Preliminary Study On Molecular Imaging Diagnosis And Immunotherapy Of Tumors Targeting PSMA

Objectives1.To explore the expression of PSMA in 6 common tumor tissues;2.To analyze the diagnostic efficacy of small molecule radionuclide PET/CT imaging targeting PSMA for prostate cancer;3.To establish PDTX models of bladder urothelial carcinoma and prostate cancer,respectively,and to complete a preliminary study of PSMA-targeted immunotherapy based on the two tumor models.Methods1.A total of 145 pathological sections of 6 common kind of tumors diagnosed by the hospital from March 2016 to March 2017 were randomly selected,including 24 cases of breast cancer,25 cases of ovarian cancer,25 cases of hepatocellular carcinoma,26 cases of renal clear cell carcinoma,23 cases of bladder urothelial carcinoma and 22 cases of prostate cancer were analyzed by immunohistochemical method for the expression of PSMA protein on each tumor tissue.2.We have made a retrospective analysis of clinical data of 93 patients with suspected prostate cancer who underwent ⁶⁸Ga-PSMA-617 PET/CT and mpMRI examination from June 2017 to July 2018 in the Hospital.The 93 patients were analyzed for ⁶⁸Ga-PSMA-617PET/CT and mpMRI for the diagnosis of primary prostate cancer,with evalutation of the difference in the SUVmax value of radioactive PSMA ligand in the benign and malignant prostate tissue.3.A total of 55 specimens of prostate cancer from January 2017 to January 2019 and 16specimens of bladder urothelial carcinoma from June 2017 to November 2018 were collected to establish the PDTX models which were used to analyze the correlation between the tumor formation rate and the clinicopathological information of each specimen.The P1generation tissue sections of the PDTX model of the two tumors were separately analyzed by immunohistochemical staining for PSMA expression.PSMAb antibody immunotherapy was performed in the prostate cancer PDTX model with positive PSMA expression.Results1.There were 145 cases of pathological tissue sections of 6 common kind of tumors.The positive rates of PSMA expression were 37.5%for breast cancer,4.0%for ovarian cancer,72.0%for hepatocellular carcinoma,0 for renal clear cell carcinoma,and 69.6%for bladder urothelial carcinoma.Prostate cancer is 100%.Among the 5 tumor tissues with positive PSMA expression,except for prostate cancer,PSMA expression in the remaining 4 tumor tissues was correlated with tumor blood vessels,while PSMA expressed in both prostate cancer cells and tumor blood vessels.2.Among the 93 cases of prostate cancer enrolled,pathological results were used as the diagnostic golden standard,56 cases of prostate cancer and 37 cases of non-prostate cancer were diagnosed.The sensitivity,specificity,positive predictive value,negative predictive value of mpMRI were 87.50%,56.70%,75.38%,and 75.00%,respectively;the sensitivity,specificity,positive predictive value,negative predictive value of ⁶⁸Ga-PSMA-617 PET/CT examination were 92.80%,83.78%,89.60%,and 88.50%.The SUVmax and the PI-RADS score were used as the diagnostic parameters of the ⁶⁸Ga-PSMA-617 PET/CT examination and the multi-parameter MRI examination.The ROC curves were drawn and the optimal critical points were determined.The area under the curve of the SUVmax value was AUC₁=0.928.The area under the PI-RADS score curve was AUC₂=0.816,p=0.028,and SUVmax=4.795 was determined to be the optimal critical point.Of the 93 patients with suspected prostate,67 had total serum PSA<20 ng/ml.There were 30 significant cases of prostate cancer,37 cases of non-significant prostate cancer and negative cases.The ROC curves were plotted with the SUVmax value and the PI-RADS score as diagnostic parameters,and the optimal critical point of SUVmax was determined.The area under the curve of the SUVmax value was AUC₁=0.909,and the area under the PI-RADS score curve was AUC₂=0.695,p=0.003.We determined SUVmax=5.05 as the best critical point.Among the 93 patients with suspected prostate cancer,the difference in SUVmax value of patients with different serum total PSA values was statistically significant,and the PSA value was positively correlated with SUVmax.The SUVmax value of benign prostate tissue was lower than that of prostate cancer tissue,with a statistical significance.Among the 56 patients with prostate cancer,the difference in the SUVmax values of prostate cancer with different Gleason scores and ISUP classification groups was statistically significant,and the Gleason score and ISUP classification group were positively correlated with SUVmax values.3.From January 2017 to January 2019 and from June 2017 to November 2018,a total of55 specimens of prostate cancer and 16 specimens of bladder urothelial carcinoma were collected respectively.Till March 1,2019,a total of 14 cases of P1 prostate cancer PDTX models and 8 cases of bladder urothelial carcinoma PDTX models were established.The total tumor formation rate was 25.45%and 50.00%,respectively.The HE staining morphology and STR detection were performed to identify the established models as their P0 homologous tumors.The clinical pathological parameters of the two tumor patients were analyzed.For prostate cancer,the tumor formation rate of Gleason score 8-10 was 37.50%,and the tumor formation rate of 6-7 was 8.70%and the difference was statistically significant?P=0.016?.For bladder urothelial carcinoma,the tumor formation rate of the Ki-67 value-added index<50%group was 22.22%,and the?50%group tumor rate was 85.71%,and the difference was statistically significant?P=0.041?.PSMA expression was analyzed by immunohistochemical staining in 14 cases of PDTX prostate cancer model and 8 cases of bladder urothelial carcinoma model.13 cases of prostate cancer PDTX model had positive expression?8 cases were strongly positive,5 cases were weakly positive?,and 1case was negative.8 cases of bladder urothelial carcinoma were negatively expressed in PDTX models.PSMAb antibody immunotherapy was performed in a prostate cancer PDTX model with positive PSMA expression.After 8 days of administration and 11 days of drug withdrawal,the tumor volume of the PSMAb-treated group was significantly smaller than that of the IgG-negative control group according to the tumor growth curve.The above results indicated that PSMAb might be able to inhibit the growth of PSMA-positive prostate cancer in vivo.Conclusions1.PSMA was positively expressed in the cell envelope and tumor blood vessels of prostate cancer,but it was only positively expressed in tumor neovascularization for breast cancer,ovarian cancer,hepatocellular carcinoma and bladder urothelial carcinoma.2.The PSMA-targeted ⁶⁸Ga-PSMA-617 PET/CT imaging test might be superior to mpMRI in the diagnosis performance,especially in the specificity of prostate cancer.The PSA value,Gleason score and ISUP classification group were positively correlated with SUVmax value,and the SUVmax value was able to be used as a meaningful reference index to diagnose clinically significant prostate cancer to avoid overdiagnosis.3.PSMAb antibody had a certain inhibitory effect on PSMA expression of positive prostate cancer PDTX model,suggesting that PSMA might be used as an effective target for prostate cancer immunotherapy.