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Background Chimeric Antigen Receptor T (CAR T) cell therapies have achieved curative outcomes in some hematological malignancies, but these successes have not yet been extended to solid tumors. This gap is particularly evident in aggressive diseases such as metastatic castration-resistant prostate cancer (mCRPC), where the 5-year survival rate is ~30%, underscoring an urgent unmet clinical need. A central obstacle for developing targeted therapies against such solid tumors is the critical task of identifying targets that are broadly expressed on tumor cells but absent from healthy, normal tissues.To address this critical challenge in mCRPC, we have developed AB-3028, a sequential ‘AND’ logic gated CAR T cell therapy that is engineered with both a priming receptor (PrimeR) and a cytolytic CAR. In this system, the binding of the PrimeR to its target antigen initiates a signaling cascade that induces the expression of the CAR. Subsequently, the now-active CAR T cell can recognize and eliminate tumor cells that present the CAR target antigen. AB-3028 is also engineered to contain a shRNA-miR module targeting FAS and TGFβR2 designed to resist tumor microenvironment suppression, and a synthetic pathway activator designed to potentiate long-term functional persistence.Methods To evaluate suitable target antigens for AB-3028, we first conducted a comprehensive in silico analyses with bulk RNA-seq datasets from the The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases. Upon shortlisting target antigens, immunohistochemical (IHC) validation studies were conducted in tumor and normal tissues.Results Here, we describe the identification of attractive priming and cytolytic target antigens. In silico analysis with the TCGA dataset found that the targets are both expressed in 97% of prostate tumors (n=496). Subsequent immunohistochemical (IHC) validation confirmed robust protein expression of both antigens in a majority of prostate tumors throughout all stages of disease progression, from castration-sensitive to castration-resistant settings. Importantly, we also describe the normal tissues that exhibit positivity for the antigens by RNA-seq and IHC. While the CAR target is an established target, pairing it with the PrimeR target significantly limits potential normal tissue exposure compared to targeting the CAR target alone, suggesting a potential enhanced safety profile.Conclusions These collective data support the development of AB-3028 for mCRPC.