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https://www.readbyqxmd.com/read/29773717/stk11-lkb1-mutations-and-pd-1-inhibitor-resistance-in-kras-mutant-lung-adenocarcinoma
#1
Ferdinandos Skoulidis, Michael E Goldberg, Danielle M Greenawalt, Matthew D Hellmann, Mark M Awad, Justin F Gainor, Alexa B Schrock, Ryan J Hartmaier, Sally E Trabucco, Laurie Gay, Siraj M Ali, Julia A Elvin, Gaurav Singal, Jeffrey S Ross, David Fabrizio, Peter M Szabo, Han Chang, Ariella Sasson, Sujaya Srinivasan, Stefan Kirov, Joseph Szustakowski, Patrik Vitazka, Robin Edwards, Jose A Bufill, Neelesh Sharma, Sai-Hong I Ou, Nir Peled, David R Spigel, Hira Rizvi, Elizabeth Jimenez Aguilar, Brett W Carter, Jeremy Erasmus, Darragh F Halpenny, Andrew J Plodkowski, Niamh M Long, Mizuki Nishino, Warren L Denning, Ana Galan-Cobo, Haifa Hamdi, Taghreed Hirz, Pan Tong, Jing Wang, Jaime Rodriguez-Canales, Pamela A Villalobos, Edwin R Parra, Neda Kalhor, Lynette M Sholl, Jennifer L Sauter, Achim A Jungbluth, Mari Mino-Kenudson, Roxana Azimi, Yasir Y Elamin, Jianjun Zhang, Giulia C Leonardi, Fei Jiang, Kwok-Kin Wong, J Jack Lee, Vassiliki A Papadimitrakopoulou, Ignacio I Wistuba, Vincent A Miller, Garrett M Frampton, Jedd D Wolchok, Alice T Shaw, Pasi A Jänne, Philip J Stephens, Charles M Rudin, William J Geese, Lee A Albacker, John V Heymach
KRAS is the most common oncogenic driver in lung adenocarcinoma (LUAC). We previously reported that STK11/LKB1 (KL) or TP53 (KP) co-mutations define distinct subgroups of KRAS-mutant LUAC. Here, we examine the efficacy of PD-1 inhibitors in these subgroups. Objective response rates to PD-1 blockade differed significantly among KL (7.4%), KP (35.7%), and K-only (28.6%) subgroups (P<0.001) in the SU2C cohort (174 patients) with KRAS-mutant LUAC and in patients treated with nivolumab in the CheckMate-057 phase 3 trial (0% vs 57...
May 17, 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29685882/baseline-tumor-size-is-an-independent-prognostic-factor-for-overall-survival-in-patients-with-melanoma-treated-with-pembrolizumab
#2
Richard W Joseph, Jeroen Elassaiss-Schaap, Richard F Kefford, Wen-Jen Hwu, Jedd D Wolchok, Anthony Michael Joshua, Antoni Ribas, F Stephen Hodi, Omid Hamid, Caroline Robert, Adil I Daud, Roxana S Dronca, Peter Hersey, Jeffrey S Weber, Amita Patnaik, Dinesh P de Alwis, Andrea M Perrone, Jin Zhang, Soonmo Peter Kang, Scot W Ebbinghaus, Keaven M Anderson, Tara Gangadhar
PURPOSE: To assess the association of baseline tumor size (BTS) with other baseline clinical factors and outcomes in pembrolizumab-treated patients with advanced melanoma in KEYNOTE-001 (NCT01295827). EXPERIMENTAL DESIGN: BTS was quantified by adding the sum of the longest dimensions of all measurable baseline target lesions. BTS as a dichotomous and continuous variable was evaluated with other baseline factors using logistic regression for objective response rate (ORR) and Cox regression for overall survival (OS)...
