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1.
Gastrointestinal Tract Adverse Events.
Abu-Sbeih, H, Wang, Y
Advances in experimental medicine and biology. 2020;:247-253
Abstract
Immune checkpoint inhibitors (ICIs) have shown significant benefit in cancer patients. Their success, however, is associated with immune-related adverse events (irAEs), which commonly affect the gastrointestinal tract, resulting in diarrhea and colitis. IrAEs range from mild self-limiting to severe life-threatening diseases and potentially limit the use of these medications. Diagnosis of ICI-induced enterocolitis is based on clinical symptoms, physical examination, stool tests, endoscopic and histologic evaluation, and/or imaging. Current management strategy is mainly anti-diarrheal agents for mild symptoms and immunosuppressants (e.g., corticosteroids, and infliximab or vedolizumab) for more severe diseases.
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2.
T-cell agonists in cancer immunotherapy.
Choi, Y, Shi, Y, Haymaker, CL, Naing, A, Ciliberto, G, Hajjar, J
Journal for immunotherapy of cancer. 2020;(2)
Abstract
Cancer cells can evade immune surveillance in the body. However, immune checkpoint inhibitors can interrupt this evasion and enhance the antitumor activity of T cells. Other mechanisms for promoting antitumor T-cell function are the targeting of costimulatory molecules expressed on the surface of T cells, such as 4-1BB, OX40, inducible T-cell costimulator and glucocorticoid-induced tumor necrosis factor receptor. In addition, CD40 targets the modulation of the activation of antigen-presenting cells, which ultimately leads to T-cell activation. Agonists of these costimulatory molecules have demonstrated promising results in preclinical and early-phase trials and are now being tested in ongoing clinical trials. In addition, researchers are conducting trials of combinations of such immune modulators with checkpoint blockade, radiotherapy and cytotoxic chemotherapeutic drugs in patients with advanced tumors. This review gives a comprehensive picture of the current knowledge of T-cell agonists based on their use in recent and ongoing clinical trials.
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3.
Molecular imaging and advanced MRI findings following immunotherapy in patients with brain tumors.
Galldiks, N, Lohmann, P, Werner, JM, Ceccon, G, Fink, GR, Langen, KJ
Expert review of anticancer therapy. 2020;(1):9-15
Abstract
Introduction: Currently, immunotherapy using vaccination strategies or oncolytic virus approaches, cell-based immunotherapy, and the blockade of immune checkpoints are under evaluation in patients with brain cancer. Here we summarize clinically significant imaging findings such as treatment-related changes detected by advanced neuroimaging techniques following the most suitable immunotherapy options currently used in neuro-oncology. We, furthermore, provide an overview of how these advanced imaging techniques may help to overcome shortcomings of standard MRI in the assessment and follow-up of patients with brain cancer.Areas covered: The current literature on neuroimaging for immunotherapy in the field of brain tumors, with a focus on gliomas and brain metastases is summarized.Expert commentary: Data suggest that imaging parameters primarily derived from amino acid PET, diffusion- and perfusion-weighted MRI, or MR spectroscopy are particularly helpful for the evaluation of treatment response and provide valuable information for the differentiation of treatment-induced changes from actual brain tumor progression following various immunotherapy approaches.
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4.
Tumor infiltrating lymphocytes after neoadjuvant IRX-2 immunotherapy in oral squamous cell carcinoma: Interim findings from the INSPIRE trial.
Wolf, GT, Liu, S, Bellile, E, Sartor, M, Rozek, L, Thomas, D, Nguyen, A, Zarins, K, McHugh, JB, ,
Oral oncology. 2020;:104928
Abstract
OBJECTIVES IRX-2 is a primary-cell-derived immune-restorative consisting of multiple human cytokines that act to overcome tumor-mediated immunosuppression and provide an in vivo tumor vaccination to increase tumor infiltrating lymphocytes (TILs). A randomized phase II trial was conducted of the IRX regimen 3 weeks prior to surgery consisting of an initial dose of cyclophosphamide followed by 10 days of regional perilymphatic IRX-2 cytokine injections and daily oral indomethacin, zinc and omeprazole (Regimen 1) compared to the identical regimen without IRX-2 cytokines (Regimen 2). METHODS A total of 96 patients with previously untreated, stage II-IV oral cavity SCC were randomized 2:1 to experimental (1) or control (2) regimens (64:32). Paired biopsy and resection specimens from 62 patients were available for creation of tissue microarray (n = 39), and multiplex immunohistology (n = 54). Increases in CD8+ TIL infiltrate scores of at least 10 cells/mm2 were used to characterize immune responders (IR). RESULTS Regimen 1 was associated with significant increases in CD8+ infiltrates (p = 0.01) compared to Regimen 2. In p16 negative cancers (n = 26), significant increases in CD8+ and overall TILs were evident in Regimen 1 (p = 0.004, and 0.04 respectively). IRs were more frequent in Regimen 1 (74% vs 31%, p = 0.01). Multiplex immunohistology for PD-L1 expression confirmed an increase in PD-L1 H score for Regimen 1 compared to Regimen 2 (p = 0.11). CONCLUSIONS The findings demonstrate significant increases in TILs after perilymphatic IRX-2 injections. Three quarters of patients showed significant immune responses to IRX-2. (NCT02609386).
