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202. Corrigendum to “What Experts Think About Prostate Cancer Management During the COVID-19 Pandemic: Report from the Advanced Prostate Cancer Consensus Conference 2021” [Eur Urol 82(1):6–11]

Author

Turco, Fabio, Armstrong, Andrew, Attard, Gerhardt, Beer, Tomasz M., Beltran, Himisha, Bjartell, Anders, Bossi, Alberto, Briganti, Alberto, Bristow, Rob G., Bulbul, Muhammad, Caffo, Orazio, Chi, Kim N., Clarke, Caroline, Clarke, Noel, Davis, Ian D., de Bono, Johann, Duran, Ignacio, Eeles, Ros, Efstathiou, Eleni, Efstathiou, Jason, Evans, Christopher P., Fanti, Stefano, Feng, Felix Y., Fizazi, Karim, Frydenberg, Mark, George, Dan, Gleave, Martin, Halabi, Susan, Heinrich, Daniel, Higano, Celestia, Hofman, Michael S., Hussain, Maha, James, Nicholas, Jones, Rob, Kanesvaran, Ravindran, Khauli, Raja B., Klotz, Laurence, Leibowitz, Raya, Logothetis, Christopher, Maluf, Fernando, Millman, Robin, Morgans, Alicia K., Morris, Michael J., Mottet, Nicolas, Mrabti, Hind, Murphy, Declan G., Murthy, Vedang, Oh, William K., Ekeke, Onyeanunam Ngozi, Ost, Piet, O'Sullivan, Joe M., Padhani, Anwar R., Parker, Christopher, Poon, Darren M.C., Pritchard, Colin C., Rabah, Danny M., Rathkopf, Dana, Reiter, Robert E., Rubin, Mark, Ryan, Charles J., Saad, Fred, Sade, Juan Pablo, Sartor, Oliver, Scher, Howard I., Shore, Neal, Skoneczna, Iwona, Small, Eric, Smith, Matthew, Soule, Howard, Spratt, Daniel, Sternberg, Cora N., Suzuki, Hiroyoshi, Sweeney, Christopher, Sydes, Matthew, Taplin, Mary-Ellen, Tilki, Derya, Tombal, Bertrand, Türkeri, Levent, Uemura, Hiroji, Uemura, Hirotsugu, van Oort, Inge, Yamoah, Kosj, Ye, Dingwei, Zapatero, Almudena, Gillessen, Silke, and Omlin, Aurelius

Published
2022
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206. Identifying the Best Candidates for Prostate-specific Membrane Antigen Positron Emission Tomography/Computed Tomography as the Primary Staging Approach Among Men with High-risk Prostate Cancer and Negative Conventional Imaging

Author

Ma, Ting Martin, Gafita, Andrei, Shabsovich, David, Juarez, Jesus, Grogan, Tristan R., Thin, Pan, Armstrong, Wesley, Sonni, Ida, Nguyen, Kathleen, Lok, Vincent, Reiter, Robert E., Rettig, Matthew B., Steinberg, Michael L., Kupelian, Patrick A., Yang, David D., Muralidhar, Vinayak, Chu, Carissa, Feng, Felix, Savjani, Ricky, Deng, Jie, Parikh, Neil R., Nickols, Nicholas G., Elashoff, David, Czernin, Johannes, Calais, Jeremie, and Kishan, Amar U.

Abstract

Prostate-specific membrane antigen (PSMA) positron emission tomography (PET)/computed tomography (CT) is an emerging imaging modality with greater sensitivity and specificity over conventional imaging for prostate cancer (PCa) staging. Using data from two prospective trials (NCT03368547 and NCT04050215), we explored predictors of overall upstaging (nodal and metastatic) by PSMA PET/CT among patients with cN0M0 National Comprehensive Cancer Network high-risk PCa on conventional imaging (n = 213). Overall, 21.1%, 8.9%, and 23.9% of patients experienced nodal, metastatic, and overall upstaging, respectively, without histologic confirmation. On multivariable analysis, Gleason grade group (GG) and percent positive core (PPC) on systematic biopsy significantly predict overall upstaging (odds ratio [OR] 2.15, 95% confidence interval [CI] 1.33–3.45; p =  0.002; and OR 1.03, 95% CI 1.01–1.04; p <  0.001). Overall upstaging was significantly more frequent among men with GG 5 disease (33.0% vs. 17.6%; p =  0.0097) and PPC ≥50% (33.0% vs 15.0%; p =  0.0020). We constructed a nomogram that predicts overall upstaging using initial prostate-specific antigen, PPC, GG, and cT stage, with coefficients estimated from a standard logistic regression model (using maximum likelihood estimation). It is internally validated with a tenfold cross-validated area under the receiver operating characteristic curve estimated at 0.74 (95% CI 0.67–0.82). In our cohort, 90% of patients who had a nomogram-estimated risk below the cutoff of 22% for overall upstaging could have been spared PSMA PET/CT as our model correctly predicted no upstaging. In other words, the predictive model only missed 10% of patients who would otherwise have benefitted from PSMA PET/CT.