April 23, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29658848/neoadjuvant-pd-1-blockade-in-resectable-lung-cancer
#3
Patrick M Forde, Jamie E Chaft, Kellie N Smith, Valsamo Anagnostou, Tricia R Cottrell, Matthew D Hellmann, Marianna Zahurak, Stephen C Yang, David R Jones, Stephen Broderick, Richard J Battafarano, Moises J Velez, Natasha Rekhtman, Zachary Olah, Jarushka Naidoo, Kristen A Marrone, Franco Verde, Haidan Guo, Jiajia Zhang, Justina X Caushi, Hok Yee Chan, John-William Sidhom, Robert B Scharpf, James White, Edward Gabrielson, Hao Wang, Gary L Rosner, Valerie Rusch, Jedd D Wolchok, Taha Merghoub, Janis M Taube, Victor E Velculescu, Suzanne L Topalian, Julie R Brahmer, Drew M Pardoll
Background Antibodies that block programmed death 1 (PD-1) protein improve survival in patients with advanced non-small-cell lung cancer (NSCLC) but have not been tested in resectable NSCLC, a condition in which little progress has been made during the past decade. Methods In this pilot study, we administered two preoperative doses of PD-1 inhibitor nivolumab in adults with untreated, surgically resectable early (stage I, II, or IIIA) NSCLC. Nivolumab (at a dose of 3 mg per kilogram of body weight) was administered intravenously every 2 weeks, with surgery planned approximately 4 weeks after the first dose...
April 16, 2018: New England Journal of Medicine
https://www.readbyqxmd.com/read/29657128/genomic-features-of-response-to-combination-immunotherapy-in-patients-with-advanced-non-small-cell-lung-cancer
#4
Matthew D Hellmann, Tavi Nathanson, Hira Rizvi, Benjamin C Creelan, Francisco Sanchez-Vega, Arun Ahuja, Ai Ni, Jacki B Novik, Levi M B Mangarin, Mohsen Abu-Akeel, Cailian Liu, Jennifer L Sauter, Natasha Rekhtman, Eliza Chang, Margaret K Callahan, Jamie E Chaft, Martin H Voss, Megan Tenet, Xue-Mei Li, Kelly Covello, Andrea Renninger, Patrik Vitazka, William J Geese, Hossein Borghaei, Charles M Rudin, Scott J Antonia, Charles Swanton, Jeff Hammerbacher, Taha Merghoub, Nicholas McGranahan, Alexandra Snyder, Jedd D Wolchok
Combination immune checkpoint blockade has demonstrated promising benefit in lung cancer, but predictors of response to combination therapy are unknown. Using whole-exome sequencing to examine non-small-cell lung cancer (NSCLC) treated with PD-1 plus CTLA-4 blockade, we found that high tumor mutation burden (TMB) predicted improved objective response, durable benefit, and progression-free survival. TMB was independent of PD-L1 expression and the strongest feature associated with efficacy in multivariable analysis...
April 12, 2018: Cancer Cell
https://www.readbyqxmd.com/read/29656892/cancer-germline-antigen-expression-discriminates-clinical-outcome-to-ctla-4-blockade
#5
Sachet A Shukla, Pavan Bachireddy, Bastian Schilling, Christina Galonska, Qian Zhan, Clyde Bango, Rupert Langer, Patrick C Lee, Daniel Gusenleitner, Derin B Keskin, Mehrtash Babadi, Arman Mohammad, Andreas Gnirke, Kendell Clement, Zachary J Cartun, Eliezer M Van Allen, Diana Miao, Ying Huang, Alexandra Snyder, Taha Merghoub, Jedd D Wolchok, Levi A Garraway, Alexander Meissner, Jeffrey S Weber, Nir Hacohen, Donna Neuberg, Patrick R Potts, George F Murphy, Christine G Lian, Dirk Schadendorf, F Stephen Hodi, Catherine J Wu
CTLA-4 immune checkpoint blockade is clinically effective in a subset of patients with metastatic melanoma. We identify a subcluster of MAGE-A cancer-germline antigens, located within a narrow 75 kb region of chromosome Xq28, that predicts resistance uniquely to blockade of CTLA-4, but not PD-1. We validate this gene expression signature in an independent anti-CTLA-4-treated cohort and show its specificity to the CTLA-4 pathway with two independent anti-PD-1-treated cohorts. Autophagy, a process critical for optimal anti-cancer immunity, has previously been shown to be suppressed by the MAGE-TRIM28 ubiquitin ligase in vitro...
