scholarly journals Immune checkpoint inhibitor combination therapies very frequently induce secondary adrenal insufficiency

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Katsunori Manaka ◽  
Junichiro Sato ◽  
Maki Takeuchi ◽  
Kousuke Watanabe ◽  
Hidenori Kage ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Adrenal Insufficiency ◽  
Cancer Patients ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Delayed Diagnosis ◽  
Secondary Adrenal Insufficiency ◽  
Acth Deficiency ◽  
Life Threatening ◽  
Inhibitor Combination

AbstractImmune checkpoint inhibitors (ICIs) are potent therapeutic options for many types of advanced cancer. The expansion of ICIs use however has led to an increase in immune-related adverse events (irAEs). Secondary adrenal insufficiency (AI) can be life-threatening especially in patients with delayed diagnosis. We retrospectively investigated secondary AI in ICI-treated patients. A total of 373 cancer patients treated with ICIs were included and evaluated. An adrenocorticotropic hormone (ACTH) deficiency was described in 13 patients. Among 24 patients with a combination of nivolumab and ipilimumab therapy, 7 patients (29%) developed secondary AI in a median time of 8 weeks during the combination therapy and 2 of 15 patients (13%) developed isolated ACTH deficiency during maintenance nivolumab monotherapy following the combination therapy. More than half of the patients (4/7) with a combination therapy-induced multiple anterior hormone deficiencies was diagnosed as secondary AI based on regular ACTH and cortisol tests with slight subjective symptoms. Secondary AI can arise frequently and rapidly in cancer patients receiving a combination ICI therapy, and thus we speculate active surveillance of AI using regular ACTH and cortisol tests during the combination therapy might be useful for avoiding life-threatening conditions due to secondary AI.

scholarly journals SAT-242 Isolated Adrenocorticotropic Hormone Deficiency Secondary to the PD-1 Inhibitor Pembrolizumab

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Justin Mathew ◽  
Priyanka Mathias ◽  
Noah Bloomgarden
Keyword(s):  
Adrenal Insufficiency ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Hormone Deficiency ◽  
Immune Checkpoints ◽  
Laboratory Evaluation ◽  
Advanced Malignancy ◽  
Isolated Acth Deficiency ◽  
Acth Deficiency

Abstract Background: Immune checkpoint inhibitors (ICI’s) are now indicated in the treatment of several solid tumors and have improved the prognosis of patients with advanced malignancy. The expanded use of ICI’s has led to the rise of otherwise rare autoimmune sequelae. The overall incidence of ICI-induced autoimmune hypophysitis has increased to approximately 10%, but is only estimated to be 0.4% with PD-1 inhibitors specifically (1). Isolated ACTH deficiency from immune checkpoint inhibitors is rare, and very few cases secondary to the PD-1 inhibitor pembrolizumab have thus far been reported. Clinical Case: A 75-year old woman with history of Stage IV lung adenocarcinoma presented to oncology clinic in July 2019 with progressive weakness, weight loss, and confusion for several weeks. She was found to be hypotensive and dehydrated in the clinic and subsequently was admitted to the hospital. A comprehensive infectious work-up was non-contributory. History revealed that after treatment failure with carboplatin, she was treated with pembrolizumab from January 2017 to June 2019 with excellent response. Laboratory evaluation on admission demonstrated an undetectable AM cortisol level of < 1 ug/dL (n 5-25 ug/dL) with concomitant ACTH < 5pg/mL (Roche cobas, n 7.2-63 pg/mL), consistent with central adrenal insufficiency. Testing of the remainder of the pituitary axis, including TSH (0.83uU/mL, n 0.4-4.6 uU/mL), FSH (34.7 mIU/mL, n <150mIU/mL), LH (12.6mIU/mL, n <60 mIU/mL), and IGF-1 (33ng/mL, n 34-245ng/mL), all returned within normal limits. Further chart review verified that she had not been exposed to any form of glucocorticoids within the past 6 months. MRI brain with contrast demonstrated no obvious pituitary disease. The patient was started on 5mg of prednisone daily, with significant improvement in mental status, appetite, and blood pressure. She was discharged home on maintenance prednisone for adrenal insufficiency due to presumed isolated corticotroph destruction. Conclusions: Isolated ACTH deficiency is a very rare but potential consequence of pembrolizumab use. It can be especially difficult to diagnose in patients on chemotherapy who are at higher risk for dehydration and failure to thrive. Duration of pembrolizumab therapy should not preclude the diagnosis of isolated ACTH deficiency, as it can occur even as late as 2.5 years into therapy. Reference: (1) Chang, L., Barroso-Sousa, R., Tolaney S., Hodi F.S., Kaiser, U.B., Min, L. Endocrine Toxicity of Cancer Immunotherapy Targeting Immune Checkpoints, Endocr Rev. 2019;40;17–65.

scholarly journals Results from a Meta-analysis of Combination of PD-1/PD-L1 and CTLA-4 Inhibitors in Malignant Cancer Patients: Does PD-L1 Matter?