Published
2022
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211. Detection Threshold and Reproducibility of 68Ga-PSMA11 PET/CT in a Mouse Model of Prostate Cancer

Author

Lückerath, Katharina, Stuparu, Andreea D, Wei, Liu, Kim, Woosuk, Radu, Caius G, Mona, Christine E, Calais, Jeremie, Rettig, Matthew, Reiter, Robert E, Czernin, Johannes, Slavik, Roger, Herrmann, Ken, Eiber, Matthias, and Fendler, Wolfgang P

Subjects
Male, Urologic Diseases, Image Processing, Clinical Sciences, Gallium Radioisotopes, Bioengineering, Inbred C57BL, Cell Line, Mice, Computer-Assisted, Positron Emission Tomography Computed Tomography, PSMA, threshold, Animals, 2.1 Biological and endogenous factors, Aetiology, reproducibility, Gallium Isotopes, Edetic Acid, Cancer, Neoplastic, Tumor, Animal, Prostate Cancer, Prostatic Neoplasms, Reproducibility of Results, Biological Transport, Nuclear Medicine & Medical Imaging, PET, Good Health and Well Being, Gene Expression Regulation, Disease Models, Biomedical Imaging, Oligopeptides, Biotechnology
Abstract

To improve prostate-specific membrane antigen (PSMA)-targeted theranostic approaches, robust murine models of prostate cancer are needed. However, important characteristics of preclinical PSMA imaging-that is, the reproducibility of the imaging signal and the relationship between quantitative cell surface PSMA expression and lesion detectability with small-animal PET/CT-have not been defined yet. Methods: Murine prostate cancer RM1 sublines (ras myc transformed cells of C57BL/6 prostate origin) expressing varying levels of human PSMA were injected into the shoulder of C57BL/6 mice on day 0. 68Ga-PSMA11 PET/CT was performed on days 7 and 8 and interpreted by 2 masked readers to determine interday and interreader reproducibility. PSMA expression was quantified on days 7 and 8 by flow cytometry of fine-needle aspiration tumor biopsy samples. Cell surface PSMA expression was correlated with PET signal. The threshold for PET positivity was based on the clinical Prostate Cancer Molecular Imaging Standardized Evaluation (PROMISE) criteria. Results: The maximum and average percentages of injected 68Ga-PSMA11 activity per gram of tissue (%IA/g) correlated nearly perfectly as determined by 2 independent readers and on 2 separate days (intraclass correlation coefficient, 1.00/0.89 and 0.95/0.88, respectively). The number of PSMA molecules per cell increased from the RM1-yellow fluorescent protein subline (PSMA-; 2,000/cell) to the RM1-low subline (PSMA+; 17,000/cell), the RM1-medium subline (PSMA++; 22,000/cell), and the RM1-PGLS subline (PSMA-positive, green fluorescent protein-positive, and luciferase-positive; PSMA+++; 45,000/cell). Expression levels correlated with the visual positivity rate on 68Ga-PSMA11 PET and with the PSMA PET %IA/g. The PSMA threshold for PET positivity was approximately 20,000 per cell. Signal correlation was close at lower PSMA levels (RM1-low to RM1-medium; 10-23 %IA/g) but was lost at higher PSMA levels (RM1-medium to RM1-PGLS; 23-27 %IA/g). Conclusion: The in vivo relationship between 68Ga-PSMA11 PET/CT and PSMA expression level in a murine model of prostate cancer was robust for lower cell surface PSMA expression levels (≤22,000/cell). Thus, preclinical 68Ga-PSMA11 PET/CT can be used as an imaging biomarker to test PSMA-targeted interventions in murine models.

Published
2018

214. Dynamic contrast-enhanced (DCE) MR imaging: the role of qualitative and quantitative parameters for evaluating prostate tumors stratified by Gleason score and PI-RADS v2

Author

Afshari Mirak, Sohrab, primary, Mohammadian Bajgiran, Amirhossein, additional, Sung, Kyunghyun, additional, Asvadi, Nazanin H., additional, Markovic, Daniela, additional, Felker, Ely R., additional, Lu, David, additional, Sisk, Anthony, additional, Reiter, Robert E., additional, and Raman, Steven S., additional

Published
2019
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216. 18F-fluciclovine PET-CT and 68Ga-PSMA-11 PET-CT in patients with early biochemical recurrence after prostatectomy: a prospective, single-centre, single-arm, comparative imaging trial

