Copper-64/Actinium-225-human anti-PSCA-IgG4 theranostics of a prostate cancer model

Ziel/Aim Although CAR T-cell therapy has demonstrated tremendous clinical efficacy particularly in hematological malignancies, the success in solid tumors is still limited. The combination of the immunotherapeutic (Uni)CAR T-cell therapy with target modules (TM) in solid tumors and radiotherapy could be an additional treatment option. Therefore, we developed a human prostate stem cell antigen (PSCA)-specific, IgG4-based TM radiolabeled with copper-64 (Cu-64) for imaging and with actinium-225 (Ac-225) for treatment.

Methodik/Methods A novel human PSCA-specific IgG4-based TM was conjugated with DOTAGA and radiolabeled with (Cu-64) and (Ac-255). The imaging and therapy were studied in NMRI Foxn1 nu/nu mice with xenotransplanted PSCA-expressing PC-3 tumors. Metabolic changes of the tumors were visualized with 18F-PSMA (PET), the physical size of the tumors and the distance between the vessels in the tumors (US) were measured.

Ergebnisse/Results The radiochemical yield for the Cu-64/Ac-255 TM was 96 % and 52 % respectively, the RCP of the products were g.t. 97 %. The xenotransplanted mice were intravenously injected with the Cu-64 labeled TM given as single dose. After fast distribution, the blood activity concentration decreased very slowly. At 31 h p.i. the activity was maximal in the tumors thereby reaching the optimal tumor to background ratios and only the liver was also visible with much lower activity. The Ac-225 treatment resulted in significant lower tumor size as compared with the control group after 40 days. Doubling time of tumor volume was increased from 15.0 days (control) to 38.6 days of the treatment group. The 18F-PSMA ligand uptake was decreased in the tumor periphery. In comparison to the tumor size the vessel density decreased to a lower extent.

Schlussfolgerungen/Conclusions We here present a Cu-64/Ac-225 labeled TM that allows the combination of (Uni)CAR T-cell immunotherapy with imaging with the Cu-64 labeled TM version and radiotherapy with the Ac-225 labeled TM version combined as radioimmunotheranostics.