2021 ◽  
Vol 12 ◽  
Author(s):  
Yuqian Feng ◽  
Huimin Jin ◽  
Kaibo Guo ◽  
Yuying Xiang ◽  
Yiting Zhang ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Cancer Patients ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Malignant Tumors ◽  
Checkpoint Inhibitors ◽  
Meta Analysis ◽  
Objective Response ◽  
Progression Free Survival ◽  
Combination Immunotherapy

Background: Combination therapy with immune checkpoint inhibitors (ICIs) has been widely used for clinical treatment in recent years, which has a better survival benefit. However, not all patients can derive clinical benefit from combination immunotherapy. Therefore, it is necessary to explore the biomarkers of combination immunotherapy.Methods: We retrieved articles from electronic databases including PubMed, EMBASE and Cochrane. The statistical analysis was performed using RevMan software. Progression free survival (PFS), overall survival (OS) and objective response rate (ORR) were the outcome indicators. In the unselect population, we compared combination therapy with other treatments. In addition, we also conducted subgroup analysis on PFS, OS and ORR according to PD-L1 status.Results: Seven studies were included in the analysis for a total of 3,515 cases. In the unselected population, we found that combination therapy has longer PFS, OS, and better ORR than other treatments for cancer patients. The longer PFS was showed in PD-L1 ≥ 5% cases (HR = 0.64, 95% CI: 0.56–0.76; p < 0.001) than PD-L1 ≥ 1% cases (HR = 0.72, 95% CI: 0.66–0.79; p < 0.001), while ORR and OS have not related to the status of PD-L1.Conclusion: This study supported the efficacy of combination therapy with immune checkpoint inhibitors (ICIs), and also showed that PFS in patients with malignant tumors is positively correlated with PD-L1 expression. Due to the limited number of trials included, more high-quality clinical randomized controlled trials should be conducted to confirm the review findings.

scholarly journals De novo necroptosis creates an inflammatory environment mediating tumor susceptibility to immune checkpoint inhibitors

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Samuel T. Workenhe ◽  
Andrew Nguyen ◽  
David Bakhshinyan ◽  
Jiarun Wei ◽  
David N. Hare ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cell ◽  
Combination Therapy ◽  
Cancer Patients ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
De Novo ◽  
Checkpoint Inhibitors ◽  
Cytotoxic T Cell ◽  
Cell Infiltrate

Abstract Cancer immunotherapies using monoclonal antibodies to block inhibitory checkpoints are showing durable remissions in many types of cancer patients, although the majority of breast cancer patients acquire little benefit. Human melanoma and lung cancer patient studies suggest that immune checkpoint inhibitors are often potent in patients that already have intratumoral T cell infiltrate; although it remains unknown what types of interventions can result in an intratumoral T cell infiltrate in breast cancer. Using non-T cell-inflamed mammary tumors, we assessed what biological processes and downstream inflammation can overcome the barriers to spontaneous T cell priming. Here we show a specific type of combination therapy, consisting of oncolytic virus and chemotherapy, activates necroptosis and limits tumor growth in autochthonous tumors. Combination therapy activates proinflammatory cytokines; intratumoral influx of myeloid cells and cytotoxic T cell infiltrate in locally treated and distant autochthonous tumors to render them susceptible to immune checkpoint inhibitors.

scholarly journals A digital single-molecule nanopillar SERS platform for predicting and monitoring immune toxicities in immunotherapy

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Junrong Li ◽  
Alain Wuethrich ◽  
Abu A. I. Sina ◽  
Han-Hao Cheng ◽  
Yuling Wang ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Single Molecule ◽  
Immune Checkpoint ◽  
Inflammatory Responses ◽  
Checkpoint Inhibitors ◽  
Cytokine Detection ◽  
Dynamic Tracking ◽  
Highly Sensitive ◽  
Life Threatening ◽  
Melanoma Patients

