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1.
[Immunotherapy for head and neck cancer : Highlights of the 2019 ASCO Annual Meeting].
Doescher, J, Busch, CJ, Wollenberg, B, Dietz, A, Würdemann, N, Schuler, P, Hoffmann, TK, Laban, S
HNO. 2019;(12):905-911
Abstract
BACKGROUND In the field of immunotherapy of head and neck squamous cell carcinoma (HNSCC), a high level of study activity can still be observed. The results of the Keynote-048 study on first-line therapy with pembrolizumab were a highlight at this year's meeting of the American Society of Clinical Oncology (ASCO). MATERIALS AND METHODS All abstracts and presentations on immunotherapy of head and neck tumors presented at ASCO 2019 were evaluated for relevance and the most interesting studies were summarized. RESULTS The Keynote-048 study showed an improvement in overall survival with pembrolizumab monotherapy for patients with measurable programmed cell death ligand 1 (PD-L1) expression according to the combined positive score (CPS), and for the whole cohort with the combination of pembrolizumab and platin/5-fluorouracil (FU). The EAGLE study on durvalumab ± tremelimumab in second-line therapy did not demonstrate any improvement in response rates or overall survival compared to standard therapy. In addition, several new immunotherapeutic approaches and combinations were presented. CONCLUSION The results of the Keynote-048 study have already led to the approval of pembrolizumab in the first line for platin-sensitive HNSCC in the USA and the expected approval in Europe will presumably change the therapeutic landscape in the long term. In the future, effective therapies for patients without a response to programmed cell death 1 (PD-1)/PD-L1 inhibition will be needed.
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2.
Neoplasia and intraocular inflammation: From masquerade syndromes to immunotherapy-induced uveitis.
Touhami, S, Audo, I, Terrada, C, Gaudric, A, LeHoang, P, Touitou, V, Bodaghi, B
Progress in retinal and eye research. 2019;:100761
Abstract
Masquerade syndromes represent a large set of ophthalmological entities that mimic inflammatory conditions. Any delay in their diagnosis may be correlated with systemic dissemination or worsening of the causal disease and, therefore, with poor prognosis. One of the disadvantages of the new potent treatments of uveitis is the delay that they can induce in the diagnosis of neoplastic intraocular infiltrations. Thorough and careful clinical examination of all patients referred for uveitis, especially when they are Caucasian, over 50 years of age, and with posterior segment involvement, is of paramount importance in this context. Ancillary investigations and often-invasive histo-pathologic evaluation of tissue specimens or ocular fluids are regularly required in these situations. The most common masquerade syndrome is primary vitreoretinal lymphoma (PVRL). New molecular diagnostic tools may be helpful in challenging cases lacking cytological confirmation. Therapeutic strategies targeting tumoral cells in the eye and also in the central nervous system can improve the life expectancy of affected patients. In this review, we discuss diagnostic strategies and current therapies in PVRL and provide an overview of other conditions that can mimic primary ocular inflammation, especially in the field of oncology and its new therapeutic armamentarium.
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3.
Hepatotoxicity of immune check point inhibitors: Approach and management.
Lleo, A, Rimassa, L, Colombo, M
Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver. 2019;(8):1074-1078
Abstract
Therapeutic reversal of immune tolerance following immune checkpoint inhibitors (ICPI) administration, has proven effective in prolonging survival of patients with a variety of solid and liquid tumors, often however at the expenses of discrete toxicities known as immune-related adverse events (AEs). Such reactions result from activation of the immune system and often present with generalized symptoms including fatigue or fever and, in some patients, may cause organ-specific damage. Skin, gut, endocrine, lung and musculoskeletal are the most frequent targets of ICPI toxicity whereas, cardiovascular, hematologic, renal, neurologic and ophthalmologic AEs occur much less frequently. While the majority of AEs are mild to moderate, serious, occasionally life-threatening reactions have been reported, including severe colitis, pneumonitis, encephalitis, toxic epidermal necrolysis, myocarditis, and diabetic ketoacidosis, with a death toll of 2%. Hepatocellular carcinoma (HCC) is becoming an attractive area for immunotherapy. Owing to the fact that the association of HCC with cirrhosis may jeopardize tolerability of ICPI therapy, attention has been paid to identifying, preventing, and treating the AEs associated with ICPI, with a focus on liver safety. Though in most studies AEs resolved with interruption of treatment and short course of steroids, identification of predictive biomarkers of response might help sparing patients from potentially life-threatening toxicity in the absence of clinical benefit.
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4.
Navigating metabolic pathways to enhance antitumour immunity and immunotherapy.
