respectively, regarding cellular immunotherapy and checkpoint blockade.
References
More filters
Journal ArticleDOI
PD-1 blockade induces responses by inhibiting adaptive immune resistance
Paul C. Tumeh,Christina L. Harview,Jennifer H. Yearley,I. Peter Shintaku,Emma Taylor,Lidia Robert,Bartosz Chmielowski,Marko Spasic,Gina Henry,Voicu Ciobanu,Alisha N. West,Manuel Carmona,Christine Kivork,Elizabeth Seja,Grace Cherry,Antonio Gutierrez,Tristan Grogan,Christine Mateus,Gorana Tomasic,John A. Glaspy,Ryan O. Emerson,Harlan Robins,Robert H. Pierce,David Elashoff,Caroline Robert,Antoni Ribas +25 more
TL;DR: It is shown that pre-existing CD8+ T cells distinctly located at the invasive tumour margin are associated with expression of the PD-1/PD-L1 immune inhibitory axis and may predict response to therapy.
Journal ArticleDOI
Nivolumab plus Ipilimumab in Advanced Melanoma
Jedd D. Wolchok,Harriet Kluger,Margaret K. Callahan,Michael A. Postow,Naiyer A. Rizvi,Alexander M. Lesokhin,Neil H. Segal,Charlotte E. Ariyan,Ruth-Ann Gordon,Kathleen Reed,Matthew M. Burke,Anne Caldwell,Stephanie Anne Kronenberg,Blessing Agunwamba,Xiaoling Zhang,Israel Lowy,Hector David Inzunza,William Feely,Christine Horak,Quan Hong,Alan J. Korman,Jon M. Wigginton,Ashok Kumar Gupta,Mario Sznol +23 more
TL;DR: Conurrent therapy with nivolumab and ipilimumab had a manageable safety profile and provided clinical activity that appears to be distinct from that in published data on monotherapy, with rapid and deep tumor regression in a substantial proportion of patients.
Journal ArticleDOI
PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression
Cheryl L. Day,Daniel Kaufmann,Photini Kiepiela,Julia A. Brown,Eshia Moodley,Sharon Reddy,Elizabeth W Mackey,Joseph D. Miller,Alasdair Leslie,Chantal DePierres,Zenele Mncube,Jaikumar Duraiswamy,Baogong Zhu,Quentin Eichbaum,Marcus Altfeld,E. John Wherry,Hoosen M. Coovadia,Philip J. R. Goulder,Philip J. R. Goulder,Philip J. R. Goulder,Paul Klenerman,Rafi Ahmed,Gordon J. Freeman,Bruce D. Walker,Bruce D. Walker,Bruce D. Walker +25 more
TL;DR: The data indicate that the immunoregulatory PD-1/PD-L1 pathway is operative during a persistent viral infection in humans, and define a reversible defect in HIV-specific T-cell function.
Journal ArticleDOI
Molecular mechanisms of T cell co-stimulation and co-inhibition
TL;DR: The mechanisms through which T cell activation, differentiation and function is controlled by co-stimulatory and co-inhibitory receptors are reviewed.
Journal ArticleDOI
PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: Mechanisms, response biomarkers, and combinations
TL;DR: Evaluating several potential therapeutic response markers including the PD-L1 and PD-1 expression pattern, genetic mutations within cancer cells and neoantigens, cancer epigenetics and effector T cell landscape, and microbiota and the mechanisms of action of these markers clarify.
Related Papers (5)
Improved Survival with Ipilimumab in Patients with Metastatic Melanoma.
F. Stephen Hodi,Steven J. O'Day,David F. McDermott,R. W. Weber,Jeffrey A. Sosman,John B. A. G. Haanen,Rene Gonzalez,Caroline Robert,Dirk Schadendorf,Jessica C. Hassel,Wallace Akerley,Alfons J.M. van den Eertwegh,Jose Lutzky,Paul Lorigan,Julia Vaubel,Gerald P. Linette,David W. Hogg,Christian H. Ottensmeier,Céleste Lebbé,Christian Peschel,Ian Quirt,Joseph I. Clark,Jedd D. Wolchok,Jeffrey S. Weber,Jason Tian,Michael Yellin,Geoffrey M. Nichol,Axel Hoos,Walter J. Urba +28 more
Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma.
James Larkin,Vanna Chiarion-Sileni,Rene Gonzalez,Jean-Jacques Grob,C. Lance Cowey,Christopher D. Lao,Dirk Schadendorf,Reinhard Dummer,Michael Smylie,Piotr Rutkowski,Pier Francesco Ferrucci,A. Hill,John Wagstaff,Matteo S. Carlino,John B A G Haanen,Michele Maio,Ivan Marquez-Rodas,Grant A. McArthur,Paolo A. Ascierto,Georgina V. Long,Margaret K. Callahan,Michael A. Postow,Michael A. Postow,Kenneth F. Grossmann,Mario Sznol,Brigitte Dréno,Lars Bastholt,Arvin Yang,Linda Rollin,Christine Horak,F. Stephen Hodi,Jedd D. Wolchok,Jedd D. Wolchok +32 more
Mutations Associated with Acquired Resistance to PD-1 Blockade in Melanoma
Jesse M. Zaretsky,Angel Garcia-Diaz,Daniel Sanghoon Shin,Helena Escuin-Ordinas,Willy Hugo,Siwen Hu-Lieskovan,Davis Y. Torrejon,Gabriel Abril-Rodriguez,Salemiz Sandoval,Lucas Barthly,Justin Saco,Blanca Homet Moreno,Riccardo Mezzadra,Bartosz Chmielowski,Kathleen Ruchalski,I. Peter Shintaku,Phillip J. Sanchez,Cristina Puig-Saus,Grace Cherry,Elizabeth Seja,Xiangju Kong,Jia Pang,Beata Berent-Maoz,Begoña Comin-Anduix,Thomas G. Graeber,Paul C. Tumeh,Ton N. Schumacher,Roger S. Lo,Antoni Ribas +28 more