Work

12485 Evaluating B7-H3-CAR T Cell Therapy In Preclinical Models Of Pediatric Adrenocortical Tumors

Year: 2024

Type: article

Abstract: Disclosure: E.M. Pinto: None. R. Epperly: None. T. Santiago: None. H. Sheppard: None. M. Clay: None. C. Morton: None. P. Nguyen: None. Y. Zhou: None. M.A. Woolard: None. C. O'Reilly: None. J. Justice: None. W. Akers: None. M. Johnson: None. C. Cheng: None. G. Zambetti: None. A.M. Davidoff: None. R. Ribeiro: None. C. DeRenzo: None. Over the past decade, significant progress has been achieved in understanding the underlying molecular mechanisms driving adrenocortical tumorigenesis, with the identification of several genetic and molecular drivers of this disease. However, a lack of preclinical models has hindered the discovery of new therapeutic treatment modalities, particularly in the pediatric population. In this study we describe the development of three patient-derived xenograft models for pediatric adrenocortical tumors (SJ-ACC3, SJ-ACC4, and SJACT030812_X1), which recapitulate the molecular features and heterogeneity of these rare tumors. All three models were derived from aggressive tumors, harboring TP53 and ATRX variants. We evaluated the efficacy of various chemotherapeutic agents in two models. SJ-ACC3 tumors exhibited sensitivity to cisplatin and topotecan, while SJ-ACC4 demonstrated limited response to all evaluated drugs including cisplatin, doxorubicin, and etoposide. Consistent with adult adrenocortical tumors, we found that most primary pediatric adrenocortical tumors express the tumor associated antigen B7-H3 (CD276), regardless of their molecular subtype. Notably, B7-H3 was highly expressed in two of our models, SJ-ACC4 and SJACT030812_X1, with limited expression in SJ-ACC3. Critically, we demonstrated that B7-H3 CAR T cells exhibited significant antitumor activity in both B7-H3-positive models, clearing tumors in most mice. These findings suggested that CAR T cells therapy targeting B7-H3 might be a promising therapeutic strategy for pediatric patients with high-risk adrenocortical tumors. Presentation: 6/3/2024

Source: Journal of the Endocrine Society

DOI: 10.1210/jendso/bvae163.177