Prostate cancer (PCa) remains a leading cause of cancer-related mortality in men globally, with castration-resistant prostate cancer (CRPC) representing a particularly challenging stage of disease. Despite therapeutic advances, including androgen receptor inhibitors (ARPIs), taxane-based chemotherapy, and radiopharmaceuticals, durable responses in metastatic CRPC (mCRPC) are limited. Immunotherapy, especially chimeric antigen receptor (CAR) T cell therapy, has revolutionized hematologic malignancies, yet its application in solid tumors like prostate cancer remains under investigation. We conducted a systematic review in accordance with PRISMA guidelines to evaluate all published and registered clinical trials (2014–2024) involving CAR-T therapy in prostate cancer. Databases searched included PubMed, ClinicalTrials.gov, and Cochrane. Studies were screened using stringent inclusion/exclusion criteria and analyzed for trial phase, antigen targets, dosing, safety (cytokine release syndrome CRS, neurotoxicity, dose-limiting toxicities DLTs), and early efficacy outcomes. Data extraction was performed independently by two reviewers with AI-assisted adjudication. Out of 32,565 records, 27 trials met inclusion, of which 8 had published outcomes. Eight early-phase trials investigated CAR-T therapies targeting PSMA, PSCA, and other tumor-associated antigens (e.g., CD70, GD2, TGFβDN). PSMA-directed CAR-T trials showed variable safety and preliminary efficacy, with some reporting PSA reductions > 50% and radiographic partial responses. CRS (Grade 1–2) occurred in up to 100% of patients, with isolated cases of neurotoxicity and fatal adverse events in higher-dose cohorts. Trials employing armored CARs (e.g., TGFβDN, iCasp9 switches) demonstrated improved persistence and early anti-tumor activity. The use of dual-target CARs and gene-editing strategies (e.g., piggyBac transposons, PD-1 knockouts) reflect the field’s evolving precision. CAR-T therapy in prostate cancer, particularly mCRPC, is a promising yet nascent field marked by heterogeneous safety profiles and early signs of efficacy. PSMA remains the most validated target, though antigen escape and tumor microenvironment barriers continue to limit success. Innovative constructs and combinatorial strategies may enhance clinical outcomes. Continued trial development and refinement are critical to unlocking CAR-T’s potential in solid tumors. Question: What are the current advancements and challenges in CAR-T cell therapies for metastatic castration-resistant prostate cancer (mCRPC)? Findings: Multiple phase I/II trials targeting various antigens such as PSMA, PSCA, CLDN6, STEAP2, EpCAM, and others demonstrate partial responses and disease stabilization with variable safety profiles. Novel strategies include PD-1 blockade, incorporation of costimulatory domains like 4-1BB, and targeting unique T-cell subsets such as γδ T cells. Challenges remain with CAR-T cell persistence, tumor microenvironment resistance, and immune-related toxicities. Meaning: CAR-T therapy for mCRPC shows promise but requires multimodal approaches and further optimization to overcome tumor heterogeneity and immunosuppressive microenvironments for improved efficacy and safety.
Zadeh et al. (Sat,) studied this question.