PSMA-RLT技术最新进展：161Tb与联合治疗策略

3.1.2 Novel Radionuclides and Therapeutic Strategies PSMA-RLT is a rapidly emerging diagnostic and therapeutic technique that combines targeting molecules capable of specifically recognizing tumor markers with radiopharmaceuticals. The radiopharmaceuticals release energy to disrupt the DNA structure of tumor cells, precisely killing them. Currently, [177Lu]Lu-PSMA-617 is one of the most extensively studied drugs in PSMA-RLT, but it still has certain limitations. To overcome the physical limitations of 177Lu (such as insufficient efficacy against micrometastases), the novel radionuclide 161Tb has emerged. A study on the safety data of 161Tb-PSMA-I&T in mCRPC patients revealed that the advantage of 161Tb is its ability to simultaneously emit β particles and ultra-short-range Auger electrons, releasing high energy at nanometer distances. This theoretically provides stronger cytotoxicity against micrometastases and heterogeneous lesions. The study also showed that at a maximum dose of 7.4 GBq, only 3% of patients experienced grade 3 treatment-related adverse events, with no grade 4 events or treatment-related deaths. All patients completed their planned treatments, with a PSA response rate (decline ≥50%) of 63%, and a median progression-free survival of 7.9 months. Based on these results, researchers have initiated higher-dose (9.5 GBq) explorations to lay the groundwork for subsequent phase III randomized controlled trials. 3.2 Breakthroughs in Combination Therapy Strategies 3.2.1 Synergy with Targeted Therapy The synergistic effects of PSMA-targeted therapy combined with novel targeted drugs have become a research hotspot. Studies are underway to evaluate the efficacy of pocenbrodib (a CBP/p300 inhibitor) + [177Lu]Lu-PSMA-617 in combination therapy for mCRPC. Additionally, a study involving PSMA-directed PROTAC degraders has shown that targeting the androgen receptor (PSMA-ARD-203) and BET proteins (PSMA-ARV-771) by conjugating degraders to PSMA ligands via cleavable linkers achieves specific targeting of prostate cancer cells. In the 22Rv1 xenograft model, PSMA-ARD-203 demonstrated higher tumor drug exposure and a longer half-life, with significantly better antitumor effects compared to traditional PROTACs. Importantly, PSMA-ARV-771 achieved an 88.6% inhibition of tumor growth in the LNCaP model, providing a new strategy to overcome treatment resistance. 3.2.2 Synergy with Immunotherapy The combination of PSMA-targeted radiotherapy and immune checkpoint inhibitors also shows broad prospects. Preclinical studies have shown that tumor antigens released by PSMA-targeted radiotherapy can activate CD8+ T cells, and when combined with PD-1 inhibitors, this can significantly extend the survival of mice from 32 days to 51.5 days. This mechanism may be related to the immunogenic cell death induced by radiotherapy and the reprogramming of the tumor microenvironment. Clinical observations have also found that PD-L1 expression is upregulated after PSMA-targeted therapy, suggesting the potential advantages of sequential treatment.