Dual-Targeted Radionuclide Therapy with 161Tb Instigates Anticancer Immunity in "Cold" Murine Prostate Tumor

Area of Science:

• Nuclear medicine
• Oncology
• Immunotherapy

Background:

• Lutetium-177 (¹⁷⁷Lu) targeted radionuclide therapy (TRT) is successful for advanced prostate cancer.
• ¹⁷⁷Lu has moderate radiation energy, requiring high doses and showing limited efficacy against "cold" prostate tumors.
• There is a need for more effective TRT agents that can overcome these limitations and enhance antitumor immunity.

Purpose of the Study:

• To develop and evaluate a novel dual-targeted peptide (S1R/PSMA-P) labeled with terbium-161 (¹⁶¹Tb) for prostate cancer therapy.
• To compare the efficacy of ¹⁶¹Tb-S1R/PSMA-P with ¹⁷⁷Lu-labeled counterparts.
• To investigate the potential of ¹⁶¹Tb-S1R/PSMA-P to inhibit tumor growth and boost anticancer immunity.

Main Methods:

• Synthesis and characterization of Sigma-1 receptor and prostate-specific membrane antigen (PSMA) dual-targeted peptide (S1R/PSMA-P).
• Labeling of S1R/PSMA-P with ¹⁶¹Tb and ¹⁷⁷Lu for comparative studies.
• In vitro assessment of cytotoxicity, DNA double-strand breaks, and reactive oxygen species induction.
• In vivo evaluation of tumor uptake, selectivity, and therapeutic efficacy in a prostate cancer model (RM1-PSMA⁺/RM1).
• Assessment of tumor sensitization to αPD1 immune checkpoint blockade therapy.

Main Results:

• ¹⁶¹Tb-S1R/PSMA-P demonstrated significantly enhanced cytotoxicity and immunogenic cell death compared to ¹⁷⁷Lu-S1R/PSMA-P.
• ¹⁶¹Tb-S1R/PSMA-P induced greater DNA double-strand breaks and reactive oxygen species.
• High tumor uptake and selectivity were observed for ¹⁶¹Tb-S1R/PSMA-P.
• A single dose of 7.4 MBq ¹⁶¹Tb-S1R/PSMA-P achieved a 60% complete tumor regression rate.
• Combined therapy with 3.7 MBq ¹⁶¹Tb-S1R/PSMA-P and αPD1 resulted in a 50% cure rate and durable antitumor immunity.

Conclusions:

• ¹⁶¹Tb-S1R/PSMA-P is a potent theranostic agent for prostate cancer treatment.
• The high LET Auger electrons from ¹⁶¹Tb enhance therapeutic efficacy and immunogenic cell death.
• This novel agent effectively inhibits prostate tumors and sensitizes them to immunotherapy, offering a promising strategy for advanced prostate cancer.