Preliminary Clinical Application Study Of PSMA-targeted Precision Diagnosis And Treatment In Various Solid Tumor

Project Ⅰ Head-to-head comparison of[68Ga]Ga-P16-093 and[68Ga]Ga-PSMA-617 in dynamic PET/CT evaluation of the same group of recurrent prostate cancer patientsPurpose:We synthesized a new PSMA-targeted molecular probe,named P16-093.This study was prospectively designed to evaluate the early dynamic organ distribution and tumor detection capability of[68Ga]Ga-P 16-093,which was compared with[68Ga]GaPSMA-617 in the same group of recurrent prostate cancer patients.Methods:With approved by the Institutional Review Board of Peking Union Medical College Hospital,Chinese Academy of Medical Sciences and Peking Union Medical College,twenty patients with recurrent prostate cancer were enrolled and written informed consent was obtained from all subjects.In 2 consecutive days,each patient underwent a 60-min dynamic PET/CT scan after intravenous administration of 148-185 MBq(4-5 mCi)[68Ga]Ga-P 16-093 and[68Ga]Ga-PSMA-617,respectively.Following a low-dose CT scan,serial dynamic PET scans were performed from head to proximal thigh at 9 time points(30 s/bed at 4,7,10,13,and 16 min;1 min/bed at 20,30,and 45 min;and 2 min/bed at 60 min).The standardized uptake value(SUV)of the two tracers in physiological organs(parotid gland,blood pool,liver,spleen,kidney,bladder)at each time point,and the number of tumors detected were compared.Results:[68Ga]Ga-P 16-093 PET/CT revealed a significantly higher tumor uptake(at 4 min,SUVmax 7.88 ± 5.26 vs.6.01 ± 3.88,P<0.001),less blood pool retention(at 4 min,SUVmean 5.12±1,16 vs.6.14 ± 0.98,P<0.001),and lower bladder accumulation(at 60 min,SUVmean 31.33 ± 27.47 vs.48.74 ± 34.01,P=0.042)than[68Ga]Ga-PSMA-617 scan.Significantly higher[68Ga]Ga-P 16-093 uptakes were also observed in the parotid gland,liver,spleen,and kidney.Besides,[68Ga]Ga-P 16-093 PET/CT exhibited a better detectability of tumor than[68Ga]Ga-PSMA-617 PET/CT(366 vs.321,P=0.009).Conclusions:[68Ga]Ga-P 16-093 is a promising molecular probe targeting PSMA.Compared with[68Ga]Ga-PSMA-617,[68Ga]Ga-P 16-093 show the advantages of fast blood clearance,low bladder background,and high tumor uptake,which may be of potential advantages in the detection of prostate cancer and Lu-177 radioligand therapy.Project Ⅱ Head-to-Head comparison of[68Ga]Ga-P16-093/[68Ga]Ga-PSMA-617 PET/CT and[68Ga]Ga-P16-093/[68Ga]Ga-PSMA-11 PET/CT in patients with primary prostate cancerPurpose:We previously conducted a preliminary clinical study of a new molecular probe[68Ga]Ga-P 16-093 and found that[68Ga]Ga-P 16-093 showed higher tumor uptake and lower bladder background than[68Ga]Ga-PSMA-617,which may give[68Ga]Ga-P 16-093 an advantage in detecting intraprostatic leison.We aimed to further compare the diagnostic performance of[68Ga]Ga-P 16-093 and[68Ga]Ga-PSMA-617,[68Ga]Ga-PSMA-11 PET/CT in primary prostate cancer(PCa)patients.Patients and Methods:With approved by the Institutional Review Board of Peking Union Medical College Hospital,a total of 80 patients with pathologically confirmed primary PCa were enrolled.Among them,30 patients underwent[68Ga]Ga-P 16-093 and[68Ga]GaPSMA-617 PET/CT within one week.Fifty patients underwent[68Ga]Ga-P 16-093 and[68Ga]Ga-PSMA-11 PET/CT within a week.The number of lesions detected by the two tracers and the SUVmax of tumor lesions were compared.Results:[68Ga]Ga-P 16-093 PET/CT detected more positive tumors than[68Ga]Ga-PSMA617 PET/CT(67 vs.56,P=0.002),especially for intraprostatic lesions(29 vs.24,P=0.025)and lymph node metastases(23 vs.17,P=0.034).Further,[68Ga]Ga-P 16-093 PET/CT exhibited significantly higher SUVmax of matched tumors(18.3±14.4 vs.13.9± 11.8,P<0.001).Besides,the SUVmax of high-risk patients on[68Ga]Ga-P16-093 PET/CT was significantly higher than that of low-and intermediate-risk PCa patients(20.9± 9.9 vs.8.9 ± 9.1 vs.10.1 ± 5.2,P=0.007).The SUVmax of tumor measured by[68Ga]GaP16-093 PET/CT had a moderate association with biopsy Gleason score(r=0.462,P=0.005)and prostate-specific antigen value(r=0.491,P=0.002),and significantly correlated with PSMA expression(r=0.732,P<0.001).