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Department of Radiology, Stony Brook University, Stony Brook, New York 11794, United States.
Published: September 2022
AI Article Synopsis
Article Abstract
An immunosuppressive tumor microenvironment and tumor heterogeneity have led to the resilience of metastatic castrate resistant prostate cancer (mCRPC) to current treatments. To address these challenges, we developed and evaluated a new drug paradigm, Radio-IMmunostimulant (RIMS), in a syngeneic model of murine prostate cancer. RIMS-1 was generated using a convergent synthesis employing solid phase peptide and solution chemistries. The prostate-specific membrane antigen (PSMA) inhibitory constant for Lu-RIMS-1 was determined, and radiolabeling with Lu generated Lu-RIMS-1. The TLR 7/8 agonist payload release from Lu-RIMS-1 was determined using a cathepsin B assay. The biodistribution of Lu-RIMS-1 was evaluated in a bilateral xenograft model in NCru nude mice bearing PSMA(+) (PC3-PiP) and PSMA(-) (PC3-Flu) tumors at 2, 24, and 72 h. The therapeutic effect of Lu-RIMS-1 was evaluated in C57BL/6J mice bearing RM1-PGLS (PSMA-positive, green fluorescent protein-positive, and luciferase-positive) tumors and compared to that of Lu-PSMA-617 at the same total administered radioactivity of 57 MBq and molar activity of 5.18 MBq/nmol. Lu-RIMS-1 and vehicle were evaluated as the controls. Immuno-positron emission tomography (PET) using Zr-DFO-anti-CD3 was used to visualize T-cell distribution during treatment. Lu-RIMS-1 was quantitatively radiolabeled at >99% radiochemical purity and maintained a high affinity toward PSMA ( = 3.77 ± 0.5 nM). Cathepsin B efficiently released the entire immunostimulant payload in 17.6 h. Lu-RIMS-1 displayed a sustained uptake in PSMA(+) tumor tissue up to 72 h (2.65 ± 1.03% ID/g) and was not statistically different ( = 0.1936) compared to Lu-PSMA-617 (3.65 ± 0.59% ID/g). All animals treated with Lu-RIMS-1 displayed tumor growth suppression and provided a median survival of 30 days ( = 0.0007) while Lu-PSMA-617 provided a median survival of 15 days, which was not statistically significant ( = 0.3548) compared to the vehicle group (14 days). ImmunoPET analysis revealed 2-fold more tumor infiltrating T-cells in Lu-RIMS-1-treated animals compared to Lu-PSMA-617-treated animals; Lu-RIMS-1 improves therapeutic outcomes in a syngeneic model of mouse prostate cancer and elicits greater T-cell infiltration to the tumor compared to Lu-PSMA-617. These results support further investigation of the RIMS paradigm as the first example of a single molecular entity combining radiotherapy and immunostimulation.