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5.
Competitive glucose metabolism as a target to boost bladder cancer immunotherapy.
Afonso, J, Santos, LL, Longatto-Filho, A, Baltazar, F
Nature reviews. Urology. 2020;(2):77-106
Abstract
Bladder cancer - the tenth most frequent cancer worldwide - has a heterogeneous natural history and clinical behaviour. The predominant histological subtype, urothelial bladder carcinoma, is characterized by high recurrence rates, progression and both primary and acquired resistance to platinum-based therapy, which impose a considerable economic burden on health-care systems and have substantial effects on the quality of life and the overall outcomes of patients with bladder cancer. The incidence of urothelial tumours is increasing owing to population growth and ageing, so novel therapeutic options are vital. Based on work by The Cancer Genome Atlas project, which has identified targetable vulnerabilities in bladder cancer, immune checkpoint inhibitors (ICIs) have arisen as an effective alternative for managing advanced disease. However, although ICIs have shown durable responses in a subset of patients with bladder cancer, the overall response rate is only ~15-25%, which increases the demand for biomarkers of response and therapeutic strategies that can overcome resistance to ICIs. In ICI non-responders, cancer cells use effective mechanisms to evade immune cell antitumour activity; the overlapping Warburg effect machinery of cancer and immune cells is a putative determinant of the immunosuppressive phenotype in bladder cancer. This energetic interplay between tumour and immune cells leads to metabolic competition in the tumour ecosystem, limiting nutrient availability and leading to microenvironmental acidosis, which hinders immune cell function. Thus, molecular hallmarks of cancer cell metabolism are potential therapeutic targets, not only to eliminate malignant cells but also to boost the efficacy of immunotherapy. In this sense, integrating the targeting of tumour metabolism into immunotherapy design seems a rational approach to improve the therapeutic efficacy of ICIs.
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6.
A Phase Ib Trial of Personalized Neoantigen Therapy Plus Anti-PD-1 in Patients with Advanced Melanoma, Non-small Cell Lung Cancer, or Bladder Cancer.
Ott, PA, Hu-Lieskovan, S, Chmielowski, B, Govindan, R, Naing, A, Bhardwaj, N, Margolin, K, Awad, MM, Hellmann, MD, Lin, JJ, et al
Cell. 2020;(2):347-362.e24
Abstract
Neoantigens arise from mutations in cancer cells and are important targets of T cell-mediated anti-tumor immunity. Here, we report the first open-label, phase Ib clinical trial of a personalized neoantigen-based vaccine, NEO-PV-01, in combination with PD-1 blockade in patients with advanced melanoma, non-small cell lung cancer, or bladder cancer. This analysis of 82 patients demonstrated that the regimen was safe, with no treatment-related serious adverse events observed. De novo neoantigen-specific CD4+ and CD8+ T cell responses were observed post-vaccination in all of the patients. The vaccine-induced T cells had a cytotoxic phenotype and were capable of trafficking to the tumor and mediating cell killing. In addition, epitope spread to neoantigens not included in the vaccine was detected post-vaccination. These data support the safety and immunogenicity of this regimen in patients with advanced solid tumors (Clinicaltrials.gov: NCT02897765).
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7.
Activating Antibodies to The Calcium-sensing Receptor in Immunotherapy-induced Hypoparathyroidism.
Lupi, I, Brancatella, A, Cetani, F, Latrofa, F, Kemp, EH, Marcocci, C
The Journal of clinical endocrinology and metabolism. 2020;(5)
Abstract
CONTEXT Immune checkpoint inhibitors (ICIs), such as programmed cell death protein-1 (PD-1), programmed cell death protein-ligand 1 (PD-L1), and cytotoxic T lymphocyte antigen-4 (CTLA-4) monoclonal antibodies, are approved for the treatment of some types of advanced cancer. Their main treatment-related side-effects are immune-related adverse events (irAEs), especially thyroid dysfunction and hypophysitis. Hypoparathyroidism, on the contrary, is an extremely rare irAE. OBJECTIVES The aim of the study was to investigate the etiology of autoimmune hypoparathyroidism in a lung cancer patient treated with pembrolizumab, an anti-PD-1. METHODS Calcium-sensing receptor (CaSR) autoantibodies, their functional activity, immunoglobulin (Ig) subclasses and epitopes involved in the pathogenesis of autoimmune hypoparathyroidism were tested. RESULTS The patient developed hypocalcemia after 15 cycles of pembrolizumab. Calcium levels normalized with oral calcium carbonate and calcitriol and no remission of hypocalcemia was demonstrated during a 9-month follow-up. The patient was found to be positive for CaSR-stimulating antibodies, of IgG1 and IgG3 subclasses, that were able to recognize functional epitopes on the receptor, thus causing hypocalcemia. CONCLUSION The finding confirms that ICI therapy can trigger, among other endocrinopathies, hypoparathyroidism, which can be caused by pathogenic autoantibodies.