Li, X, Wenes, M, Romero, P, Huang, SC, Fendt, SM, Ho, PC
Nature reviews. Clinical oncology. 2019;(7):425-441
Abstract
The development of immunotherapies over the past decade has resulted in a paradigm shift in the treatment of cancer. However, the majority of patients do not benefit from immunotherapy, presumably owing to insufficient reprogramming of the immunosuppressive tumour microenvironment (TME) and thus limited reinvigoration of antitumour immunity. Various metabolic machineries and nutrient-sensing mechanisms orchestrate the behaviour of immune cells in response to nutrient availability in the TME. Notably, tumour-infiltrating immune cells typically experience metabolic stress as a result of the dysregulated metabolic activity of tumour cells, leading to impaired antitumour immune responses. Moreover, the immune checkpoints that are often exploited by tumour cells to evade immunosurveillance have emerging roles in modulating the metabolic and functional activity of T cells. Thus, repurposing of drugs targeting cancer metabolism might synergistically enhance immunotherapy via metabolic reprogramming of the TME. In addition, interventions targeting the metabolic circuits that impede antitumour immunity have been developed, with several clinical trials underway. Herein, we discuss how these metabolic circuits regulate antitumour immunity and the possible approaches to targeting these pathways in the context of anticancer immunotherapy. We also describe hypothetical combination treatments that could be used to better unleash the potential of adoptive cell therapies by enhancing T cell metabolism.
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5.
Metabolism and Gut Microbiota in Cancer Immunoediting, CD8/Treg Ratios, Immune Cell Homeostasis, and Cancer (Immuno)Therapy: Concise Review.
Kareva, I
Stem cells (Dayton, Ohio). 2019;(10):1273-1280
Abstract
The concept of immunoediting, a process whereby the immune system eliminates immunogenic cancer cell clones, allowing the remaining cells to progress and form a tumor, has evolved with growing appreciation of the importance of cancer ecology on tumor progression. As cancer cells grow and modify their environment, they create spatial and nutrient constraints that may affect not only immune cell function but also differentiation, tipping the balance between cytotoxic and regulatory immunity to facilitate tumor growth. Here, we review how immunometabolism may contribute to cancer escape from the immune system, as well as highlight an emerging role of gut microbiota, its effects on the immune system and on response to immunotherapy. We conclude with a discussion of how these pieces can be integrated to devise better combination therapies and highlight the role of computational approaches as a potential tool to aid in combination therapy design. Stem Cells 2019;37:1273-1280.
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6.
Messenger RNA therapy for rare genetic metabolic diseases.
Berraondo, P, Martini, PGV, Avila, MA, Fontanellas, A
Gut. 2019;(7):1323-1330
Abstract
Decades of intense research in molecular biology and biochemistry are fructifying in the emergence of therapeutic messenger RNAs (mRNA) as a new class of drugs. Synthetic mRNAs can be sequence optimised to improve translatability into proteins, as well as chemically modified to reduce immunogenicity and increase chemical stability using naturally occurring uridine modifications. These structural improvements, together with the development of safe and efficient vehicles that preserve mRNA integrity in circulation and allow targeted intracellular delivery, have paved the way for mRNA-based therapeutics. Indeed, mRNAs formulated into biodegradable lipid nanoparticles are currently being tested in preclinical and clinical studies for multiple diseases including cancer immunotherapy and vaccination for infectious diseases. An emerging application of mRNAs is the supplementation of proteins that are not expressed or are not functional in a regulated and tissue-specific manner. This so-called 'protein replacement therapy' could represent a solution for genetic metabolic diseases currently lacking effective treatments. Here we summarise this new class of drugs and discuss the preclinical evidence supporting the potential of liver-mediated mRNA therapy for three rare genetic conditions: methylmalonic acidaemia, acute intermittent porphyria and ornithine transcarbamylase deficiency.
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7.
The Changing Landscape of Systemic Treatment of Advanced Hepatocellular Carcinoma: New Targeted Agents and Immunotherapies.
Marquardt, JU, Saborowski, A, Czauderna, C, Vogel, A
Targeted oncology. 2019;(2):115-123
Abstract
Hepatocellular carcinoma (HCC) is one of the most common and deadliest cancers worldwide with a rising incidence in the Western world. HCCs are characterized by high resistance to systemic therapies induced by phenotypic and molecular heterogeneity. For almost 10 years, the tyrosine kinase inhibitor sorafenib was the only approved treatment for advanced HCCs in patients with preserved liver function, and until 2016, no new compounds tested in large phase III studies have led to a survival benefit. The tyrosine kinase inhibitor regorafenib, a fluorinated sorafenib analog, was the first substance that showed a significant improvement in overall survival after failure of sorafenib treatment, which subsequently led to its regulatory approval in a second-line setting in 2017. In addition, the non-inferiority of lenvatinib in comparison with sorafenib opened another therapeutic first-line option in the same year. Furthermore, several other compounds showed promising results in recent phase III studies, including ramucirumab in patients with elevated alpha-fetoprotein (AFP) levels as well as cabozantinib in second- and third-line settings. In addition, promising early reports of the immune checkpoint inhibitors nivolumab and pembrolizumab, with objective response rates of 15-20%, paved the way for immuno-oncological interventions for HCC and these will probably gain increasing attention as mono- and combination therapies. In summary, following the approval of sorafenib in 2007 and almost 10 years of therapeutic stagnation, results from recent clinical trials in first- and further-line settings for the first time demonstrated efficacy of several active compounds in advanced HCCs. Thus, a sequential approach should now be implemented in HCC treatment and will improve the survival of HCC patients.
