Host immunity contributes to the anti-melanoma activity of BRAF inhibitors
Deborah A. Knight,Shin Foong Ngiow,Shin Foong Ngiow,Ming Li,Ming Li,Tiffany Parmenter,Tiffany Parmenter,Stephen Mok,Ashley A. Cass,Nicole M. Haynes,Nicole M. Haynes,Kathryn M Kinross,Kathryn M Kinross,Hideo Yagita,Richard C. Koya,Thomas G. Graeber,Antoni Ribas,Grant A. McArthur,Grant A. McArthur,Mark J. Smyth,Mark J. Smyth +20 more
Reads0
Chats0
TLDR
It is found that PLX4720 treatment downregulated tumor Ccl2 gene expression and decreased tumor CCL2 expression in both Braf(V600E) mouse melanoma transplants and in de novo melanomas in a manner that was coincident with reduced tumor growth.Abstract:
The BRAF mutant, BRAF(V600E), is expressed in nearly half of melanomas, and oral BRAF inhibitors induce substantial tumor regression in patients with BRAF(V600E) metastatic melanoma. The inhibitors are believed to work primarily by inhibiting BRAF(V600E)-induced oncogenic MAPK signaling; however, some patients treated with BRAF inhibitors exhibit increased tumor immune infiltration, suggesting that a combination of BRAF inhibitors and immunotherapy may be beneficial. We used two relatively resistant variants of Braf(V600E)-driven mouse melanoma (SM1 and SM1WT1) and melanoma-prone mice to determine the role of host immunity in type I BRAF inhibitor PLX4720 antitumor activity. We found that PLX4720 treatment downregulated tumor Ccl2 gene expression and decreased tumor CCL2 expression in both Braf(V600E) mouse melanoma transplants and in de novo melanomas in a manner that was coincident with reduced tumor growth. While PLX4720 did not directly increase tumor immunogenicity, analysis of SM1 tumor-infiltrating leukocytes in PLX4720-treated mice demonstrated a robust increase in CD8(+) T/FoxP3(+)CD4(+) T cell ratio and NK cells. Combination therapy with PLX4720 and anti-CCL2 or agonistic anti-CD137 antibodies demonstrated significant antitumor activity in mouse transplant and de novo tumorigenesis models. These data elucidate a role for host CCR2 in the mechanism of action of type I BRAF inhibitors and support the therapeutic potential of combining BRAF inhibitors with immunotherapy.read more
Citations
More filters
Journal ArticleDOI
The immune contexture in cancer prognosis and treatment
Wolf H. Fridman,Laurence Zitvogel,Catherine Sautès-Fridman,Catherine Sautès-Fridman,Catherine Sautès-Fridman,Guido Kroemer +5 more
TL;DR: The immune contexture, which is determined by the density, composition, functional state and organization of the leukocyte infiltrate of the tumour, can yield information that is relevant to prognosis, prediction of a treatment response and various other pharmacodynamic parameters.
Journal ArticleDOI
T-cell invigoration to tumour burden ratio associated with anti-PD-1 response
Alexander C. Huang,Michael A. Postow,Michael A. Postow,Robert J. Orlowski,Rosemarie Mick,Bertram Bengsch,Sasikanth Manne,Wei Xu,Shannon Harmon,Josephine R. Giles,Brandon Wenz,Matthew Adamow,Deborah Kuk,Katherine S. Panageas,Cristina Carrera,Cristina Carrera,Phillip Wong,Felix Quagliarello,Bradley Wubbenhorst,Kurt D'Andrea,Kristen E. Pauken,Ramin S. Herati,Ryan P. Staupe,Jason M. Schenkel,Suzanne McGettigan,Shawn Kothari,Sangeeth M. George,Robert H. Vonderheide,Ravi K. Amaravadi,Giorgos C. Karakousis,Lynn M. Schuchter,Xiaowei Xu,Katherine L. Nathanson,Jedd D. Wolchok,Tara C. Gangadhar,E. John Wherry +35 more
TL;DR: Blood profiling of peripheral blood from patients with stage IV melanoma before and after treatment with the PD-1-targeting antibody pembrolizumab is used to identify pharmacodynamic changes in circulating exhausted-phenotype CD8 T cells (Tex cells) and identify a clinically accessible potential on-treatment predictor of response to PD- 1 blockade.
Journal ArticleDOI
Immunological Effects of Conventional Chemotherapy and Targeted Anticancer Agents.
