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Immune checkpoint therapy

Isabella Zhang, Silvia C Formenti, Jonathan P S Knisely
The brain has long been considered an immunologically privileged site, and the role of immunotherapy in treating intracranial disease has only recently been revived-with preclinical evidence showing that the systemic immune system responds to immunotherapy for intracranial disease, and with clinical evidence demonstrating improved locoregional control and survival compared with historical outcomes when immune-directed therapies are combined with radiation. Pharmaceutical industry-supported multi-institutional drug efficacy studies routinely exclude patients with brain metastases, so current evidence for treatment of brain metastases using stereotactic radiosurgery combined with immunotherapy comes from single-institution studies...
March 15, 2018: Oncology (Williston Park, NY)
Amar Patel, Lawrence Fong
Immunotherapies have emerged as a revolutionary modality for cancer treatment, and a variety of immune-based approaches are currently being investigated in the field of prostate cancer. Despite the 2010 approval of sipuleucel-T, subsequent progress in prostate cancer immunotherapy development has been limited by disappointing results with novel vaccination approaches and by prostate cancer's general resistance to immune checkpoint blockade. Nevertheless, there remains strong preclinical and clinical evidence to suggest that prostate cancer is a susceptible target for immune therapies...
March 15, 2018: Oncology (Williston Park, NY)
Michael Platten, David A Reardon
Strategies to empower the immune system to successfully attack cancers, including vaccination approaches, adaptive T cell therapies, and immune checkpoint modulators, have recently achieved remarkable success across a spectrum of cancer indications. Nonetheless, with rare exception, only a minority of patients with a given type of cancer respond to an immunotherapeutic when administered as single-agent therapy. Although under extensive laboratory and clinical investigation, the role of these approaches for glioma patients remains to be determined...
February 2018: Seminars in Neurology
William Pao, Chia-Huey Ooi, Fabian Birzele, Astrid Ruefli-Brasse, Michael A Cannarile, Bernhard Reis, Sebastian H Scharf, David A Schubert, Klas Hatje, Nadege Pelletier, Olivia Spleiss, John C Reed
Checkpoint inhibitor therapy has been a breakthrough in cancer research, but only some patients with cancer derive substantial benefit. Although mechanisms underlying sensitivity and resistance to checkpoint inhibitors are being elucidated, the importance of organ-specific regulation of immunity is currently underappreciated. Here, we call for a greater understanding of tissue-specific immunoregulation, namely, "tissue-specific immunostats," to make advances in treatments for cancer. A better understanding of how individual organs at baseline regulate the immune system could enable an improved precision medicine approach to cancer immunotherapy...
March 15, 2018: Cancer Discovery
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
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
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
Weinan Guo, Jinyuan Ma, Tianli Pei, Tao Zhao, Sen Guo, Xiuli Yi, Yu Liu, Shiyu Wang, Guannan Zhu, Zhe Jian, Tianwen Gao, Chunying Li, Wenjun Liao, Qiong Shi
Melanoma is the most malignant skin cancer with increasing incidence worldwide. Although innovative therapies such as BRAF inhibitor and immune checkpoint inhibitor have gained remarkable advances, metastatic melanoma remains an incurable disease for its notorious aggressiveness. Therefore, further clarification of the underlying mechanism of melanoma pathogenesis is critical for the improvement of melanoma therapy. Ubiquitination is an important regulatory event for cancer hallmarks and melanoma development, and the deubiquitinating enzymes including ubiquitin-specific peptidase (USP) families are greatly implicated in modulating cancer biology...
March 14, 2018: Journal of Cellular and Molecular Medicine
Taigo Kato, Tatsuo Matsuda, Yuji Ikeda, Jae-Hyun Park, Matthias Leisegang, Sachiko Yoshimura, Tetsuro Hikichi, Makiko Harada, Makda Zewde, Sho Sato, Kosei Hasegawa, Kazuma Kiyotani, Yusuke Nakamura
Neoantigens are the main targets of tumor-specific T cells reactivated by immune checkpoint-blocking antibodies or when using tumor-infiltrating T cells for adoptive therapy. While cancers often accumulate hundreds of mutations and harbor several immunogenic neoantigens, the repertoire of mutation-specific T cells in patients might be restricted. To bypass suboptimal conditions, which impede the reactivation of existing T cells or the priming of neoantigen-specific T cells in a patient, we employ T cells of healthy donors with an overlapping HLA repertoire to target cancer neoantigens...
February 16, 2018: Oncotarget
Lisa M Ebert, Wenbo Yu, Tessa Gargett, Michael P Brown
Chimeric antigen receptor (CAR)-T cell therapy has been clinically validated as a curative treatment for the difficult to treat malignancies of relapsed/refractory B-cell acute lymphoblastic leukaemia and lymphoma. Here, the CAR-T cells are re-directed towards a single antigen, CD19, which is recognised as a virtually ideal CAR target antigen because it has strong, uniform expression on cancer cells, and is otherwise expressed only on healthy B cells, which are 'dispensable'. Notwithstanding the clinical success of CD19-CAR-T cell therapy, its single specificity has driven therapeutic resistance in 30% or more of cases with CD19-negative leukaemic relapses...
