Development of an Adrenocortical Cancer Humanized Mouse Model to Characterize Anti-PDI Effects on Tumor Microenvironment

• Published in: The journal of clinical endocrinology and metabolism Vol. 105; no. 1; p. 26
• Main Authors: Lang, Julie, Capasso, Anna, Jordan, Kimberly R, French, Jena D, Kar, Adwitiya, Bagby, Stacey M, Barbee, Jacob, Yacob, Betelehem W, Head, Lia S, Tompkins, Kenneth D, Freed, Brian M, Somerset, Hilary, Clark, Toshimasa J, Pitts, Todd M, Messersmith, Wells A, Eckhardt, S. Gail, Wierman, Margaret E, Leong, Stephen, Kiseljak-Vassiliades, Katja
• Format: Journal Article
• Language: English
• Published: Oxford University Press 01.01.2020
• Subjects: Animal models in research; Health aspects; Immunotherapy; Monoclonal antibodies; Physiological aspects; United States
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/clinem/dgz014

Context: Although the development of immune checkpoint inhibitors has transformed treatment strategies of several human malignancies, research models to study immunotherapy in adrenocortical carcinoma (ACC) are lacking. Objective: To explore the effect of anti-PD1 immunotherapy on the alteration of the immune milieu in ACC in a newly generated preclinical model and correlate with the response of the matched patient. Design, Setting, and Intervention: To characterize the CU-ACC2-M2B patient-derived xenograft in a humanized mouse model, evaluate the effect of a PD-1 inhibitor therapy, and compare it with the CU-ACC2 patient with metastatic disease. Results: Characterization of the CU-ACC2-humanized cord blood-BALB/c-[Rag2.sup.null][Il2n/.sup.null][Sirpa.sup.WOD] model confirmed ACC origin and match with the original human tumor. Treatment of the mice with pembrolizumab demonstrated significant tumor growth inhibition (60%) compared with controls, which correlated with increased tumor infiltrating lymphocyte activity, with an increase of human CD8+ T cells (P < 0.05), HLA-DR+ T cells (P < 0.05) as well as Granzyme [B.sup.+] [CD8.sup.+] T cells (<0.001). In parallel, treatment of the CU-ACC2 patient, who had progressive disease, demonstrated a partial response with 79% to 100% reduction in the size of target lesions, and no new sites of metastasis. Pretreatment analysis of the patient's metastatic liver lesion demonstrated abundant intratumoral [CD8.sup.+] T cells by immunohistochemistry. Conclusions: Our study reports the first humanized ACC patient-derived xenograft mouse model, which may be useful to define mechanisms and biomarkers of response and resistance to immune-based therapies, to ultimately provide more personalized care for patients with ACC. (J Clin Endocrinol Metab 105: 26-42, 2020) Keywords: Adrenocortical carcinoma, anti-PD-1, humanized mouse PDX model, immunotherapy