April 6, 2018: Cell
https://www.readbyqxmd.com/read/29617360/toxicological-and-pharmacological-assessment-of-agen1884-a-novel-human-igg1-anti-ctla-4-antibody
#6
Randi B Gombos, Ana Gonzalez, Mariana Manrique, Dhan Chand, David Savitsky, Benjamin Morin, Ekaterina Breous-Nystrom, Christopher Dupont, Rebecca A Ward, Cornelia Mundt, Benjamin Duckless, Hao Tang, Mark A Findeis, Andrea Schuster, Jeremy D Waight, Dennis Underwood, Christopher Clarke, Gerd Ritter, Taha Merghoub, David Schaer, Jedd D Wolchok, Marc van Dijk, Jennifer S Buell, Jean-Marie Cuillerot, Robert Stein, Elise E Drouin, Nicholas S Wilson
CTLA-4 and CD28 exemplify a co-inhibitory and co-stimulatory signaling axis that dynamically sculpts the interaction of antigen-specific T cells with antigen-presenting cells. Anti-CTLA-4 antibodies enhance tumor-specific immunity through a variety of mechanisms including: blockade of CD80 or CD86 binding to CTLA-4, repressing regulatory T cell function and selective elimination of intratumoral regulatory T cells via an Fcγ receptor-dependent mechanism. AGEN1884 is a novel IgG1 antibody targeting CTLA-4. It potently enhanced antigen-specific T cell responsiveness that could be potentiated in combination with other immunomodulatory antibodies...
2018: PloS One
https://www.readbyqxmd.com/read/29567705/cancer-immunotherapy-using-checkpoint-blockade
#7
REVIEW
Antoni Ribas, Jedd D Wolchok
The release of negative regulators of immune activation (immune checkpoints) that limit antitumor responses has resulted in unprecedented rates of long-lasting tumor responses in patients with a variety of cancers. This can be achieved by antibodies blocking the cytotoxic T lymphocyte-associated protein 4 (CTLA-4) or the programmed cell death 1 (PD-1) pathway, either alone or in combination. The main premise for inducing an immune response is the preexistence of antitumor T cells that were limited by specific immune checkpoints...
March 23, 2018: Science
https://www.readbyqxmd.com/read/29504948/pd-l1-in-tumor-microenvironment-mediates-resistance-to-oncolytic-immunotherapy
#8
Dmitriy Zamarin, Jacob M Ricca, Svetlana Sadekova, Anton Oseledchyk, Ying Yu, Wendy M Blumenschein, Jerelyn Wong, Mathieu Gigoux, Taha Merghoub, Jedd D Wolchok
Intralesional therapy with oncolytic viruses (OVs) leads to the activation of local and systemic immune pathways, which may present targets for further combinatorial therapies. Here, we used human tumor histocultures as well as syngeneic tumor models treated with Newcastle disease virus (NDV) to identify a range of immune targets upregulated with OV treatment. Despite tumor infiltration of effector T lymphocytes in response to NDV, there was ongoing inhibition through programmed death ligand 1 (PD-L1), acting as a mechanism of early and late adaptive immune resistance to the type I IFN response and T cell infiltration, respectively...