March 14, 2018: Biochemical Society Transactions
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
David A Schaer, Richard P Beckmann, Jack A Dempsey, Lysiane Huber, Amelie Forest, Nelusha Amaladas, Yanxia Li, Ying Cindy Wang, Erik R Rasmussen, Darin Chin, Andrew Capen, Carmine Carpenito, Kirk A Staschke, Linda A Chung, Lacey M Litchfield, Farhana F Merzoug, Xueqian Gong, Philip W Iversen, Sean Buchanan, Alfonso de Dios, Ruslan D Novosiadly, Michael Kalos
Abemaciclib, an inhibitor of cyclin dependent kinases 4 and 6 (CDK4/6), has recently been approved for the treatment of hormone receptor-positive breast cancer. In this study, we use murine syngeneic tumor models and in vitro assays to investigate the impact of abemaciclib on T cells, the tumor immune microenvironment and the ability to combine with anti-PD-L1 blockade. Abemaciclib monotherapy resulted in tumor growth delay that was associated with an increased T cell inflammatory signature in tumors. Combination with anti-PD-L1 therapy led to complete tumor regressions and immunological memory, accompanied by enhanced antigen presentation, a T cell inflamed phenotype, and enhanced cell cycle control...
March 13, 2018: Cell Reports
Xuyao Zhang, Wei Chen, Jiajun Fan, Shaofei Wang, Zongshu Xian, Jingyun Luan, Yubin Li, Yichen Wang, Yanyang Nan, Man Luo, Song Li, Wenzhi Tian, Dianwen Ju
CD47-targeting immune checkpoint inhibitors have been investigated for immunotherapy of several cancers, glioblastoma, one of the most common tumors in brain, was still a challenge for CD47-targeting therapy. Herein, we reported novel strategies for glioblastoma therapy via blocking CD47-SIRPα by SIRPα-Fc alone or in combination with autophagy inhibition. Our results showed that SIRPα-Fc increased macrophages-triggered cytotoxicity and phagocytosis of glioblastoma cells then elicited potent anti-tumor efficacy...
March 10, 2018: Carcinogenesis
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
Mei Zhang, Julian A Kim, Alex Yee-Chen Huang
Immunotherapy is revolutionizing cancer treatment. Recent clinical success with immune checkpoint inhibitors, chimeric antigen receptor T-cell therapy, and adoptive immune cellular therapies has generated excitement and new hopes for patients and investigators. However, clinically efficacious responses to cancer immunotherapy occur only in a minority of patients. One reason is the tumor microenvironment (TME), which potently inhibits the generation and delivery of optimal antitumor immune responses. As our understanding of TME continues to grow, strategies are being developed to change the TME toward one that augments the emergence of strong antitumor immunity...
2018: Frontiers in Immunology
Xuanwei Zhang, Gabriele Niedermann
PURPOSE: Hypofractionated radiation therapy (hRT) combined with immune checkpoint blockade can induce T-cell-mediated local and abscopal antitumor effects. We had previously observed peak levels of tumor-infiltrating lymphocytes (TILs) between days 5 and 8 after hRT. Because TILs are regarded as radiosensitive, hRT schedules extending into this period might be less immunogenic, prompting us to compare clinically relevant, short and extended schedules with equivalent biologically effective doses combined with anti-programmed cell death 1 (PD1) antibody treatment...
February 3, 2018: International Journal of Radiation Oncology, Biology, Physics
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
Giulia C Leonardi, Luca Falzone, Rossella Salemi, Antonino Zanghì, Demetrios A Spandidos, James A Mccubrey, Saverio Candido, Massimo Libra
In less than 10 years, melanoma treatment has been revolutionized with the approval of tyrosine kinase inhibitors and immune checkpoint inhibitors, which have been shown to have a significant impact on the prognosis of patients with melanoma. The early steps of this transformation have taken place in research laboratories. The mitogen‑activated protein kinase (MAPK) pathway, phosphoinositol‑3‑kinase (PI3K) pathway promote the development of melanoma through numerous genomic alterations on different components of these pathways...
April 2018: International Journal of Oncology
Theresa L Whiteside
Regulatory T cells (Treg) characterized by expression of FOXP3 and strong immunosuppressive activity play a key role in regulating homeostasis in health and disease. Areas covered: Human Treg are highly diverse phenotypically and functionally. In the tumor microenvironment (TME), Treg are reprogrammed by the tumor, acquiring an activated phenotype and enhanced suppressor functions. No unique phenotypic markers for Treg accumulating in human tumors exist. Treg are heterogeneous and use numerous mechanisms to mediate suppression, which either silences anti-tumor immune surveillance or prevents tissue damage by activated T cells...
March 13, 2018: Expert Opinion on Therapeutic Targets
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
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