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8.
Tumor hypermetabolism confers resistance to immunotherapy.
Liu, A, Curran, MA
Seminars in cancer biology. 2020;:155-163
Abstract
Advances in our understanding of tumor immune biology and development of cancer immunotherapies have led to improved outcomes for patients that suffer from aggressive cancers such as metastatic melanoma. Despite these advances, a significant proportion of patients still fail to benefit, and as a result, attention has shifted to understanding how cancer cells escape immune destruction. Of particular interest is the metabolic landscape of the tumor microenvironment, as recent studies have demonstrated how both competition for essential nutrients and depletion of specific amino acids can promote T cell dysfunction. Here, we will discuss the major energetic pathways engaged by both T cells and cancer cells, metabolic substrates present in the tumor microenvironment, and emerging therapeutic strategies that seek to improve T cell metabolic fitness and bolster the antitumor immune response.
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9.
Central nervous system injury from novel cancer immunotherapies.
Winter, SF, Vaios, EJ, Dietrich, J
Current opinion in neurology. 2020;(6):723-735
Abstract
PURPOSE OF REVIEW Neurotoxicity from antineoplastic treatment remains a challenge in oncology. Cancer treatment-induced central nervous system (CNS) injury can be therapy-limiting, severely disabling, and even fatal. While emerging cancer immunotherapies have revolutionized oncology during the past decade, their immunomodulatory properties can cause immune-related adverse effects (IRAE) across organ systems, including the nervous system. Central neurologic IRAEs from chimeric antigen receptor T cells (CAR-T) and immune checkpoint inhibitors (ICPI) are challenging complications of such therapies.We aim to provide clinicians with a comprehensive review of the relevant forms of CAR-T and ICPI-associated CNS toxicity, focusing on clinical features of such complications, diagnostic workup, predictive biomarkers, and management considerations in affected patients. RECENT FINDINGS Unique forms of CAR-T and ICPI-related CNS toxicity have been characterized in the recent literature. CAR-T-related neurotoxicity is common and clinically well delineated. ICPI-related CNS toxicity is relatively rare but includes a heterogenous spectrum of severe and diagnostically challenging conditions. While putative risk factors, neurotoxicity biomarkers, imaging correlates and treatment strategies have been put forward, development of tailored diagnostic and management consensus guidelines awaits further clinical investigation. SUMMARY As CAR-T and ICPI become more widely adopted, early recognition, documentation, and management of immunotherapy-related CNS toxicity are of paramount importance in the clinical setting.
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10.
[Thyroid dysfunctions secondary to cancer immunotherapy].
Cugnet Anceau, C, Abeillon, J, Maillet, D, Borson-Chazot, F, Disse, E
Bulletin du cancer. 2020;(2):262-271
Abstract
The immune checkpoint inhibitors (CPI) such as anti-PD(L)1 or anti-CTLA4 had improved long-term patients' outcomes in different malignancies. Thyroid disorders are the most frequent endocrine side effects from CPI reported in clinical trials and in clinical routine practice. The incidence of thyroid dysfunction is variable according to ICP used (more frequent under anti-programmed cell death 1 (PD1) or anti-programmed cell death-ligand 1 (PDL1)). Most thyroid dysfunctions have been reported to occur 2 to 4 courses after CPI initiation. The clinical symptoms are generally nonspecific (asthenia, weight change, rarely cardiac rhythm disorder). These thyroid dysfunctions are commonly painless thyroiditis with a biphasic evolution: thyrotoxicosis followed by a secondary hypothyroidism frequently definitive. Diagnosis is made on a thyroid test (TSH and FT4). In most cases, no further exam is necessary. Beta blockers therapy is recommended in symptomatic thyrotoxicosis with palpitations. Thyroid hormones therapy will be introduced quickly in case of hypothyroidism. Thyroid dysfunctions are not a contra-indication to the continuation of immunotherapy. Due to the high frequency of these complications, close monitoring of the thyroid status is recommended under CPI.