April 2, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29489427/alterations-in-dna-damage-response-and-repair-genes-as-potential-marker-of-clinical-benefit-from-pd-1-pd-l1-blockade-in-advanced-urothelial-cancers
#9
Min Yuen Teo, Kenneth Seier, Irina Ostrovnaya, Ashley M Regazzi, Brooke E Kania, Meredith M Moran, Catharine K Cipolla, Mark J Bluth, Joshua Chaim, Hikmat Al-Ahmadie, Alexandra Snyder, Maria I Carlo, David B Solit, Michael F Berger, Samuel Funt, Jedd D Wolchok, Gopa Iyer, Dean F Bajorin, Margaret K Callahan, Jonathan E Rosenberg
Purpose Alterations in DNA damage response and repair (DDR) genes are associated with increased mutation load and improved clinical outcomes in platinum-treated metastatic urothelial carcinoma. We examined the relationship between DDR alterations and response to PD-1/PD-L1 blockade. Methods Detailed demographic, treatment response, and long-term outcome data were collected on patients with metastatic urothelial carcinoma treated with atezolizumab or nivolumab who had targeted exon sequencing performed on pre-immunotherapy tumor specimens...
February 28, 2018: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/29478729/pre-existing-immunity-to-oncolytic-virus-potentiates-its-immunotherapeutic-efficacy
#10
Jacob M Ricca, Anton Oseledchyk, Tyler Walther, Cailian Liu, Levi Mangarin, Taha Merghoub, Jedd D Wolchok, Dmitriy Zamarin
Anti-viral immunity presents a major hurdle for systemically administered oncolytic viruses (OV). Intratumoral OV therapy has a potential to overcome this problem through activation of anti-tumor immune response, with local and abscopal effects. However, the effects of anti-viral immunity in such a setting are still not well defined. Using Newcastle Disease Virus (NDV) as a model, we explore the effects of pre-existing anti-viral immunity on therapeutic efficacy in syngeneic mouse tumor models. Unexpectedly, we find that while pre-existing immunity to NDV limits its replication in tumors, tumor clearance, abscopal anti-tumor immune effects, and survival are not compromised and, on the contrary, are superior in NDV-immunized mice...
April 4, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29476022/introducing-a-new-series-immunotherapy-facts-and-hopes
#11
EDITORIAL
Ignacio Melero, Mario Sznol, Marlowe S Tessmer, Theresa L Whiteside, Jedd D Wolchok
No abstract text is available yet for this article.
April 15, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29468834/peripheral-blood-clinical-laboratory-variables-associated-with-outcomes-following-combination-nivolumab-and-ipilimumab-immunotherapy-in-melanoma
#12
Samuel Rosner, Erica Kwong, Alexander N Shoushtari, Claire F Friedman, Allison S Betof, Mary Sue Brady, Daniel G Coit, Margaret K Callahan, Jedd D Wolchok, Paul B Chapman, Katherine S Panageas, Michael A Postow
Both the combination of nivolumab + ipilimumab and single-agent anti-PD-1 immunotherapy have demonstrated survival benefit for patients with advanced melanoma. As the combination has a high rate of serious side effects, further analyses in randomized trials of combination versus anti-PD-1 immunotherapy are needed to understand who benefits most from the combination. Clinical laboratory values that were routinely collected in randomized studies may provide information on the relative benefit of combination immunotherapy...
March 2018: Cancer Medicine
https://www.readbyqxmd.com/read/29442540/management-of-immune-related-adverse-events-in-patients-treated-with-immune-checkpoint-inhibitor-therapy-american-society-of-clinical-oncology-clinical-practice-guideline
#13
Julie R Brahmer, Christina Lacchetti, Bryan J Schneider, Michael B Atkins, Kelly J Brassil, Jeffrey M Caterino, Ian Chau, Marc S Ernstoff, Jennifer M Gardner, Pamela Ginex, Sigrun Hallmeyer, Jennifer Holter Chakrabarty, Natasha B Leighl, Jennifer S Mammen, David F McDermott, Aung Naing, Loretta J Nastoupil, Tanyanika Phillips, Laura D Porter, Igor Puzanov, Cristina A Reichner, Bianca D Santomasso, Carole Seigel, Alexander Spira, Maria E Suarez-Almazor, Yinghong Wang, Jeffrey S Weber, Jedd D Wolchok, John A Thompson
Purpose To increase awareness, outline strategies, and offer guidance on the recommended management of immune-related adverse events in patients treated with immune checkpoint inhibitor (ICPi) therapy. Methods A multidisciplinary, multi-organizational panel of experts in medical oncology, dermatology, gastroenterology, rheumatology, pulmonology, endocrinology, urology, neurology, hematology, emergency medicine, nursing, trialist, and advocacy was convened to develop the clinical practice guideline. Guideline development involved a systematic review of the literature and an informal consensus process...