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8.
Molecular targeted and immune checkpoint therapy for advanced hepatocellular carcinoma.
Liu, Z, Lin, Y, Zhang, J, Zhang, Y, Li, Y, Liu, Z, Li, Q, Luo, M, Liang, R, Ye, J
Journal of experimental & clinical cancer research : CR. 2019;(1):447
Abstract
Molecular targeted therapy for advanced hepatocellular carcinoma (HCC) has changed markedly. Although sorafenib was used in clinical practice as the first molecular targeted agent in 2007, the SHARPE and Asian-Pacific trials demonstrated that sorafenib only improved overall survival (OS) by approximately 3 months in patients with advanced HCC compared with placebo. Molecular targeted agents were developed during the 10-year period from 2007 to 2016, but every test of these agents from phase II or phase III clinical trial failed due to a low response rate and high toxicity. In the 2 years after, 2017 through 2018, four successful novel drugs emerged from clinical trials for clinical use. As recommended by updated Barcelona Clinical Liver cancer (BCLC) treatment algorithms, lenvatinib is now feasible as an alternative to sorafenib as a first-line treatment for advanced HCC. Regorafenib, cabozantinib, and ramucirumab are appropriate supplements for sorafenib as second-line treatment for patients with advanced HCC who are resistant, show progression or do not tolerate sorafenib. In addition, with promising outcomes in phase II trials, immune PD-1/PD-L1 checkpoint inhibitors nivolumab and pembrolizumab have been applied for HCC treatment. Despite phase III trials for nivolumab and pembrolizumab, the primary endpoints of improved OS were not statistically significant, immune PD-1/PD-L1 checkpoint therapy remains to be further investigated. This review summarizes the development and progression of molecular targeted and immune-based checkpoint therapies in HCC.
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9.
The Gut Microbiota in Causation, Detection, and Treatment of Cancer.
Murphy, CL, OʼToole, PW, Shanahan, F
The American journal of gastroenterology. 2019;(7):1036-1042
Abstract
The gut microbiota has emerged as an important consideration in clinical oncology. The role of the microbiome in cancer extends beyond causation and cancer risk. It is now known that the microbiome not only acts at a local epithelial level in the gut but also modifies immune responses within intestinal and extraintestinal tumors. Microbial signaling influences the clinical course of cancer including the efficacy, bioavailability, and toxicity of chemotherapeutic and immunotherapy agents. This has focused research on microbiota profiling in different cancer states with an aim of developing prognostic biomarkers of risk. The potential value of microbiome manipulation with live biotherapeutics or microbial transplantation has also become a realistic consideration. Maintenance of microbial diversity in patients with cancer is a variable challenge given the modifying influences of the tumor itself, chemotherapy, nutritional status, and sporadic antimicrobial therapy. Here, we address current evidence for the role of the microbiome in cancer therapy.
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10.
Expert opinion on pituitary complications in immunotherapy.
Briet, C, Albarel, F, Kuhn, E, Merlen, E, Chanson, P, Cortet, C
Annales d'endocrinologie. 2018;(5):562-568
Abstract
Hypophysitis is a frequent toxic endocrine side-effect of immunotherapy. Prevalence is higher with anti-CTLA-4 antibodies (4-20%) or in association with PD-1 inhibitors (8%). Diagnosis is presumptive, based on poorly specific clinical symptoms (usually, headache and asthenia) and/or hyponatremia and/or at least one pituitary deficit and/or abnormal imaging. Visual disorder or polyuropolydipsic syndrome are exceptional. In decreasing order of frequency, deficits are thyrotropic (86-100%), gonadotropic (85-100%) or corticotropic (50-73%); somatotropin deficit or abnormal prolactin level are rarer. Pituitary MRI in acute phase shows variable moderate increase in pituitary volume, ruling out differential diagnoses, especially pituitary metastasis. Treatment of corticotropin deficiency requires systematic emergency replacement therapy, with the usual modalities, while treatment of other deficits depends on clinical status and progression. Thyrotropin and gonadotropin deficits usually recover, but corticotropin deficiency persists over the long term, requiring education and specialized endocrinologic follow-up. Onset of hypophysitis does not contraindicate continuation of immunotherapy and does not usually require high dose synthetic glucocorticoids.