Nivolumab in Metastatic Adrenocortical Carcinoma: Results of a Phase 2 Trial

Carneiro, Benedito A.; Konda, Bhavana; Costa, Rubens B.; Costa, Ricardo; Sagar, Vinay; Gursel, Demirkan; Kirschner, Lawrence S.; Chae, Young Kwang; Abdulkadir, Sarki A.; Rademaker, Alfred; Mahalingam, Devalingam; Shah, Manisha H.; Giles, Francis J.

doi:10.1210/jc.2019-00600

Cited by 89 publications

(69 citation statements)

References 23 publications

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“…31 However, so far, four small studies with a total of 115 patients have been published in ACC and overall the results were disappointing; only 15 patients experienced partial response and 12 long-term disease control for more than 12 months. [7][8][9][10] Our study may shed some light, why strong immune infiltration is rarely seen in ACC and why current immunological therapeutic options were of limited efficacy. The fact that we found a negative correlation of tumorassociated glucocorticoid excess and T helper cells supports an expected role of steroids in this context.…”

Section: Discussionmentioning

confidence: 81%

“…36 Our study might provide at least three potential explanations for the disappointing results of the first trials with checkpoint inhibitors in ACC. [7][8][9][10] (i) Many ACC are probably infiltrated by too few or no helper and cytotoxic T cells that would allow flaring up an antitumor response by checkpoint inhibitors. (ii) The fact that metastatic lesions are in average even 'colder' than the primary tumors suggests that immune escape mechanisms are even more developed in advanced ACC increasing the challenge for immunotherapies.…”

Section: Open Accessmentioning

confidence: 99%

“…Results of the first (small) trials with immunotherapy in ACC are modest, with a median progression-free survival times of 1.8, 2.1, 2.6 and 6.75 months, respectively. [7][8][9][10] However, in one study with 39 patients, disease control rate was 52% and interestingly median overall survival reached almost 25 months clearly suggesting that at least a subset of patients benefits from this therapeutic approach.…”

Section: Introductionmentioning

confidence: 99%

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Interplay between glucocorticoids and tumor-infiltrating lymphocytes on the prognosis of adrenocortical carcinoma

Landwehr

Altieri

Schreiner

et al. 2020

J Immunother Cancer

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BackgroundAdrenocortical carcinoma (ACC) is a rare endocrine malignancy. Tumor-related glucocorticoid excess is present in ~60% of patients and associated with particularly poor prognosis. Results of first clinical trials using immune checkpoint inhibitors were heterogeneous. Here we characterize tumor-infiltrating T lymphocytes (TILs) in ACC in association with glucocorticoids as potential explanation for resistance to immunotherapy.MethodsWe performed immunofluorescence analysis to visualize tumor-infiltrating T cells (CD3+), T helper cells (CD3+CD4+), cytotoxic T cells (CD3+CD8+) and regulatory T cells (Tregs; CD3+CD4+FoxP3+) in 146 ACC tissue specimens (107 primary tumors, 16 local recurrences, 23 metastases). Quantitative data of immune cell infiltration were correlated with clinical data (including glucocorticoid excess).Results86.3% of ACC specimens showed tumor infiltrating T cells (7.7 cells/high power field (HPF)), including T helper (74.0%, 6.7 cells/HPF), cytotoxic T cells (84.3%, 5.7 cells/HPF) and Tregs (49.3%, 0.8 cells/HPF). The number of TILs was associated with better overall survival (HR for death: 0.47, 95% CI 0.25 to 0.87), which was true for CD4+− and CD8+subpopulations as well. In localized, non-metastatic ACC, the favorable impact of TILs on overall and recurrence-free survival was manifested even independently of ENSAT (European Network for the Study of Adrenal Tumors) stage, resection status and Ki67 index. T helper cells were negatively correlated with glucocorticoid excess (Phi=−0.290, p=0.009). Patients with glucocorticoid excess and low TILs had a particularly poor overall survival (27 vs. 121 months in patients with TILs without glucocorticoid excess).ConclusionGlucocorticoid excess is associated with T cell depletion and unfavorable prognosis. To reactivate the immune system in ACC by checkpoint inhibitors, an inhibition of adrenal steroidogenesis might be pivotal and should be tested in prospective studies.

