Analysis of CAR T-cell therapy engineering strategies in advanced prostate cancer: innovations to overcome the hostile TME.
| NCT number | Phase | Sponsor | Recruitment status | Description | Engineering innovation/Armoring strategy | |
|---|---|---|---|---|---|---|
| 1 | NCT01140373 | I | Memorial Sloan Kettering Cancer Center | Active, not recruiting | Adoptive transfer of autologous T cells targeted to PSMA in mCRPC | A foundational, first-generation PSMA CAR-T study that established early proof-of-concept and safety benchmarks for the field. |
| 2 | NCT04633148 | I | AvenCell Europe GmbH | Terminated | UniCAR02-T cells and PSMA target module in mCRPC with progressive disease after systemic therapy | Modular “universal” CAR-T system. The CAR-T cells are inert until a soluble PSMA-targeting module is administered, allowing for precise, on-demand control of CAR-T activity to manage toxicity. |
| 3 | NCT04222725 | I/II | Tarsier Pharma | Completed | CART-PSMA-TGFβRDN in mCRPC | Armored CAR-T design. Co-expression of a dominant-negative TGF-β receptor (TGFβRDN) renders the cells resistant to a key immunosuppressive cytokine in the prostate TME, aiming to improve persistence and efficacy. |
| 4 | NCT03873805 | I | City of Hope Medical Center | Active, not recruiting | PSCA-CAR T-cells in treating patients with PSCA + mCRPC | Targets PSCA to address tumor heterogeneity and provides an alternative for PSMA-low or -negative tumors. Utilizes a 4-1BB co-stimulatory domain for potentially improved persistence. |
| 5 | NCT03089203 | I | University of Pennsylvania | Active, not recruiting | CART-PSMA-TGFβRDN cells in mCRPC | Pioneering study of the TGF-β “armored” CAR strategy in prostate cancer, providing critical early-phase safety and efficacy data for this resistance mechanism. |
| 6 | NCT05022849 | I | Janssen Research & Development, LLC | Active, not recruiting | KLK2 CAR-T/JNJ-75229414 in mCRPC | Explores KLK2 as a novel target antigen, diversifying the therapeutic arsenal beyond the more common PSMA and PSCA. |
| 7 | NCT04249947 | I | Poseida Therapeutics, Inc. | Terminated | P-PSMA-101 CAR-T in mCRPC and advanced salivary gland cancers | Utilizes a non-viral piggyBac® transposon system for manufacturing, aiming to produce a high proportion of Tscm, which are associated with superior persistence and durability in vivo. |
| 8 | NCT05805371 | I | City of Hope Medical Center | Recruiting | PSCA-targeting CAR-T plus or minus radiation in PSCA + mCRPC | Tests a rational combination with radiotherapy, hypothesizing that radiation will induce immunogenic cell death and remodel the TME to enhance CAR-T cell infiltration and function. |
| 9 | NCT05732948 | I | Shanghai Unicar-Therapy Bio-medicine Technology Co., Ltd. | Unknown status | PD-1 silent PSMA/PSCA targeted CAR-T for prostate cancer | Dual-targeting (PSMA/PSCA) CAR-T with a “PD-1 silent” domain. This aims to prevent T-cell exhaustion within the TME by blocking endogenous PD-1 signaling, effectively combining CAR-T with intrinsic checkpoint inhibition. |
| 10 | NCT00664196 | I | Roger Williams Medical Center | Suspended | PSMA CAR-T + IL-2 in advanced prostate cancer after non-myeloablative conditioning | An early landmark trial exploring the role of lymphodepletion and exogenous IL-2 support to enhance the expansion and persistence of first-generation CAR-T cells. |
| 11 | NCT06236139 | I/II | Fred Hutchinson Cancer Center | Recruiting | STEAP2-targeted CAR T-cell with TGF-β resistance in mCRPC | Introduces STEAP2 as a new target and combines it with the validated TGFβRDN armoring strategy, representing a next-generation approach targeting a novel antigen while countering a key resistance pathway. |
| 12 | NCT06267729 | I/II | AstraZeneca | Recruiting | PSMA-targeted CAR T-cell therapy in advanced prostate cancer | A contemporary PSMA-targeted CAR-T candidate, likely incorporating lessons learned from prior generations regarding co-stimulation and manufacturing. |
| 13 | NCT04637503 | I/II | Shenzhen Geno-Immune Medical Institute | Unknown status | PSMA-directed CAR T-cell therapy (P-PSMA-101) in mCRPC | (See NCT04249947) Highlights the ongoing development of this non-viral, Tscm-enriched product candidate. |
CAR: chimeric antigen receptor; CRS: cytokine release syndrome; ICANS: immune effector cell-associated neurotoxicity syndrome; IL-2: interleukin-2; KLK2: Kallikrein 2; mCRPC: metastatic castration-resistant prostate cancer; NCT: National Clinical Trial; PSCA: prostate stem cell antigen; PSMA: prostate-specific membrane antigen; STEAP2: six-transmembrane epithelial antigen of the prostate 2; TGF-β: transforming growth factor beta; TGFβRDN: transforming growth factor-beta receptor dominant negative; TME: tumor microenvironment; Tscm: T stem cell memory. Adapted from Meng et al. [6] with added analysis of engineering features.