TL;DR: The tremendous clinical success of checkpoint blockers illustrates the potential of reestablishing latent immunosurveillance for cancer therapy, and their in-depth comprehension will facilitate the design of novel combinatorial regimens with improved clinical efficacy.
Journal ArticleDOI
Loss of PTEN Promotes Resistance to T Cell–Mediated Immunotherapy
Weiyi Peng,Jie Qing Chen,Chengwen Liu,Shruti Malu,Caitlin Creasy,Michael T. Tetzlaff,Chunyu Xu,Jodi A. McKenzie,Chunlei Zhang,Xiaoxuan Liang,Leila Williams,Wanleng Deng,Guo Chen,Rina M. Mbofung,Alexander J. Lazar,Carlos A. Torres-Cabala,Zachary A. Cooper,Pei-Ling Chen,Trang N. Tieu,Stefani Spranger,Xiaoxing Yu,Chantale Bernatchez,Marie-Andree Forget,Cara Haymaker,Rodabe N. Amaria,Jennifer L. McQuade,Isabella C. Glitza,Tina Cascone,Haiyan S. Li,Lawrence N. Kwong,Timothy P. Heffernan,Jianhua Hu,Roland L. Bassett,Marcus Bosenberg,Scott E. Woodman,Willem W. Overwijk,Gregory Lizée,Jason Roszik,Thomas F. Gajewski,Jennifer A. Wargo,Jeffrey E. Gershenwald,Laszlo Radvanyi,Michael A. Davies,Patrick Hwu +43 more
TL;DR: It is demonstrated that loss of PTEN in tumor cells in preclinical models of melanoma inhibits T cell-mediated tumor killing and decreases T-cell trafficking into tumors, and support the rationale to explore combinations of immunotherapies and PI3K-AKT pathway inhibitors.
Journal ArticleDOI
Tumor infiltrating lymphocytes are prognostic in triple negative breast cancer and predictive for trastuzumab benefit in early breast cancer: results from the FinHER trial
Sherene Loi,Sherene Loi,Stefan Michiels,Stefan Michiels,Roberto Salgado,Nicolas Sirtaine,Vinu Jose,Debora Fumagalli,P-L Kellokumpu-Lehtinen,Petri Bono,Vesa Kataja,Christine Desmedt,Martine Piccart,Sibylle Loibl,Carsten Denkert,Mark J. Smyth,Heikki Joensuu,Christos Sotiriou +17 more
TL;DR: Higher levels of TILs present at diagnosis were significantly associated with decreased distant recurrence rates in primary TNBC, and an association between higher levels ofTILs and increased trastuzumab benefit in HER2+ disease is reported for the first time.
References
More filters
Journal ArticleDOI
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
TL;DR: Ipilimumab, with or without a gp100 peptide vaccine, as compared with gp100 alone, improved overall survival in patients with previously treated metastatic melanoma.
Journal ArticleDOI
Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.
Suzanne L. Topalian,F. Stephen Hodi,Julie R. Brahmer,Scott N. Gettinger,David Smith,David F. McDermott,John D. Powderly,Richard D. Carvajal,Jeffrey A. Sosman,Michael B. Atkins,Philip D. Leming,David R. Spigel,Scott J. Antonia,Leora Horn,Charles G. Drake,Drew M. Pardoll,Lieping Chen,William H. Sharfman,Robert A. Anders,Janis M. Taube,Tracee L. McMiller,Haiying Xu,Alan J. Korman,Maria Jure-Kunkel,Shruti Agrawal,Dan McDonald,Georgia Kollia,Ashok Kumar Gupta,Jon M. Wigginton,Mario Sznol +29 more
TL;DR: Anti-PD-1 antibody produced objective responses in approximately one in four to one in five patients with non-small-cell lung cancer, melanoma, or renal-cell cancer; the adverse-event profile does not appear to preclude its use.
Journal ArticleDOI
The blockade of immune checkpoints in cancer immunotherapy
TL;DR: Preliminary clinical findings with blockers of additional immune-checkpoint proteins, such as programmed cell death protein 1 (PD1), indicate broad and diverse opportunities to enhance antitumour immunity with the potential to produce durable clinical responses.
Journal ArticleDOI
New Colorimetric Cytotoxicity Assay for Anticancer-Drug Screening
Philip Skehan,Ritsa Storeng,Dominic A. Scudiero,Anne Monks,James B. McMahon,David T. Vistica,Jonathan T. Warren,Heidi R. Bokesch,Susan Kenney,Michael R. Boyd +9 more
TL;DR: The SRB assay provides a sensitive measure of drug-induced cytotoxicity, is useful in quantitating clonogenicity, and is well suited to high-volume, automated drug screening.
