Abstract 315: B7H3 is a potential therapeutic target in advanced metastatic prostate cancer
Authors: Agarwal Supreet , Fang Lei , Yin Juan Juan , Hurt Elaine , Kelly Kathleen 
Published: June 2022

Abstract
B7H3 is an immunomodulatory protein of the B7 family which inhibits T cell function. B7H3 mRNA is ubiquitously expressed in normal human tissues, but the protein is expressed at low levels, suggesting a tight post-transcriptional regulation. By contrast, B7H3 protein is overexpressed in several solid tumors and often correlates with poor survival, higher tumor grade, and metastasis independently of immune regulation. A few studies also have reported an association between B7H3 overexpression and therapy resistance. Since B7H3 protein is preferentially expressed on cancer cells and tumor vasculature, it is an attractive target for developing novel cancer therapies.
Here we analyzed the expression of B7H3 in 26 mCRPC organoid models and examined whether B7H3 can serve as a novel therapeutic target for advanced mPCa patients that fail current treatment regimens. The B7H3 protein expression in PDXOs of various lineages including adenocarcinoma (n=19), double-negative (DNPC, n= 2), and neuroendocrine (NE, n =5) lineages, was analyzed using simple western™ assay, immunofluorescence, and flow cytometry. We tested the ex-vivo drug response of PDXOs and performed PDX preclinical trials using humanized B7H3-ADC armed with a pyrrolobenzodiazepine (PBD) warhead. PBD dimers are DNA interstrand cross-linking agents and are a poor substrate of P-gp drug transporters.
Our results showed that B7-H3 was overexpressed in several PDX derived organoids of mPCa. Organoids with adenocarcinoma phenotype (n=19) demonstrated a range of B7H3 protein expression whereas RB1/TP53 mutated small cell neuroendocrine or double negative prostate cancer showed a relatively more uniform and low expression. Nonetheless, PDXOs of neuroendocrine, double negative or adenocarcinoma origin responded with maximum efficacy to B7H3-ADC ex vivo. Adenocarcinoma organoid models (n=19) displayed a wide range of responses, which was only partially correlated with B7H3 protein levels. Genetically-engineered loss of B7-H3 converted a responder to a non-responder phenotype. Our investigation for potential biomarkers of B7H3-PBD sensitivity suggested that RB1-deficiency induced replication stress and/or expression of SLFN11, an interferon pathway transcriptional target, to be the strong predictors of B7H3-PBD response, independent of tumor lineage. We further performed preclinical trials using four PDX models based on their RB1 and SLFN11 status, including a model of advanced adenocarcinoma lineage with low B7H3 expression. B7H3-PBD eradicated large established subcutaneous tumors and metastases and improved long-term overall survival in either RB1 deficient and/or SLFN11HIGH models, but showed no response in RB1+/SLFN11- tumors.
In conclusion, B7H3-PBD treatment has potential to produce complete and durable response in appropriately-selected, heavily-pretreated metastatic CRPC and NEPC.
Citation Format: Supreet Agarwal, Lei Fang, Juan Juan Yin, Elaine Hurt, Kathleen Kelly. B7H3 is a potential therapeutic target in advanced metastatic prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 315.