Endocrine and Neuroendocrine Tumors Special Issue—Checkpoint Inhibitors for Adrenocortical Carcinoma and Metastatic Pheochromocytoma and Paraganglioma: Do They Work?

SIMPLE SUMMARY: In the past decade, the landscape of cancer treatment has radically changed after the introduction of immunotherapy. Adrenocortical carcinoma and metastatic pheochromocytoma/paraganglioma are rare cancers with limited responses to traditional cancer treatments. The use of immunotherapy against these cancers has yielded a few responses when used alone or in combination with other drugs. We reviewed the current literature to summarize the role of immunotherapy in these rare cancers. ABSTRACT: Adrenocortical cancers and metastatic pheochromocytomas are the most common malignancies originating in the adrenal glands. Metastatic paragangliomas are extra-adrenal tumors that share similar genetic and molecular profiles with metastatic pheochromocytomas and, subsequently, these tumors are studied together. Adrenocortical cancers and metastatic pheochromocytomas and paragangliomas are orphan diseases with limited therapeutic options worldwide. As in any other cancers, adrenocortical cancers and metastatic pheochromocytomas and paragangliomas avoid the immune system. Hypoxia-pseudohypoxia, activation of the PD-1/PD-L1 pathway, and/or microsatellite instability suggest that immunotherapy with checkpoint inhibitors could be a therapeutic option for patients with these tumors. The results of clinical trials with checkpoint inhibitors for adrenocortical carcinoma or metastatic pheochromocytoma or paraganglioma demonstrate limited benefits; nevertheless, these results also suggest interesting mechanisms that might enhance clinical responses to checkpoint inhibitors. These mechanisms include the normalization of tumor vasculature, modification of the hormonal environment, and vaccination with specific tumor antigens. Combinations of checkpoint inhibitors with classical therapies, such as chemotherapy, tyrosine kinase inhibitors, radiopharmaceuticals, and/or novel therapies, such as vaccines, should be evaluated in clinical trials.