AbstractThe introduction of immune checkpoint inhibitors has demonstrated significant improvements in survival for subsets of cancer patients. However, they carry significant and sometimes life-threatening toxicities. Prompt prediction and monitoring of immune toxicities have the potential to maximise the benefits of immune checkpoint therapy. Herein, we develop a digital nanopillar SERS platform that achieves real-time single cytokine counting and enables dynamic tracking of immune toxicities in cancer patients receiving immune checkpoint inhibitor treatment - broader applications are anticipated in other disease indications. By analysing four prospective cytokine biomarkers that initiate inflammatory responses, the digital nanopillar SERS assay achieves both highly specific and highly sensitive cytokine detection down to attomolar level. Significantly, we report the capability of the assay to longitudinally monitor 10 melanoma patients during immune inhibitor blockade treatment. Here, we show that elevated cytokine concentrations predict for higher risk of developing severe immune toxicities in our pilot cohort of patients.

Silent, isolated ACTH deficiency in malignant melanoma patients treated with immune checkpoint inhibitors

2021 ◽  
Vol 14 (5) ◽  
pp. e241981
Author(s):  
Ansgar Heck ◽  
Anna K Winge-Main
Keyword(s):  
Malignant Melanoma ◽  
Adrenal Insufficiency ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Adrenal Crisis ◽  
Suspected Case ◽  
Acth Deficiency ◽  
Melanoma Patients ◽  
Central Adrenal Insufficiency

Treatment with immune checkpoint inhibitors (ICI) has drastically improved the prognosis for melanoma patients, but immune-mediated adverse events can occur in any organ, including the pituitary. In ICI-induced hypophysitis, lymphocytic infiltration and hypersensitivity reactions cause headache and pituitary deficiency. Most cases with ICI-induced hypophysitis develop central adrenal insufficiency. Here, we describe three patients treated with anticytotoxic T-lymphocyte-associated protein 4 (ipilimumab) for metastatic malignant melanoma: case 1 was asymptomatic when hypocortisolism was suspected; case 2 had symptoms of hypocortisolism and suspected severe systemic infection; case 3 had unspecific fatigue. In all cases, routine cortisol measurements and clinical suspicion (cases 2 and 3) led to the diagnosis of adrenocortical hormone (ACTH) deficiency and thereby central adrenal insufficiency. Undiagnosed and untreated, central adrenal insufficiency results in adrenal crisis. In patients treated with ICI, particularly, ipilimumab, hypophysitis and ACTH deficiency must be considered if morning cortisol is low or unspecific clinical symptoms of hypocortisolism are present.

Hypophysitis due to Immune Checkpoint Inhibitors

2021 ◽  
Vol 5 (1) ◽  
pp. 01-07
Author(s):  
Sami Azar
Keyword(s):  
Adverse Events ◽  
Immune Checkpoint ◽  
Anterior Pituitary ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Pituitary Hormones ◽  
High Dose ◽  
Antineoplastic Drugs ◽  
Secondary Adrenal Insufficiency ◽  
Life Threatening

Immune checkpoint inhibitors are antineoplastic drugs associated with adverse events that result from unleashing the immune system against self-antigens while attacking neoplastic cells. Endocrinopathies are among the most common associated adverse events and hypophysitis is a frequent endocrine side effect of this treatment. We conducted a systematic search of the literature in 2 databases: PubMed and Medline. Articles that reported endocrine adverse events of immune checkpoint inhibitors were reviewed. Hypophysitis is most commonly seen with cytotoxic T-lymphocytes associated protein 4 (CTLA-4) inhibitors and can result in different anterior pituitary hormones deficiencies. Monitoring for this complication is of particular interest due to the life-threatening nature of secondary adrenal insufficiency and thyroid dysfunction if not promptly recognized and treated. Hypophysitis is the most common endocrinopathy seen and is usually treated by adequate hormonal replacement. The use of high dose corticosteroids has not been established as a treatment of this endocrine toxicity. Hormonal screening should be a part of baseline laboratory testing of all patients undergoing treatment with immune checkpoint inhibitors.

Abstract #514 Secondary Adrenal Insufficiency Due to the Immune Checkpoint Inhibitor Pembrolizumab

2019 ◽  
Vol 25 ◽  
pp. 256
Author(s):  
Mohammad Ansari ◽  
Ula Tarabichi ◽  
Hadoun Jabri ◽  
Qiang Nai ◽  
Anis Rehman ◽  
...  
Keyword(s):  
Adrenal Insufficiency ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Secondary Adrenal Insufficiency
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