Hematological toxicity of [225Ac]Ac-PSMA-617 and [177Lu]Lu-PSMA-617 in RM1-PGLS syngeneic mouse model

Abstract

Background

Prostate cancer (PC) has a 34% 5-year survival rate after progressing to metastatic castration-resistant prostate cancer (mCRPC), which occurs in 20–30% of cases. Treatments like chemotherapy, immunotherapy, and PSMA-targeted radioligand therapy (RLT) show promise, but challenges remain with tumor resistance, side effects, and dose-limiting toxicity in kidneys and bone marrow. This study investigated the hematotoxicity, treatment efficacy, and recovery after [¹⁷⁷Lu]Lu-PSMA-617 and [²²⁵Ac]Ac-PSMA-617 treatment in a syngeneic PC mouse model.

Method

Twenty-five male C57BL/6 mice were inoculated with RM1-PGLS cells and monitored using [⁶⁸Ga]Ga-PSMA-11 PET/CT. The mice were divided into five groups as follows: (1) [²²⁵Ac]Ac-PSMA-617 treatment with tumors, (2) [¹⁷⁷Lu]Lu-PSMA-617 treatment with tumors, (3) control group with tumors, (4) [²²⁵Ac]Ac-PSMA-617 treatment without tumors, and (5) [¹⁷⁷Lu]Lu-PSMA-617 treatment without tumors. Tumor volume was measured weekly, and animals were sacrificed when tumors reached 1.5 cm³. Endpoint criteria included tumor size, survival, and body mass. Blood samples were collected at different time points to assess blood cell counts and liver and kidney function.

Results

Both treatments significantly slowed tumor progression and extended survival. [²²⁵Ac]Ac-PSMA-617-treated mice had a median survival of 70 days, compared to 58 days for [¹⁷⁷Lu]Lu-PSMA-617-treated mice and 30 days for the control group. Tumor volumes were significantly reduced in both treatment groups (P < 0.05). Hematological analysis showed that both treatments reduced WBCs, RBCs, and platelets, but values normalized within 35–42 days. Liver and kidney functions remained unaffected, and no significant renal or hepatic toxicity was observed.

Conclusion

Both [²²⁵Ac]Ac-PSMA-617 and [¹⁷⁷Lu]Lu-PSMA-617 caused transient hematotoxicity without prolonged effects. The data do not explicitly support the necessity of immunocompetent models for studying therapeutic outcomes in this context. Future studies incorporating immune profiling are warranted to investigate immune system interactions in radioligand therapy further.