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pd-1 and cancer

Sophie Outh-Gauer, Marie Alt, Christophe Le Tourneau, Jérémy Augustin, Chloé Broudin, Cassandre Gasne, Thomas Denize, Haitham Mirghani, Elizabeth Fabre, Madeleine Ménard, Florian Scotte, Eric Tartour, Cécile Badoual
Cancer occurrence can be understood as the result of dysfunctions in immune tumoral microenvironment. Here we review the recent understandings of those microenvironment changes, regarding their causes and prognostic significance in head and neck (HN) carcinoma. We will focus on HN squamous cell cancer (SCC) and nasopharyngeal carcinomas (NPC). Their overall poor prognosis may be improved with immunotherapy in a subset of patients, as supported by current clinical trials. However, finding reliable markers of therapeutic response is crucial for patient selection, due to potential severe adverse reactions and high costs...
March 1, 2018: Cancer Treatment Reviews
Clémence Granier, Alain Gey, Charles Dariane, Arnaud Mejean, Marc-Olivier Timsit, Charlotte Blanc, Virginie Verkarre, Camélia Radulescu, Elisabeth Fabre, Yann Vano, Stéphane Oudard, Cécile Badoual, Éric Tartour
T cells harboring multiple co-inhibitory molecules lose their anti-tumoral functionality. PD-1 is a clinically approved target in cancer therapy, but its expression alone does not mean dysfunctionality. The expression of Tim-3 on numerous cell types (T cell, Treg, dendritic cell, myeloid cells) favors tumor escape to immune cells. Within many tumors, PD-1/Tim-3 coexpressing CD8-T cells lose their ability to secrete cytokines (IFNγ, IL-2, TNFα) and their intratumoral infiltration correlates with a bad prognosis...
March 2018: Médecine Sciences: M/S
Hao Hu, Qian Zhu, Xian Shi Luo, Xiong Wen Yang, Hai Dong Wang, Chang Ying Guo
Background: Programmed cell death 1 (PD-1) and programmed cell death-ligand 1(PD-L1) inhibitors have captured our attention as new therapeutic options for several tumor types. Nonetheless, the differences in efficacy between PD-1/PD-L1 inhibitors and conventional treatments (chemotherapy or targeted therapy) in pretreated advanced cancer patients remain unclear. Materials and Methods: A systematic literature search was conducted to identify phase III randomized controlled trials (RCTs)-based investigations of PD-1(nivolumab, pembrolizumab)/PD-L1 inhibitors (atezolizumab) against pretreated advanced cancer...
February 20, 2018: Oncotarget
Marina Chiara Garassino, Byoung-Chul Cho, Joo-Hang Kim, Julien Mazières, Johan Vansteenkiste, Hervé Lena, Jesus Corral Jaime, Jhanelle E Gray, John Powderly, Christos Chouaid, Paolo Bidoli, Paul Wheatley-Price, Keunchil Park, Ross A Soo, Yifan Huang, Catherine Wadsworth, Phillip A Dennis, Naiyer A Rizvi
BACKGROUND: Immune checkpoint inhibitors are a new standard of care for patients with advanced non-small-cell lung cancer (NSCLC) without EGFR tyrosine kinase or anaplastic lymphoma kinase (ALK) genetic aberrations (EGFR-/ALK-), but clinical benefit in patients with EGFR mutations or ALK rearrangements (EGFR+/ALK+) has not been shown. We assessed the effect of durvalumab (anti-PD-L1) treatment in three cohorts of patients with NSCLC defined by EGFR/ALK status and tumour expression of PD-L1...
March 12, 2018: Lancet Oncology
Yuta Takashima, Jun Sakakibara-Konishi, Yutaka Hatanaka, Kanako C Hatanaka, Yoshihito Ohhara, Satoshi Oizumi, Yasuhiro Hida, Kichizo Kaga, Ichiro Kinoshita, Hirotoshi Dosaka-Akita, Yoshihiro Matsuno, Masaharu Nishimura
BACKGROUND: Approximately 20% to 30% of non-small-cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR)-activating mutations are not responsive to EGFR tyrosine kinase inhibitors (TKIs). Although primary resistance to EGFR-TKIs has been attributed to various genetic alterations, little is known about the clinical and immunopathologic features of patients with primary resistance. The tumor immune microenvironment, including tumor-infiltrating lymphocytes (TILs) and programmed cell death ligand 1 (PD-L1), has been reported to play an important role in tumor progression in those with NSCLC...