Journal ArticleDOI
Safety and Activity of Anti–PD-L1 Antibody in Patients with Advanced Cancer
Julie R. Brahmer,Scott S. Tykodi,Scott S. Tykodi,Laura Q.M. Chow,Wen-Jen Hwu,Suzanne L. Topalian,Patrick Hwu,Charles G. Drake,Luis H. Camacho,John S. Kauh,Kunle Odunsi,Henry C. Pitot,Omid Hamid,Shailender Bhatia,Renato G. Martins,Keith D. Eaton,Shuming Chen,Theresa M. Salay,Suresh Alaparthy,Joseph F. Grosso,Alan J. Korman,Susan M. Parker,Shruti Agrawal,Stacie M. Goldberg,Drew M. Pardoll,Ashok Kumar Gupta,Jon M. Wigginton +26 more
TL;DR: Antibody-mediated blockade of PD-L1 induced durable tumor regression and prolonged stabilization of disease in patients with advanced cancers, including non-small-cell lung cancer, melanoma, and renal-cell cancer.
Related Papers (5)
BRAF inhibition is associated with enhanced melanoma antigen expression and a more favorable tumor microenvironment in patients with metastatic melanoma
Dennie T. Frederick,Adriano Piris,Alexandria P. Cogdill,Zachary A. Cooper,Cecilia Lezcano,Cristina R. Ferrone,Devarati Mitra,Andrea Boni,Lindsay P. Newton,Chengwen Liu,Weiyi Peng,Ryan J. Sullivan,Donald P. Lawrence,F. Stephen Hodi,Willem W. Overwijk,Gregory Lizée,George F. Murphy,Patrick Hwu,Keith T. Flaherty,David E. Fisher,Jennifer A. Wargo +20 more
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
Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation
Paul B. Chapman,Axel Hauschild,Caroline Robert,John B. A. G. Haanen,Paolo A. Ascierto,James Larkin,Reinhard Dummer,Claus Garbe,Alessandro Testori,Michele Maio,David W. Hogg,Paul Lorigan,Céleste Lebbé,Thomas Jouary,Dirk Schadendorf,Antoni Ribas,Jeffrey A. Sosman,John M. Kirkwood,Brigitte Dréno,K. B. Nolop,Jiang Li,B. Nelson,Jeannie Hou,Richard J. Lee,Keith T. Flaherty,Grant A. McArthur +25 more
Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.
Suzanne L. Topalian,F. Stephen Hodi,Julie R. Brahmer,Scott N. Gettinger,David Smith,David F. McDermott,John D. Powderly,Richard D. Carvajal,Jeffrey A. Sosman,Michael B. Atkins,Philip D. Leming,David R. Spigel,Scott J. Antonia,Leora Horn,Charles G. Drake,Drew M. Pardoll,Lieping Chen,William H. Sharfman,Robert A. Anders,Janis M. Taube,Tracee L. McMiller,Haiying Xu,Alan J. Korman,Maria Jure-Kunkel,Shruti Agrawal,Dan McDonald,Georgia Kollia,Ashok Kumar Gupta,Jon M. Wigginton,Mario Sznol +29 more
Mutations of the BRAF gene in human cancer
Helen Davies,Graham R. Bignell,Charles Cox,Philip J. Stephens,Sarah Edkins,S. M. Clegg,Jon W. Teague,Hayley Woffendin,Mathew J. Garnett,William Bottomley,Neil Davis,Ed Dicks,Rebecca Ewing,Yvonne Floyd,Kristian Gray,S. Hall,Rachel Hawes,Jaime Hughes,Vivian Kosmidou,Andrew Menzies,Catherine Mould,Adrian Parker,Claire Stevens,Stephen Watt,Steven Hooper,Rebecca Wilson,Hiran Jayatilake,Barry A. Gusterson,Colin Cooper,Janet Shipley,Darren Hargrave,Kathy Pritchard-Jones,Norman J. Maitland,Georgia Chenevix-Trench,Gregory J. Riggins,Darell D. Bigner,Giuseppe Palmieri,Antonio Cossu,Adrienne M. Flanagan,Andrew G. Nicholson,Judy W. C. Ho,Suet Yi Leung,Siu Tsan Yuen,Barbara L. Weber,Hilliard F. Seigler,Timothy L. Darrow,Hugh Paterson,Richard Marais,Christopher J. Marshall,Richard Wooster,Michael R. Stratton,P. Andrew Futreal +51 more