Author

Calais, Jeremie, primary, Ceci, Francesco, additional, Eiber, Matthias, additional, Hope, Thomas A, additional, Hofman, Michael S, additional, Rischpler, Christoph, additional, Bach-Gansmo, Tore, additional, Nanni, Cristina, additional, Savir-Baruch, Bital, additional, Elashoff, David, additional, Grogan, Tristan, additional, Dahlbom, Magnus, additional, Slavik, Roger, additional, Gartmann, Jeannine, additional, Nguyen, Kathleen, additional, Lok, Vincent, additional, Jadvar, Hossein, additional, Kishan, Amar U, additional, Rettig, Matthew B, additional, Reiter, Robert E, additional, Fendler, Wolfgang P, additional, and Czernin, Johannes, additional

Published
2019
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218. Molecular Hallmarks of Multiparametric Magnetic Resonance Imaging Visibility in Prostate Cancer

Author

Houlahan, Kathleen E., primary, Salmasi, Amirali, additional, Sadun, Taylor Y., additional, Pooli, Aydin, additional, Felker, Ely R., additional, Livingstone, Julie, additional, Huang, Vincent, additional, Raman, Steven S., additional, Ahuja, Preeti, additional, Sisk, Anthony E., additional, Boutros, Paul C., additional, and Reiter, Robert E., additional

Published
2019
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220. Detection and Localization of Prostate Cancer at 3-T Multiparametric MRI Using PI-RADS Segmentation

Author

Wibulpolprasert, Pornphan, primary, Raman, Steven S., additional, Hsu, William, additional, Margolis, Daniel J. A., additional, Asvadi, Nazanin H., additional, Khoshnoodi, Pooria, additional, Moshksar, Amin, additional, Tan, Nelly, additional, Ahuja, Preeti, additional, Maehara, Cleo K., additional, Huang, Jiaoti, additional, Sayre, James, additional, Lu, David S. K., additional, and Reiter, Robert E., additional

Published
2019
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221. Assessment of 68Ga-PSMA-11 PET Accuracy in Localizing Recurrent Prostate Cancer

Author

Fendler, Wolfgang P., primary, Calais, Jeremie, additional, Eiber, Matthias, additional, Flavell, Robert R., additional, Mishoe, Ashley, additional, Feng, Felix Y., additional, Nguyen, Hao G., additional, Reiter, Robert E., additional, Rettig, Matthew B., additional, Okamoto, Shozo, additional, Emmett, Louise, additional, Zacho, Helle D., additional, Ilhan, Harun, additional, Wetter, Axel, additional, Rischpler, Christoph, additional, Schoder, Heiko, additional, Burger, Irene A., additional, Gartmann, Jeannine, additional, Smith, Raven, additional, Small, Eric J., additional, Slavik, Roger, additional, Carroll, Peter R., additional, Herrmann, Ken, additional, Czernin, Johannes, additional, and Hope, Thomas A., additional

Published
2019
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223. Do contemporary imaging and biopsy techniques reliably identify unilateral prostate cancer? Implications for hemiablation patient selection

Author

Johnson, David C., primary, Yang, Jason J., additional, Kwan, Lorna, additional, Barsa, Danielle E., additional, Mirak, Sohrab A., additional, Pooli, Aydin, additional, Sadun, Taylor, additional, Jayadevan, Rajiv, additional, Zhou, Steve, additional, Priester, Alan M., additional, Natarajan, Shyam, additional, Bajgiran, Amirhossein M., additional, Shakeri, Sepideh, additional, Sisk, Anthony, additional, Felker, Ely R., additional, Raman, Steven S., additional, Marks, Leonard S., additional, and Reiter, Robert E., additional

Published
2019
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224. Detection of Individual Prostate Cancer Foci via Multiparametric Magnetic Resonance Imaging

Author

Johnson, David C., primary, Raman, Steven S., additional, Mirak, Sohrab A., additional, Kwan, Lorna, additional, Bajgiran, Amirhossein M., additional, Hsu, William, additional, Maehara, Cleo K., additional, Ahuja, Preeti, additional, Faiena, Izak, additional, Pooli, Aydin, additional, Salmasi, Amirali, additional, Sisk, Anthony, additional, Felker, Ely R., additional, Lu, David S.K., additional, and Reiter, Robert E., additional

Published
2019
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225. PD05-03 MOLECULAR HALLMARKS OF MPMRI VISIBILITY IN PROSTATE CANCER

Author

Sadun*, Taylor Y., primary, Houlahan, Kathleen E., additional, Salmasi, Amirali, additional, Pooli, Aydin, additional, Felker, Ely R., additional, Raman, Steven S., additional, Ahuja, Preeti, additional, Sisk, Anthony E., additional, Boutros, Paul C., additional, and Reiter, Robert E., additional