February 19, 2018: Clinical Lung Cancer
Julian A Marin-Acevedo, Bhagirathbhai Dholaria, Aixa E Soyano, Keith L Knutson, Saranya Chumsri, Yanyan Lou
Immune checkpoints consist of inhibitory and stimulatory pathways that maintain self-tolerance and assist with immune response. In cancer, immune checkpoint pathways are often activated to inhibit the nascent anti-tumor immune response. Immune checkpoint therapies act by blocking or stimulating these pathways and enhance the body's immunological activity against tumors. Cytotoxic T lymphocyte-associated molecule-4 (CTLA-4), programmed cell death receptor-1 (PD-1), and programmed cell death ligand-1(PD-L1) are the most widely studied and recognized inhibitory checkpoint pathways...
March 15, 2018: Journal of Hematology & Oncology
Charles S Fuchs, Toshihiko Doi, Raymond W Jang, Kei Muro, Taroh Satoh, Manuela Machado, Weijing Sun, Shadia I Jalal, Manish A Shah, Jean-Phillipe Metges, Marcelo Garrido, Talia Golan, Mario Mandala, Zev A Wainberg, Daniel V Catenacci, Atsushi Ohtsu, Kohei Shitara, Ravit Geva, Jonathan Bleeker, Andrew H Ko, Geoffrey Ku, Philip Philip, Peter C Enzinger, Yung-Jue Bang, Diane Levitan, Jiangdian Wang, Minori Rosales, Rita P Dalal, Harry H Yoon
Importance: Therapeutic options are needed for patients with advanced gastric cancer whose disease has progressed after 2 or more lines of therapy. Objective: To evaluate the safety and efficacy of pembrolizumab in a cohort of patients with previously treated gastric or gastroesophageal junction cancer. Design, Setting, and Participants: In the phase 2, global, open-label, single-arm, multicohort KEYNOTE-059 study, 259 patients in 16 countries were enrolled in a cohort between March 2, 2015, and May 26, 2016...
March 15, 2018: JAMA Oncology
Benjamin L Solomon, Ignacio Garrido-Laguna
The advent of immune checkpoint inhibitors (PD-1, PD-L1 and CTLA-4) has resulted in unprecedented long-term remissions of unresectable cancers. The efficacy of checkpoint inhibitors was recently demonstrated in gastrointestinal malignancies with mismatch repair deficiencies (dMMR). Pembrolizumab became the first tissue-agnostic US FDA-approved drug based on the presence of the predictive biomarker dMMR. In addition, the FDA in 2017 approved pembrolizumab for PD-L1-positive advanced gastric cancer in third-line and second-line hepatocellular therapy...
March 15, 2018: Future Oncology
Shrujal Baxi, Annie Yang, Renee L Gennarelli, Niloufer Khan, Ziwei Wang, Lindsay Boyce, Deborah Korenstein
OBJECTIVE: To evaluate rates of serious organ specific immune-related adverse events, general adverse events related to immune activation, and adverse events consistent with musculoskeletal problems for anti-programmed cell death 1 (PD-1) drugs overall and compared with control treatments. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Medline, Embase, Cochrane Library, Web of Science, and Scopus searched to 16 March 2017 and combined with data from ClinicalTrials...
March 14, 2018: BMJ: British Medical Journal
Alejo Rodriguez-Vida, Joaquim Bellmunt
Metastatic urothelial carcinoma (UC) remains an aggressive disease associated with limited treatment options and a reduced survival. In spite of this, the first-line treatment based on platinum-based combinations has remained virtually unchanged for the last 20-30 years. Similarly, before the advent of the immune checkpoint inhibitors, there were no FDA-approved drugs for second-line therapy. In the last few years, impressive signs of anti-tumor activity have been reported with several immunotherapy agents targeting the programmed cell death-1 (PD-1) pathway...
March 14, 2018: Expert Review of Anticancer Therapy
Anne M Stowman, Alexandra W Hickman, Ileana S Mauldin, Adela Mahmutovic, Alejandro A Gru, Craig L Slingluff
Desmoplastic melanomas (DM) have unique and challenging clinical presentations and histomorphology. A characteristic feature is the presence of scattered lymphoid aggregates. However, the nature of these aggregates is not defined. We hypothesized that they may be tertiary lymphoid structures (TLS), and may be associated with programmed death ligand 1 (PD-L1) expression. We searched our tissue database for 'pure' DMs and for scars as control tissues, collected clinical information, and reviewed H&E histology...
