The Journal of Clinical Endocrinology and Metabolism Journal Article

Development of an Adrenocortical Cancer Humanized Mouse Model to Characterize Anti-PD1 Effects on Tumor Microenvironment

September 12, 2019

Julie Lang, Anna Capasso, Kimberly R Jordan, Jena D French, Adwitiya Kar, Stacey M Bagby, Jacob Barbee, Betelehem W Yacob, Lia S Head, Kenneth D Tompkins, Brian M Freed, Hilary Somerset, Toshimasa J Clark, Todd M Pitts, Wells A Messersmith, S Gail Eckhardt, Margaret E Wierman, Stephen Leong, Katja Kiseljak-Vassiliades
The Journal of Clinical Endocrinology & Metabolism, Volume 105, Issue 1, January 2020, dgz014
https://doi.org/10.1210/clinem/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.

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