177Lu-DOTA-HYNIC-Lys(Nal)-Urea-Glu: Biokinetics, Dosimetry, and Evaluation in Patients with Advanced Prostate Cancer.

SPECT/CT images in patients have demonstrated the ability of [99mTc]Tc-EDDA/HYNIC-Lys(Nal)-Urea-Glu ([99mTc]Tc-iPSMA) to detect tumors and metastases of prostate cancer. Considering that theranostics combines the potential of therapeutic and diagnostic radionuclides in the same molecular probe, the aim of this research was to estimate the biokinetics and dosimetry of 177Lu-DOTA-HYNIC-Lys(Nal)-Urea-Glu (177Lu-iPSMA) in healthy subjects and analyze the response in patients receiving 177Lu-iPSMA therapeutic doses. 177Lu-iPSMA was obtained from lyophilized formulations with radiochemical purities >98%. Whole-body images from five healthy subjects were acquired at 20 min, 6, 24, 48, and 120 h after 177Lu-iPSMA administration (185 MBq). The image sequence was used to extrapolate the 177Lu-iPSMA time-activity curves of each organ to adjust the biokinetic model and calculate the total number of disintegrations (N) that occurred in the source regions. N data were the input for the OLINDA/EXM code to calculate internal radiation doses. Ten patients (median age: 68 y; range 58-86 y) received from 1 to 4 cycles of 177Lu-iPSMA (3.7 or 7.4 GBq) every 8-10 weeks. Response was evaluated using the 68Ga-PSMA-ligand-PET/CT or 99mTc-iPSMA-SPECT/CT diagnostic images and serum PSA levels before and after 177Lu-iPSMA treatment. The blood activity showed a half-life value of 1.1 h for the fast component (T 1/2 α = ln2/0.614), 9.2 h for the first slow component (T 1/2 ß = ln2/0.075), and 79.6 h for the second slow component (T 1/2 γ = ln2/0.008). The average absorbed doses were 0.23, 0.28, 0.88, and 1.17 Gy/GBq for the spleen, liver, kidney, and salivary glands. A total of 18 cycles were performed in 10 patients. A PSA decrease and some reduction of the radiotracer uptake (SUV) in tumor lesions occurred in 60% and 70% of the patients, respectively. 177Lu-iPSMA obtained from kit formulations showed high tumor uptake with good response rates in patients. The results obtained in this study warrant further clinical studies to establish the optimal number of treatment cycles and for evaluating the effect of this therapeutic agent on survival of patients.

Anti-prostate cancer effects of CTL cell induction in vitro by recombinant adenovirus mediated PSMA/4-1BBL dendritic cells: an immunotherapy study.

This study aimed to examine anti-prostate cancer immune response induced by dendritic cells (DCs) transduced with PSMA/4-1BBL recombinant adenoviruses in vitro. Ad-PSMA, Ad-4-1BBL, and Ad-GFP were transfected into DCs derived from peripheral blood of healthy volunteers. Ad-PSMA/4-1BBL-DC, Ad-PSMA-DC, Ad-4-1BBL-DC, Ad-GFP-DC, and normal-DC, PSMA and 4-1BBL protein levels in DCs were detected by western blot. IL-12, IFN-γ and IL-10 were measured by ELISA. Mixed lymphocyte reaction and the cytotoxicity of each group targeted to LNCap, Du145, and 22RV prostate cancer cells were determined by CCK-8 assay. PSMA and 4-1BBL protein could express on DC successfully, the IL-12 supernatant content (134.29 ± 2.22 pg) was higher than others (P < 0.05). The ability to stimulate autologous T lymphocyte proliferation in the co-transfection group was higher than others (P < 0.05). When the DCs were co-cultured with CTLs, the PSMA/4-1BBL-DC-CTL group showed the highest content of IFN-γ (1176.10 ± 14.37pg/5 x 10(6) cells), but the lowest IL-10 content (75.14 ± 2.01 pg/5 x 10(6) cells) (P < 0.05), and the strongest anti-tumor effect when the effector to target ratio was 40:1, along with a higher killing ratio of LNCap cells than others (P < 0.05). Overall, Mature DCs transfected with Ad-PSMA/4- 1BBL not only showed high secretion of IL-12, but also induced CTLs to stimulate and enhance the killing effect of PSMA specific effector cells to PSMA positively expressing prostate cancer cells. Furthermore, the DCs infected with two kinds of tumor-associated antigens would induce more effective tumor-specific CTL induction.