March 13, 2018: Melanoma Research
Triparna Sen, Carl M Gay, Lauren Averett Byers
Small cell lung cancer (SCLC) is an aggressive malignancy that accounts for 14% of all lung cancer diagnoses. Despite decades of active research, treatment options for SCLC are limited and resistance to the few Food and Drug Administration (FDA) approved therapies develops rapidly. With no approved targeted agents to date, new therapeutic strategies are desperately needed. SCLC is characterized by high mutation burden, ubiquitous loss of TP53 and RB1, mutually exclusive amplification of MYC family members, thereby, high genomic instability...
February 2018: Translational Lung Cancer Research
Takahiro Nakagomi, Taichiro Goto, Yosuke Hirotsu, Daichi Shikata, Yujiro Yokoyama, Rumi Higuchi, Kenji Amemiya, Kenichiro Okimoto, Toshio Oyama, Hitoshi Mochizuki, Masao Omata
Objectives: Pulmonary sarcomatoid carcinomas are rare and generally aggressive tumors composed of carcinomatous and sarcomatous components; however, the evolution of sarcomatoid cancer has not been elucidated. Here, we aimed to evaluate the mutational profiles and phylogeny of sarcomatoid carcinomas using next generation sequencing and in-silico analysis to facilitate the development of novel therapies. Methods: Four patients who underwent surgery for sarcomatoid cancer were enrolled...
February 13, 2018: Oncotarget
Jessica Wagner, C Leah Kline, Lanlan Zhou, Kerry S Campbell, Alexander W MacFarlane, Anthony J Olszanski, Kathy Q Cai, Harvey H Hensley, Eric A Ross, Marie D Ralff, Andrew Zloza, Charles B Chesson, Jenna H Newman, Howard Kaufman, Joseph R Bertino, Mark N Stein, Wafik El-Deiry
ONC201 is a first-in-class, orally active anti-tumor agent that upregulates cytotoxic TRAIL pathway signaling in cancer cells. ONC201 has demonstrated safety and preliminary efficacy in the first-in-human trial where patients were dosed every 3 weeks. We hypothesized that dose-intensification of ONC201 may impact anti-tumor efficacy. We discovered that ONC201 exerts dose- and schedule-dependent effects on tumor progression and cell-death signaling in vivo. With dose intensification, we note a potent anti-metastasis effect and inhibition of cancer cell migration and invasion...
March 13, 2018: Journal of Clinical Investigation
Yuying Liu, Xiaoyu Liang, Wenqian Dong, Yi Fang, Jiadi Lv, Tianzhen Zhang, Roland Fiskesund, Jing Xie, Jinyan Liu, Xiaonan Yin, Xun Jin, Degao Chen, Ke Tang, Jingwei Ma, Huafeng Zhang, Jing Yu, Jun Yan, Huaping Liang, Siqi Mo, Feiran Cheng, Yabo Zhou, Haizeng Zhang, Jing Wang, Jingnan Li, Yang Chen, Bing Cui, Zhuo-Wei Hu, Xuetao Cao, F Xiao-Feng Qin, Bo Huang
Despite the clinical successes fostered by immune checkpoint inhibitors, mechanisms underlying PD-1 upregulation in tumor-infiltrating T cells remain an enigma. Here, we show that tumor-repopulating cells (TRCs) drive PD-1 upregulation in CD8+ T cells through a transcellular kynurenine (Kyn)-aryl hydrocarbon receptor (AhR) pathway. Interferon-γ produced by CD8+ T cells stimulates release of high levels of Kyn produced by TRCs, which is transferred into adjacent CD8+ T cells via the transporters SLC7A8 and PAT4...
