225 Ac-PSMA-617-targeted alpha therapy for the treatment of metastatic castration-resistant prostate cancer: A systematic review and meta-analysis.

BACKGROUND: The aim of this systematic review and meta-analysis was to present an overview of the role of 225 Ac-PSMA (prostate-specific membrane antigen)-targeted alpha therapy (TAT) as a salvage treatment option in metastatic castration-resistant prostate cancer. METHODS: A systematic literature review was performed in databases such as Medline, Embase, PubMed, Cochrane Central Register of Controlled Clinical Trials, and the website; www.ClinicalTrials.gov until December 2020. The study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. All original articles, including retrospective, prospective, hand-searched articles, and clinical trials, were searched, and appropriate data were included for the analysis. The study's primary endpoint assessed therapeutic efficacy by biochemical response assessment criteria (any prostate-specific antigen [PSA] decline and >50% PSA decline from the baseline) after 225 Ac-PSMA-TAT. The secondary endpoints included assessing overall survival (OS), progression-free survival (PFS), molecular response, and therapy-related adverse events across all the studies. The values were expressed as pooled proportions and demonstrated graphically by forest plots using the random-effects model. RESULTS: After the data extraction and filtration process, a total of three publications, including 141 patients, were included for the final analysis. The pooled proportion of patients demonstrating any PSA decline and greater than 50% PSA decline were 83% (95% confidence interval [CI]: 77%-89%) and 59% (95% CI: 42%-76%), respectively. The pooled proportions for OS was 81% (95% CI: 74%-89%). The pooled proportion of patients who have shown complete molecular response are 17% (95% CI: 5%-29%). The median PFS was 12 months (interquartile range: 8.2-14.4 months). Across the studies, the most common side effects from 225 Ac-PSMA-617 TAT were xerostomia/dry mouth, which pertained to Gr I-II in 63.1% (89 of 141), followed by fatigue in 44.5% (45 of 101) of patients. Grade I-II and III anemia was noted in 48.5% (49 of 101) and 6% (6 of 101), respectively. Grade III leukopenia and thrombocytopenia were negligible: 0.9% (1 of 101) and 0.9% (1 of 101), respectively. Similarly, grade III nephrotoxicity was also observed only in 5 of 101 (5%) patients. CONCLUSION: Treatment with 225 Ac-PSMA-617 TAT demonstrated biochemical response, improved survival, caused low treatment-related toxicity proving a promising salvage treatment option in mCRPC patients.

Anti-prostate-specific membrane antigen liposomes loaded with 225Ac for potential targeted antivascular α-particle therapy of cancer.

UNLABELLED: This study evaluates targeted liposomes loaded with the α-particle generator (225)Ac to selectively kill prostate-specific membrane antigen (PSMA)-expressing cells with the aim to assess their potential for targeted antivascular radiotherapy. METHODS: In this study, PEGylated liposomes were loaded with (225)Ac and labeled with the mouse antihuman PSMA J591 antibody or with the A10 PSMA aptamer. The targeting selectivity, extent of internalization, and killing efficacy of liposomes were evaluated on monolayers of prostate cancer cells intrinsically expressing PSMA (human LNCaP and rat Mat-Lu cells) and on monolayers of HUVEC induced to express PSMA (induced HUVEC). RESULTS: The loading efficiency of (225)Ac into preformed liposomes ranged from 58.0% ± 4.6% to 85.6% ± 11.7% of introduced radioactivity. The conjugation reactions resulted in approximately 17 ± 2 J591 antibodies and 9 ± 2 A10 aptamers per liposome. The average size of liposomes, 107 ± 2 nm in diameter, was not affected by conjugation or loading. LNCaP cells exhibit 2:1:0.5 relative PSMA expression, compared with MatLu and induced HUVEC, respectively, based on flow cytometry detecting association of the J591 antibody. J591-labeled liposomes display higher levels of total specific binding to all cell lines than A10 aptamer-labeled liposomes. Specific cell association of targeted liposomes increases with incubation time. Cytotoxicity studies demonstrate that radiolabeled J591-labeled liposomes are most cytotoxic, with median lethal dose values, after 24 h of incubation, equal to 1.96 (5.3 × 10(-5)), 2.92 × 10(2) (7.9 × 10(-3)), and 2.33 × 10(1) Bq/mL (6.3 × 10(-4) µCi/mL) for LNCaP, Mat-Lu, and induced HUVEC, respectively, which are comparable to the values for the radiolabeled J591 antibody. For A10 aptamer-labeled liposomes, the corresponding values are 3.70 × 10(1) (1.0 × 10(-3)), 1.85 × 10(3) (5.0 × 10(-2)), and 4.07 × 10(3) Bq/mL (1.1 × 10(-1) µCi/mL), respectively. CONCLUSION: Our studies demonstrate that anti-PSMA-targeted liposomes loaded with (225)Ac selectively bind, become internalized, and kill PSMA-expressing cells including endothelial cells induced to express PSMA. These findings-combined with the unique ability of liposomes to be easily tuned, in terms of size and surface modification, for optimizing biodistributions-suggest the potential of PSMA-targeting liposomes encapsulating α-particle emitters for selective antivascular α radiotherapy.