February 14, 2018: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/29398706/altered-self-the-not-so-neo-antigens
#14
Jedd D Wolchok
No abstract text is available yet for this article.
March 2018: Nature Reviews. Immunology
https://www.readbyqxmd.com/read/29360720/introduction-by-the-guest-editors-the-pd-1-axis-in-cancer-therapy-the-irony-in-a-name
#15
Jedd D Wolchok, Margaret K Callahan
No abstract text is available yet for this article.
January 2018: Cancer Journal
https://www.readbyqxmd.com/read/29343444/activation-of-p53-in-immature-myeloid-precursor-cells-controls-differentiation-into-ly6c-cd103-monocytic-antigen-presenting-cells-in-tumors
#16
Madhav D Sharma, Paulo C Rodriguez, Brent H Koehn, Babak Baban, Yan Cui, Gang Guo, Michiko Shimoda, Rafal Pacholczyk, Huidong Shi, Eun-Joon Lee, Hongyan Xu, Theodore S Johnson, Yukai He, Taha Mergoub, Christopher Venable, Vincenzo Bronte, Jedd D Wolchok, Bruce R Blazar, David H Munn
CD103+ dendritic cells are critical for cross-presentation of tumor antigens. Here we have shown that during immunotherapy, large numbers of cells expressing CD103 arose in murine tumors via direct differentiation of Ly6c+ monocytic precursors. These Ly6c+ CD103+ cells could derive from bone-marrow monocytic progenitors (cMoPs) or from peripheral cells present within the myeloid-derived suppressor cell (MDSC) population. Differentiation was controlled by inflammation-induced activation of the transcription factor p53, which drove upregulation of Batf3 and acquisition of the Ly6c+ CD103+ phenotype...
January 16, 2018: Immunity
https://www.readbyqxmd.com/read/29341833/immune-modified-response-evaluation-criteria-in-solid-tumors-imrecist-refining-guidelines-to-assess-the-clinical-benefit-of-cancer-immunotherapy
#17
F Stephen Hodi, Marcus Ballinger, Benjamin Lyons, Jean-Charles Soria, Mizuki Nishino, Josep Tabernero, Thomas Powles, David Smith, Axel Hoos, Chris McKenna, Ulrich Beyer, Ina Rhee, Gregg Fine, Nathan Winslow, Daniel S Chen, Jedd D Wolchok
Purpose Treating solid tumors with cancer immunotherapy (CIT) can result in unconventional responses and overall survival (OS) benefits that are not adequately captured by Response Evaluation Criteria In Solid Tumors (RECIST) v1.1. We describe immune-modified RECIST (imRECIST) criteria, designed to better capture CIT responses. Patients and Methods Atezolizumab data from clinical trials in non-small-cell lung cancer, metastatic urothelial carcinoma, renal cell carcinoma, and melanoma were evaluated. Modifications to imRECIST versus RECIST v1...