March 12, 2018: Cancer Cell
Franz L Ricklefs, Quazim Alayo, Harald Krenzlin, Ahmad B Mahmoud, Maria C Speranza, Hiroshi Nakashima, Josie L Hayes, Kyungheon Lee, Leonora Balaj, Carmela Passaro, Arun K Rooj, Susanne Krasemann, Bob S Carter, Clark C Chen, Tyler Steed, Jeffrey Treiber, Scott Rodig, Katherine Yang, Ichiro Nakano, Hakho Lee, Ralph Weissleder, Xandra O Breakefield, Jakub Godlewski, Manfred Westphal, Katrin Lamszus, Gordon J Freeman, Agnieszka Bronisz, Sean E Lawler, E Antonio Chiocca
Binding of programmed death ligand-1 (PD-L1) to programmed cell death protein-1 (PD1) leads to cancer immune evasion via inhibition of T cell function. One of the defining characteristics of glioblastoma, a universally fatal brain cancer, is its profound local and systemic immunosuppression. Glioblastoma has also been shown to generate extracellular vesicles (EVs), which may play an important role in tumor progression. We thus hypothesized that glioblastoma EVs may be important mediators of immunosuppression and that PD-L1 could play a role...
March 2018: Science Advances
Takayuki Ueno, Shigehira Saji, Norikazu Masuda, Katsumasa Kuroi, Nobuaki Sato, Hiroyuki Takei, Yutaka Yamamoto, Shinji Ohno, Hiroko Yamashita, Kazufumi Hisamatsu, Kenjiro Aogi, Hiroji Iwata, Takeharu Yamanaka, Hironobu Sasano, Masakazu Toi
Background: Neoadjuvant endocrine therapy (NET) has been demonstrated to improve breast-conserving rate and is a widely accepted treatment option for postmenopausal patients with hormone receptor-positive breast cancer. There are few reports on the association of NET response and long-term outcomes. Objectives: To investigate the prognostic value of clinical response to NET. Methods: Long-term outcomes of NET were examined in 107 patients who participated in the multicentre prospective neoadjuvant exemestane study, JFMC34-0601...
2018: ESMO Open
Kent W Mouw, Panagiotis A Konstantinopoulos
Multiple clinical studies have revealed a link between genomic instability and response to anti-PD-1/PD-L1 therapy in cancer management. A recent study has revealed an important role for the ATR/Chk1 DNA damage checkpoint in regulating PD-L1 expression, raising important clinical and translational questions for therapy selection and study design.
March 13, 2018: British Journal of Cancer
Kimio Yonesaka, Koji Haratani, Shiki Takamura, Hitomi Sakai, Ryoji Kato, Naoki Takegawa, Takayuki Takahama, Kaoru Tanaka, Hidetoshi Hayashi, Masayuki Takeda, Shigeki Kato, Osamu Maenishi, Kazuko Sakai, Yasutaka Chiba, Takafumi Okabe, Keita Kudo, Yoshikazu Hasegawa, Hiroyasu Kaneda, Michiko Yamato, Kenji Hirotani, Masaaki Miyazawa, Kazuto Nishio, Kazuhiko Nakagawa
PURPOSE: Anti-programmed-death-1 (PD-1) immunotherapy improves survival in non-small cell lung cancer (NSCLC), but some cases are refractory to treatment, thereby requiring alternative strategies. B7-H3, an immune-checkpoint molecule, is expressed in various malignancies. To our knowledge, this study is the first to evaluate B7-H3 expression in NSCLCs treated with anti-PD-1 therapy and the therapeutic potential of a combination of anti-PD-1 therapy and B7-H3 targeting. EXPERIMENTAL DESIGN: B7-H3 expression was evaluated immunohistochemically in patients with NSCLC (n = 82), and its relationship with responsiveness to anti-PD-1 therapy and CD8+ tumor infiltrating lymphocytes (TILs) was analyzed...
March 12, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Fausto Petrelli, Mariangela Maltese, Gianluca Tomasello, Barbara Conti, Karen Borgonovo, Mary Cabiddu, Mara Ghilardi, Michele Ghidini, Rodolfo Passalacqua, Sandro Barni, Matteo Brighenti
Clinicopathologic and molecular characteristics of non-small-cell lung cancers (NSCLCs) associated with a strong expression of programmed death ligand 1 (PD-L1+ in > 5% of cells) have not been well elucidated. Expression of PD-L1 is a poor prognostic factor, but NSCLCs with higher levels of PD-L1 have greater benefit when treated with immunotherapy. We have performed a systematic review to synthesize the available evidence regarding clinicopathologic and molecular variables associated with PD-L1 expression in NSCLC...
February 21, 2018: Clinical Lung Cancer
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