The Immunotherapy Landscape in Adrenocortical Cancer

Abstract

Adrenocortical carcinoma (ACC) is a rare cancer of the adrenal gland that is frequently associated with excess production of adrenal hormones. Although surgical resection may be curative in early-stage disease, few effective therapeutic options exist in the inoperable advanced or metastatic setting. Immunotherapies, inclusive of a broad array of immune-activating and immune-modulating antineoplastic agents, have demonstrated clinical benefit in a wide range of solid and hematologic malignancies. Due to the broad activity across multiple cancer types, there is significant interest in testing these agents in rare tumors, including ACC. Multiple clinical trials evaluating immunotherapies for the treatment of ACC have been conducted, and many more are ongoing or planned. Immunotherapies that have been evaluated in clinical trials for ACC include the immune checkpoint inhibitors pembrolizumab, nivolumab, and avelumab. Other immunotherapies that have been evaluated include the monoclonal antibodies figitumumab and cixutumumab directed against the ACC-expressed insulin-like growth factor 1 (IGF-1) receptor, the recombinant cytotoxin interleukin-13-pseudomonas exotoxin A, and autologous tumor lysate dendritic cell vaccine. These agents have shown modest clinical activity, although nonzero in the case of the immune checkpoint inhibitors. Clinical trials are ongoing to evaluate whether this clinical activity may be augmented through combinations with other immune-acting agents or targeted therapies.

Keywords: adrenocortical carcinoma; immuno-oncology; immunotherapy.

Figure 1

Immunotherapeutic treatment modalities for ACC. Agents that have been evaluated in clinical trials are labeled proximal to their associated mechanism of action. Abbreviations: PD-1—programmed cell death protein 1, PD-L1—programmed death-ligand 1, CAR—chimeric antigen receptor, DC—dendritic cell, IL-13-PE—interleukin-13-pseudomonas exotoxin.

Figure 2

Expression of DLK-1, IGF1R, STAR, and IL13RA2 mRNA across human cancers. Data shown are from the PanCancer RNA-seq data. Each dot refers to an individual tumor. Adrenocortical carcinoma tumors are identified by a red arrow. Abbreviations: RPKM—reads per kilobase million, DLK1—protein delta homolog 1, IGF1R—insulin-like growth factor 1 receptor, STAR—steroidogenic acute regulatory protein, IL13RA2—interleukin-13 receptor subunit alpha-2, LAML—acute myeloid leukemia, ACC—adrenocortical carcinoma, BLCA—bladder, urothelial carcinoma, LGG—brain lower-grade glioma, BRCA—breast invasive carcinoma, CESC—cervical squamous cell carcinoma and endocervical adenocarcinoma, CHOL—cholangiocarcinoma, LCML—chronic myelogenous leukemia, COAD—colon adenocarcinoma, CNTL—controls, ESCA—esophageal carcinoma, GBM—glioblastoma multiforme, HNSC—head and neck squamous cell carcinoma, KICH—kidney chromophobe, KIRC—kidney renal clear cell carcinoma, KIRP—kidney renal papillary cell carcinoma, LIHC—liver hepatocellular carcinoma, LUAD—lung adenocarcinoma, LUSC—lung squamous cell carcinoma, DLBC—lymphoid neoplasm diffuse large B-cell lymphoma, MESO—mesothelioma, MISC—miscellaneous, OV—ovarian serous cystadenocarcinoma, PAAD—pancreatic adenocarcinoma, PCPG—pheochromocytoma and paraganglioma, PRAD—prostate adenocarcinoma, READ—rectum adenocarcinoma, SARC—sarcoma, SKCM—skin cutaneous melanoma, STAD—stomach adenocarcinoma, TGCT—testicular germ cell tumors, THYM—thymoma, THCA—thyroid carcinoma, UCS—uterine carcinosarcoma, UCEC—uterine corpus endometrial carcinoma, UVM—uveal melanoma, SCNlike—small-cell-like tumor. The results shown here are in whole or part based upon data generated by the TCGA Research Network: https://www.cancer.gov/tcga. Accessed on 20 April 2021.