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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.
Evaluating Immunotherapy in Nonmetastatic Colorectal Cancer.
Sinicrope, FA
Oncology (Williston Park, N.Y.). 2019;(5):178-80
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4.
Skin cancer precursor immunotherapy for squamous cell carcinoma prevention.
Rosenberg, AR, Tabacchi, M, Ngo, KH, Wallendorf, M, Rosman, IS, Cornelius, LA, Demehri, S
JCI insight. 2019;(6)
Abstract
BACKGROUND Topical calcipotriol plus 5-fluorouracil (5-FU) combination is an effective immunotherapy against actinic keratosis (AK), which is a precursor to squamous cell carcinoma (SCC). However, the long-term effectiveness of calcipotriol plus 5-FU treatment for SCC prevention is unknown. METHODS We performed a blinded prospective cohort study on participants of a randomized double-blind clinical trial in which a 4-day course of topical calcipotriol plus 5-FU combination was compared to Vaseline plus 5-FU (control) for AK treatment. SCC and basal cell carcinoma (BCC) incidences were assessed at 1, 2, and 3 years after trial. Tissues were analyzed for calcipotriol plus 5-FU-induced T cell immunity in the skin. RESULTS Calcipotriol plus 5-FU-induced tissue-resident memory T (Trm) cell formation in face and scalp skin associated with significantly higher erythema scores compared with control (P < 0.01). Importantly, more participants in the test cohort remained SCC-free over the more than 1,500-day follow-up period (P = 0.0765), and significantly fewer developed SCC on the treated face and scalp within 3 years (2 of 30 [7%] versus 11 of 40 [28%] in control group, hazard ratio 0.215 [95% CI: 0.048-0.972], P = 0.032). Accordingly, significantly more epidermal Trm cells persisted in the calcipotriol plus 5-FU-treated face and scalp skin compared with control (P = 0.0028). There was no significant difference in BCC incidence between the treatment groups. CONCLUSION A short course of calcipotriol plus 5-FU treatment on the face and scalp is associated with induction of robust T cell immunity and Trm formation against AKs and significantly lowers the risk of SCC development within 3 years of treatment. FUNDING This research was supported by internal academic funds and by grants from the Burroughs Wellcome Fund, Sidney Kimmel Foundation, Cancer Research Institute, and NIH.
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5.
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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6.
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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7.
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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8.
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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9.
Predictive value of skeletal muscle mass for immunotherapy with nivolumab in non-small cell lung cancer patients: A "hypothesis-generator" preliminary report.
Cortellini, A, Verna, L, Porzio, G, Bozzetti, F, Palumbo, P, Masciocchi, C, Cannita, K, Parisi, A, Brocco, D, Tinari, N, et al
Thoracic cancer. 2019;(2):347-351
Abstract
Sarcopenia represents one of the hallmarks of all chronic disease, including non-small cell lung cancer (NSCLC). A computed tomography scan is an easy modality to estimate the skeletal muscle mass through cross-sectional image analysis at the level of the third lumbar vertebra (L3). Baseline skeletal muscle mass (SMM) was evaluated using gender-specific cutoffs for skeletal muscle index in NSCLC patients administered immunotherapy with nivolumab to evaluate its possible correlations with clinical outcomes. From April 2015 to August 2018, 23 stage IV NSCLC patients were eligible for image analysis. Nine patients (39.1%) had low SMM. Among patients with baseline low and non-low SMM, median progression free survival was 3.1 and 3.8 months, respectively (P = 0.0560), while median overall survival was 4.1 and 13 months, respectively (P = 0.2866). This hypothesis-generating preliminary report offers the opportunity to speculate about the negative influence of sarcopenia on immune response. In our opinion, nutritional status could affect the clinical outcomes of immunotherapy, even if we cannot make definitive conclusions here. Further studies on the topic are required.
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10.
Serum very long-chain fatty acid-containing lipids predict response to immune checkpoint inhibitors in urological cancers.
Mock, A, Zschäbitz, S, Kirsten, R, Scheffler, M, Wolf, B, Herold-Mende, C, Kramer, R, Busch, E, Jenzer, M, Jäger, D, et al
Cancer immunology, immunotherapy : CII. 2019;(12):2005-2014
Abstract
Checkpoint inhibitors (CPI) have significantly changed the therapeutic landscape of oncology. We adopted a non-invasive metabolomic approach to understand immunotherapy response and failure in 28 urological cancer patients. In total, 134 metabolites were quantified in patient sera before the first, second, and third CPI doses. Modeling the association between metabolites and CPI response and patient characteristics revealed that one predictive metabolite class (n = 9/10) were very long-chain fatty acid-containing lipids (VLCFA-containing lipids). The best predictive performance was achieved through a multivariate model, including age and a centroid of VLCFA-containing lipids prior to first immunotherapy (sensitivity: 0.850, specificity: 0.825, ROC: 0.935). We hypothesize that the association of VLCFA-containing lipids with CPI response is based on enhanced peroxisome signaling in T cells, which results in a switch to fatty acid catabolism. Beyond use as a novel predictive non-invasive biomarker, we envision that nutritional supplementation with VLCFA-containing lipids might serve as an immuno sensitizer.