March 20, 2018: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/29339377/robust-antitumor-responses-result-from-local-chemotherapy-and-ctla-4-blockade
#18
Charlotte E Ariyan, Mary Sue Brady, Robert H Siegelbaum, Jian Hu, Danielle M Bello, Jamie Rand, Charles Fisher, Robert A Lefkowitz, Kathleen S Panageas, Melissa Pulitzer, Marissa Vignali, Ryan Emerson, Christopher Tipton, Harlan Robins, Taha Merghoub, Jianda Yuan, Achim Jungbluth, Jorge Blando, Padmanee Sharma, Alexander Y Rudensky, Jedd D Wolchok, James P Allison
Clinical responses to immunotherapy have been associated with augmentation of preexisting immune responses, manifested by heightened inflammation in the tumor microenvironment. However, many tumors have a noninflamed microenvironment, and response rates to immunotherapy in melanoma have been <50%. We approached this problem by utilizing immunotherapy (CTLA-4 blockade) combined with chemotherapy to induce local inflammation. In murine models of melanoma and prostate cancer, the combination of chemotherapy and CTLA-4 blockade induced a shift in the cellular composition of the tumor microenvironment, with infiltrating CD8+ and CD4+ T cells increasing the CD8/Foxp3 T-cell ratio...
February 2018: Cancer Immunology Research
https://www.readbyqxmd.com/read/29337640/molecular-determinants-of-response-to-anti-programmed-cell-death-pd-1-and-anti-programmed-death-ligand-1-pd-l1-blockade-in-patients-with-non-small-cell-lung-cancer-profiled-with-targeted-next-generation-sequencing
#19
Hira Rizvi, Francisco Sanchez-Vega, Konnor La, Walid Chatila, Philip Jonsson, Darragh Halpenny, Andrew Plodkowski, Niamh Long, Jennifer L Sauter, Natasha Rekhtman, Travis Hollmann, Kurt A Schalper, Justin F Gainor, Ronglai Shen, Ai Ni, Kathryn C Arbour, Taha Merghoub, Jedd Wolchok, Alexandra Snyder, Jamie E Chaft, Mark G Kris, Charles M Rudin, Nicholas D Socci, Michael F Berger, Barry S Taylor, Ahmet Zehir, David B Solit, Maria E Arcila, Marc Ladanyi, Gregory J Riely, Nikolaus Schultz, Matthew D Hellmann
Purpose Treatment of advanced non-small-cell lung cancer with immune checkpoint inhibitors (ICIs) is characterized by durable responses and improved survival in a subset of patients. Clinically available tools to optimize use of ICIs and understand the molecular determinants of response are needed. Targeted next-generation sequencing (NGS) is increasingly routine, but its role in identifying predictors of response to ICIs is not known. Methods Detailed clinical annotation and response data were collected for patients with advanced non-small-cell lung cancer treated with anti-programmed death-1 or anti-programmed death-ligand 1 [anti-programmed cell death (PD)-1] therapy and profiled by targeted NGS (MSK-IMPACT; n = 240)...
March 1, 2018: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/29285228/four-month-course-of-adjuvant-dabrafenib-in-patients-with-surgically-resected-stage-iiic-melanoma-characterized-by-a-brafv600e-k-mutation
#20
Parisa Momtaz, James J Harding, Charlotte Ariyan, Daniel G Coit, Taha Merghoub, Billel Gasmi, Daoqi You, Agnes Viale, Katherine S Panageas, Aliaksandra Samoila, Michael A Postow, Jedd D Wolchok, Paul B Chapman
Background: We tested the hypothesis that a 4-month course of adjuvant dabrafenib in stage IIIC BRAF-mutated melanoma would improve 2 year RFS from 24% to 51%, and that tumor-derived cell free DNA (cfDNA) in plasma would correlate with and predict recurrence. Methods: Patients with stage IIIC BRAF V600E/K mutated melanoma who were free of disease after surgical resection received 4 months of adjuvant dabrafenib. Patients were evaluated with imaging at baseline, at the end of cycles 2, 4, 6, then every 3 months until disease relapse or 2 years, whichever came first...
December 1, 2017: Oncotarget
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