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Section: Discussionmentioning

confidence: 81%

Section: Open Accessmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Interplay between glucocorticoids and tumor-infiltrating lymphocytes on the prognosis of adrenocortical carcinoma

Landwehr

Altieri

Schreiner

et al. 2020

J Immunother Cancer

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“…Finally, treating ACCs with mitotane has significant limitations of treatment, and it is well recognized that novel treatment options, such as anti-PD-1-treatment employing nivolumab (47), are urgently awaited. However, anti-PD-1-based approaches may rely on the necroinflammatory capacity of necrosis (26), e.g., as driven by ferroptosis, as demonstrated in models of myocardial necrosis (48,49).…”

Section: Discussionmentioning

confidence: 99%

Exquisite sensitivity of adrenocortical carcinomas to induction of ferroptosis

Belavgeni

Bornstein

Mäßenhausen

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Adrenocortical carcinomas (ACCs) are rare and highly malignant cancers associated with poor survival of patients. Currently, mitotane, a nonspecific derivative of the pesticide DDT (1,1-(dichlorobiphenyl)-2,2-dichloroethane), is used as the standard treatment, but its mechanism of action in ACCs remains elusive. Here we demonstrate that the human ACC NCI-H295R cell line is remarkably sensitive to induction of ferroptosis, while mitotane does not induce this iron-dependent mode of regulated necrosis. Supplementation with insulin, transferrin, and selenium (ITS) is commonly used to keep NCI-H295R cells in cell culture. We show that this supplementation prevents spontaneous ferroptosis, especially when it contains polyunsaturated fatty acids (PUFAs), such as linoleic acid. Inhibitors of apoptosis (zVAD, emricasan) do not prevent the mitotane-induced cell death but morphologically prevent membrane blebbing. The expression of glutathione peroxidase 4 (GPX4) in H295R cells, however, is significantly higher when compared to HT1080 fibrosarcoma cells, suggesting a role for ferroptosis. Direct inhibition of GPX4 in H295R cells led to high necrotic populations compared to control, while cotreatment with ferrostatin-1 (Fer-1) completely reverted ferroptosis. Interestingly, the analysis of public databases revealed that several key players of the ferroptosis pathway are hypermethylated and/or mutated in human ACCs. Finally, we also detected that growth hormone-releasing hormone (GHRH) antagonists, such as MIA602, kill H295R cells in a nonapoptotic manner. In summary, we found elevated expression of GPX4 and higher sensitivity to ferroptosis in ACCs. We hypothesize that instead of treatment with mitotane, human adrenocortical carcinomas may be much more sensitive to induction of ferroptosis.

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“…One trial demonstrated survival benefit for patients with borderline resectable tumors; 15 patients received preoperative chemotherapy and 13 (86%) underwent surgical resection and experienced a trend towards improved median disease-free survival (28.0 months vs. 13 months; p=ns) when compared to the surgery alone group [10]. Further, although studies evaluating the benefit of immunotherapy for ACC have been somewhat disappointing, some have reported modest responses in patients with metastatic ACC [11,12]. Preoperative chemotherapy and possibly the addition of nivolumab in this patient's treatment were pivotal to induce response to therapy, resulting in the potential for resection.…”

Section: Discussionmentioning

confidence: 99%

Resection of Adrenocortical Carcinoma with Bilobar Liver Metastasis Following Neoadjuvant Therapy Using a Modified Mini-ALPPS Approach: A Case Report

Kis¹,

Anaya²,

Ehab³

et al. 2020

IJSCR

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Introduction: Adrenocortical carcinoma (ACC) is an aggressive tumor with high proportion of patients presenting with metastatic disease, most commonly in the liver. Prognosis in this population is extremely poor. Resection of the primary tumor and liver metastasis offers a survival benefit in well-selected patients. However, the extent of surgery is often significant and can limit the ability to accomplish a safe marginnegative resection. Presentation of case: A 35-year-old male presented with a large left ACC (15.2cm) and multiple bilobar liver metastases (1.5-12.5cm). He was treated with mitotane and chemotherapy / immunotherapy, with excellent response. Multidisciplinary discussion led to recommendations for a curative-intent approach with surgery. A staged approach was performed for the resection, using a modified Mini-ALPPS technique. A complete margin-negative resection of all disease was accomplished. The patient recovered well and remains free of disease 24-months following diagnosis. Discussion: This case highlights novel components of treatment for metastatic ACC and for hepatectomy for bilobar liver metastasis. The decisions to proceed to surgery for complete resection and to use a staged approach with a modified Mini-ALPPS technique were both critical components to render the patient disease-free. Appropriate expertise and multidisciplinary teamwork are essential for implementation of these approaches. Conclusion: Neoadjuvant chemotherapy for stage IV ACC can result in disease control and improved selection of candidates for curative-intent surgery. In the setting of bilobar liver disease and a large primary in place, a modified Mini-ALPPS approach provides a safe and feasible way to accomplish complete resection and improved survival.

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Nivolumab in Metastatic Adrenocortical Carcinoma: Results of a Phase 2 Trial

Cited by 89 publications

References 23 publications

Interplay between glucocorticoids and tumor-infiltrating lymphocytes on the prognosis of adrenocortical carcinoma

Interplay between glucocorticoids and tumor-infiltrating lymphocytes on the prognosis of adrenocortical carcinoma

Exquisite sensitivity of adrenocortical carcinomas to induction of ferroptosis

Resection of Adrenocortical Carcinoma with Bilobar Liver Metastasis Following Neoadjuvant Therapy Using a Modified Mini-ALPPS Approach: A Case Report

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