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          The flagship journal of the Society for Endocrinology. Learn more

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      Immunotherapy failure in adrenocortical cancer: where next?

      editorial

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          Abstract

          Immunotherapy is widely used in the treatment of different cancer types, including metastatic melanoma, non-small cell lung cancer, renal cell carcinoma and urothelial cancer. The results of the phase I JAVELIN study failed to demonstrate a substantial activity of the PDL-1 inhibitor Avelumab in advanced adrenocortical carcinoma (ACC). This editorial focus on the possible mechanisms of ACC immunoevasion and suggests strategies to overcome the intrinsic immunotherapy resistance of this disease.

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          Most cited references26

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          Immune Checkpoint Immunotherapy for Non-Small Cell Lung Cancer

          Karthik Suresh, Jarushka Naidoo, Cheng Lin … (2018)
          Immune checkpoint inhibitors (ICIs) are newer, immunotherapy-based drugs that have been shown to improve survival in advanced non-small cell lung cancer (NSCLC). Unlike traditional chemotherapeutic agents, ICIs work by boosting the body's natural tumor killing response. However, this unique mechanism of action has also led to the recognition of class-specific side effects. Labeled immune-related adverse events, these toxicities can affect multiple organ systems including the lungs. Immune-mediated lung injury because of ICI use, termed checkpoint inhibitor pneumonitis (CIP), occurs in about 3% to 5% of patients receiving ICIs; however, the real-world incidence of this entity may be higher, especially now that ICIs are being used in nonclinical trial settings. In this review, we briefly introduce the biology of ICIs and the indications for ICI use in NSCLC and then discuss the epidemiology and clinical and radiologic manifestations of CIP. Next, we discuss management strategies for CIP, including the current consensus on management of steroid-refractory CIP. Given the nascent nature of this field, we highlight areas of uncertainty and emerging research questions in the burgeoning field of checkpoint inhibitor pulmonary toxicity.
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            Tumor-Induced IL-6 Reprograms Host Metabolism to Suppress Anti-tumor Immunity

            Thomas R. Flint, Tobias Janowitz, Claire M Connell … (2016)
            Summary In patients with cancer, the wasting syndrome, cachexia, is associated with caloric deficiency. Here, we describe tumor-induced alterations of the host metabolic response to caloric deficiency that cause intratumoral immune suppression. In pre-cachectic mice with transplanted colorectal cancer or autochthonous pancreatic ductal adenocarcinoma (PDA), we find that IL-6 reduces the hepatic ketogenic potential through suppression of PPARalpha, the transcriptional master regulator of ketogenesis. When these mice are challenged with caloric deficiency, the resulting relative hypoketonemia triggers a marked rise in glucocorticoid levels. Multiple intratumoral immune pathways are suppressed by this hormonal stress response. Moreover, administering corticosterone to elevate plasma corticosterone to a level that is lower than that occurring in cachectic mice abolishes the response of mouse PDA to an immunotherapy that has advanced to clinical trials. Therefore, tumor-induced IL-6 impairs the ketogenic response to reduced caloric intake, resulting in a systemic metabolic stress response that blocks anti-cancer immunotherapy.
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              Avelumab in patients with previously treated metastatic adrenocortical carcinoma: phase 1b results from the JAVELIN solid tumor trial

              Christophe Le Tourneau, Christopher Hoimes, Corrine Zarwan … (2018)
              Background We assessed the efficacy and safety of avelumab, an anti-programmed death ligand 1 (PD-L1) antibody, in patients with previously treated metastatic adrenocortical carcinoma (mACC). Methods In this phase 1b expansion cohort, patients with mACC and prior platinum-based therapy received avelumab at 10 mg/kg intravenously every 2 weeks. Continuation of mitotane was permitted; however, mitotane levels during the study were not recorded. Tumor response was assessed by Response Evaluation Criteria In Solid Tumors v1.1. Results Fifty patients received avelumab and were followed for a median of 16.5 months. Prior treatment included ≥2 lines in 74.0%; mitotane was continued in 50.0%. The objective response rate (ORR) was 6.0% (95% CI, 1.3% to 16.5%; partial response in 3 patients). Twenty-one patients (42.0%) had stable disease as best response (disease control rate, 48.0%). Median progression-free survival was 2.6 months (95% CI, 1.4 to 4.0), median overall survival (OS) was 10.6 months (95% CI, 7.4 to 15.0), and the 1-year OS rate was 43.4% (95% CI, 27.9% to 57.9%). In evaluable patients with PD-L1+ (n = 12) or PD-L1− (n = 30) tumors (≥5% tumor cell cutoff), ORR was 16.7% vs 3.3% (P = .192). Treatment-related adverse events (TRAEs) occurred in 82.0%; the most common were nausea (20.0%), fatigue (18.0%), hypothyroidism (14.0%), and pyrexia (14.0%). Grade 3 TRAEs occurred in 16.0%; no grade 4 to 5 TRAEs occurred. Twelve patients (24.0%) had an immune-related TRAE of any grade, which were grade 3 in 2 patients (4.0%): adrenal insufficiency (n = 1), and pneumonitis (n = 1). Conclusions Avelumab showed clinical activity and a manageable safety profile in patients with platinum-treated mACC. Trial registration Clinicaltrials.gov NCT01772004; registered January 21, 2013. Electronic supplementary material The online version of this article (10.1186/s40425-018-0424-9) contains supplementary material, which is available to authorized users.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Endocr Connect
                Journal ID (iso-abbrev): Endocr Connect
                Journal ID (hwp): EC
                Title: Endocrine Connections
                Publisher: Bioscientifica Ltd (Bristol )
                ISSN (Electronic): 2049-3614
                Publication date Collection: December 2018
                Publication date (Electronic): 30 October 2018
                Volume: 7
                Issue: 12
                Pages: E5-E8
                Affiliations
                [1 ]Medical Oncology Unit , Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia, ASST Spedali Civili, Brescia, Italy
                [2 ]Section of Pharmacology , Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
                [3 ]Internal Medicine , Department of Clinical and Biological Sciences, San Luigi Hospital, University of Turin, Orbassano, Italy
                Author notes
                Correspondence should be addressed to A Berruti: alfredo.berruti@ 123456gmail.com
                Article
                Publisher ID: EC-18-0398
                DOI: 10.1530/EC-18-0398
                PMC ID: 6280582
                PubMed ID: 30400026
                SO-VID: a11e1606-3f58-4975-9bff-43e422abbd13
                Copyright © © 2018 The authors
                License:

                This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

                History
                Date received : 23 October 2018
                Date accepted : 30 October 2018
                Categories
                Subject: Editorial

                Data availability:

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