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
Online: https://academic.oup.com/jcem/article/105/1/26/5568436
Issue: J Clin Endocrinol Metab. 2020 Jan 1;105(1):dgz014.
Abstract
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-Rag2nullIl2rγnullSirpaNOD 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+ CD8+ 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+ 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.
Keywords: Adrenocortical carcinoma; anti-PD-1; humanized mouse PDX model; immunotherapy.