[68Ga]Ga-P 16-093 PET/CT detected more positive tumors than[68Ga]Ga-PSMA-11 PET/CT(202 vs.190,P=0.001),both for intraprostatic lesions(48 vs.41,P=0.016)and metastatic lesions(154 vs.149,P=0.125);especially,[68Ga]Ga-P 16-093 PET/CT was superior to[68Ga]Ga-PSMA-11 PET/CT in the detection of intraprostatic lesions in patients with low-and intermediate-risk PCa(21/23 vs.15/23,P=0.031).Furthermore,[68Ga]Ga-P 16-093 PET/CT exhibited a significantly higher SUVmax of most matched tumors(13.7 ± 10.2 vs.11.4 ± 8.3,P<0.001).[68Ga]Ga-P16-093 PET/CT illustrated higher sensitivity and specificity in detecting intraprostatic tumors than[68Ga]Ga-PSMA11 PET/CT(area under the curve:0.991 vs.0.906,P=0.007).For normal organs,[68Ga]Ga-P 16-093 PET/CT showed significantly lower activity in the kidney(SUVmean:20.1±6.1 vs.29.3 ± 9.1,P<0.001)and urinary bladder(SUVmean:6.5 ± 7.1 vs.20.9±17.4,P<0.001)but higher uptake in the parotid gland(SUVmean:11.4±4.3 vs.9.2±2.3,P<0.001),liver(SUVmean:6.5 ±0.7 vs.3.6±0.6,P<0.001),and spleen(SUVmean:7.1 ± 2.6 vs.4.7±2.1,P<0.001)than[68Ga]Ga-PSMA-11 PET/CT.Conclusions:[68Ga]Ga-P 16-093 PET/CT exhibited higher tumor uptake and potentially better tumor detection capability than[68Ga]Ga-PSMA-617,[68Ga]Ga-PSMA-11 PET/CT.Project Ⅲ A multiple-cycles,low-dose,prospective study of[177Lu]Lu-EB-PSMA radioligand therapy in patients with metastatic castration-resistant prostate cancerPurpose:Our previous study demonstrated that[177Lu]Lu-EB-PSMA can increase the targeted accumulation and retention time of Lu-177 in mCRPC.Moreover,low doses of[177Lu]Lu-EB-PSMA can reveal significant therapeutic effect.[177Lu]Lu-EB-PSMA radioligand therapy(RLT)with 2.2GBq(60 mCi)may be superior to treatment with approximately 1.1 GBq(30 mCi)and approximately 3.7 GBq(100 mCi)[177Lu]Lu-EBPSMA RLT.Based on the above findings,this study continued to investigate the safety and efficacy of about 2.0 GBq(55 mCi)[177Lu]Lu-EB-PSMA RLT in the treatment of mCRPC.Methods:Approved by the Institutional Review Board of Peking Union Medical College Hospital,thirty men with progressive mCRPC previously treated with taxane-based chemotherapy and second-generation androgen deprivation therapy were enrolled.All patients received up to three cycles of approximately 2.0 GBq(55 mCi)[177Lu]Lu-EBPSMA per cycle at 8-week intervals.The primary endpoint was therapeutic safety,including the changes of hematologic status,liver function,and renal function tests;the additional primary endpoint was therapeutic efficacy,including prostate-specific antigen(PSA)response and molecular imaging response;the secondary endpoints were PSA progression-free survival(PSA-PFS)and overall survival(OS).Another endpoint was patient-reported health-related quality-of-life(HRQOL).Results:From January 2019 to December 2021,30,22 and 11 patients received 1,2 and 3 cycles of[177Lu]Lu-EB-PSMA RLT,respectively.During the entire follow-up period,33.3%of patients experienced grade 3 hematological adverse events.Seventeen(56.7%)patients achieved a PSA reduction of at least 50%.The median PSA-PFS was 4.6 mo(95%CI,2.7-6.5 mo),and the median OS was 12.6 mo(95%CI,8.1-17.1 mo).A higher wholebody PSMA mean standardized uptake value(SUVmean)was correlated with a better PSA response;higher baseline alkaline phosphatase and larger total PSMA-positive tumor volume(PSMA-VOL)were associated with worse PSA-PFS,whereas the existence of visceral metastases and PSA at baseline were significant prognosticators of worse OS.HRQOL outcomes improved significantly after[177Lu]Lu-EB-PSMA RLT.Conclusion:RLT based on approximately 2.0 GBq of[177Lu]Lu-EB-PSMA for up to 3 cycles may achieve a comparable PSA response and hematological toxicity with 7.4 GBq doses of[177Lu]Lu-PSMA-617 for up to 4-6 cycles.Further studies with more cycles of[177Lu]Lu-EB-PSMA RLT are needed to evaluate the potential benefits in terms of PFS and OS.Project Ⅳ Head-to-head comparison of[68Ga]Ga-P16-093 and 2-[18F]FDG PET/CT in patients with clear cell renal cell carcinomaPurpose:This pilot study was prospectively designed to evaluate and compare the diagnostic value of PET/CT using a PSMAspecific tracer[68Ga]Ga-P 16-093 and a glucose metabolism probe 2-[18F]FDG in clear cell renal cell carcinoma(ccRCC)patients.Methods:With approved by the Institutional Review Board of Peking Union Medical College Hospital,forty-two pathologically confirmed ccRCC patients were included.Within 1 week,each patient underwent[68Ga]Ga-P 16-093 and 2-[18F]FDG PET/CT.In addition to visual analysis of tumor number,the standardized uptake value was measured for semiquantitative comparison and correlation analysis.Results:For primary ccRCC patients,[68Ga]Ga-P 16-093 PET/CT demonstrated a significantly higher detection rate(19/22 vs.13/22,P=0.031)and higher tumor uptake(15.7±9.0 vs.5.1 ± 3.4,P<0.001)than 2-[18F]FDG PET/CT.In addition,the SUVmax of the primary tumor on[68Ga]Ga-P 16-093 and 2-[18F]FDG PET/CT was significantly correlated with pT stage(for[68Ga]Ga-P 16-093,r=0.550,P=0.008;for 2-[18F]FDG,r=0.514,P=0.014)and WHO/ISUP grade(for[68Ga]Ga-P 16-093,r=0.566,P=0.006;for 2-[18F]FDG,r=0.492,P=0.020),respectively.For metastatic ccRCC patients,[68Ga]GaP16-093 PET/CT also demonstrated a better detection rate(per-patient analysis,21/22 vs.14/22,P=0.008;per-lesion analysis,85 vs.53,P=0.001)and higher tumor uptake(11.0±6.4 vs.4.4±2.7,P<0.001)than 2-[18F]FDG PET/CT.The SUVmax on[68Ga]Ga-P16093 PET/CT had a significant association with PSMA expression in primary ccRCC(r=0.776,P<0.001)and metastatic ccRCC(r=0.626,P=0.029).Conclusions:[68Ga]Ga-P16-093 PET/CT demonstrates significantly better tumor detectability than 2-[18F]FDG PET/CT for ccRCC patients.Project Ⅴ Comparison of[68Ga]Ga-PSMA-617 and 2-[18F]FDG PET/CT in the diagnosis of adenoid cystic carcinoma of the head and neck and a pilot study of[177Lu]Lu-EB-PSMA in the treatment of metastatic adenoid cystic carcinomaPurpose:This pilot study was designed to evaluate the diagnostic value of[68Ga]Ga-PSMA-617 and 2-[18F]FDG PET/CT in adenoid cystic carcinoma(ACC)and to assess the safety and therapeutic response to PSMA RLT in ACC patients.Methods:With approved by the Institutional Review Board of Peking Union Medical College Hospital,thirty patients pathologically diagnosed with ACC were recruited into the cohort.Each patient underwent[68Ga]Ga-PSMA-617 and 2-[18F]FDG PET/CT within 1 week.The number and SUVmax of PET-positive lesions were recorded and compared.Four patients accepted RLT using[177Lu]Lu-EB-PSMA-617,in a dosage of approximately 1.85 GBq(50 mCi)per cycle for up to 3 cycles.Results:Compared with 2-[18F]FDG PET/CT,[68Ga]Ga-PSMA-617 PET/CT revealed more PET-positive extrapulmonary tumors(157 vs.141,P=0.016)and higher SUVmax(8.8 ± 3.6 vs.6.4 ± 4.2,P=0.027).However,[68Ga]Ga-PSMA-617 PET/CT revealed less PET-positive pulmonary lesions(202 vs.301,P<0.001)and lower SUVmax of tumors(3.1±3.0 vs.4.2 ± 3.9,P<0.001)than 2-[18F]FDG PET/CT.The combination of[68Ga]Ga-PSMA-617 and 2-[18F]FDG PET/CT can detect 469 PET-positive lesions,which was superior to each alone(469 vs.359 vs.442,P<0.001).Two patients achieved remarkable response after PSMA RLT,the chief complaint improved and the SUVmax of the tumor decreased significantly;while the other two patients showed reduced tumor uptake of recurrent foci,lung and liver metastases,whereas increased SUVmax of bone metastases.Conclusions:[68Ga]Ga-PSMA-617 PET/CT is a valuable imaging modality for the detection of ACC and combining with 2-[18F]FDG PET/CT will achieve a higher detection efficiency.PSMA RLT may be a promising treatment for ACC and is worth of further investigation.