Published
2019
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229. A Clinician’s Guide to Next Generation Imaging in Patients With Advanced Prostate Cancer (RADAR III)

Author

Crawford, E. David, primary, Koo, Phillip J., additional, Shore, Neal, additional, Slovin, Susan F., additional, Concepcion, Raoul S., additional, Freedland, Stephen J., additional, Gomella, Leonard G., additional, Karsh, Lawrence, additional, Keane, Thomas E., additional, Maroni, Paul, additional, Penson, David, additional, Petrylak, Daniel P., additional, Ross, Ashley, additional, Mouraviev, Vlad, additional, Reiter, Robert E., additional, Divgi, Chaitanya, additional, and Yu, Evan Y., additional

Published
2019
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230. MP78-20 PREDICTING PATHOLOGIC TUMOR SIZE IN PROSTATE CANCER BASED ON MULTIPARAMETRIC PROSTATE MRI AND PREOPERATIVE FINDINGS

Author

Pooli*, Aydin, primary, Johnson, David C., additional, Sadun, Taylor Y., additional, Markovic, Daniela, additional, Sisk, Anthony E. JR., additional, Bajgiran, Amirhossein Mohammadian, additional, Mirak, Sohrab Afshari, additional, Felker, Ely R., additional, Raman, Steven S., additional, and Reiter, Robert E., additional

Published
2019
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231. Systemic and tumor-directed therapy for oligometastatic prostate cancer: study protocol for a phase II trial for veterans with de novo oligometastatic disease

Author

Parikh, Neil R., primary, Huiza, Claudia, additional, Patel, Jill S., additional, Tsai, Sonny, additional, Kalpage, Nathisha, additional, Thein, May, additional, Pitcher, Sage, additional, Lee, Steve P., additional, Inouye, Warren S., additional, Jordan, Mark L., additional, Sanati, Homayoon, additional, Jafari, Lida, additional, Bennett, Carol J., additional, Gin, Greg E., additional, Kishan, Amar U., additional, Reiter, Robert E., additional, Lewis, Michael, additional, Sadeghi, Ahmad, additional, Aronson, William J., additional, Garraway, Isla P., additional, Rettig, Matthew B., additional, and Nickols, Nicholas G., additional

Published
2019
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232. Three Tesla Multiparametric Magnetic Resonance Imaging: Comparison of Performance with and without Endorectal Coil for Prostate Cancer Detection, PI-RADS™ version 2 Category and Staging with Whole Mount Histopathology Correlation

Author

Mirak, Sohrab Afshari, primary, Shakeri, Sepideh, additional, Bajgiran, Amirhossein Mohammadian, additional, Felker, Ely R., additional, Sung, Kyung Hyun, additional, Asvadi, Nazanin Hajarol, additional, Khoshnoodi, Pooria, additional, Markovic, Daniela, additional, Ponzini, Danielle, additional, Ahuja, Preeti, additional, Sisk, Anthony, additional, Reiter, Robert E., additional, Lu, David, additional, and Raman, Steven S., additional

Published
2019
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233. MEK-ERK signaling is a therapeutic target in metastatic castration resistant prostate cancer

Author

Nickols, Nicholas G., primary, Nazarian, Ramin, additional, Zhao, Shuang G., additional, Tan, Victor, additional, Uzunangelov, Vladislav, additional, Xia, Zheng, additional, Baertsch, Robert, additional, Neeman, Elad, additional, Gao, Allen C., additional, Thomas, George V., additional, Howard, Lauren, additional, De Hoedt, Amanda M., additional, Stuart, Josh, additional, Goldstein, Theodore, additional, Chi, Kim, additional, Gleave, Martin E., additional, Graff, Julie N., additional, Beer, Tomasz M., additional, Drake, Justin M., additional, Evans, Christopher P., additional, Aggarwal, Rahul, additional, Foye, Adam, additional, Feng, Felix Y., additional, Small, Eric J., additional, Aronson, William J., additional, Freedland, Stephen J., additional, Witte, Owen N., additional, Huang, Jiaoti, additional, Alumkal, Joshi J., additional, Reiter, Robert E., additional, and Rettig, Matthew B., additional

Published
2019
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236. Association of Gleason Grade With Androgen Deprivation Therapy Duration and Survival Outcomes

Author

Kishan, Amar U., primary, Wang, Xiaoyan, additional, Seiferheld, Wendy, additional, Collette, Laurence, additional, Sandler, Kiri A., additional, Sandler, Howard M., additional, Bolla, Michel, additional, Maingon, Philippe, additional, De Reijke, Theo, additional, Hanks, Gerald E., additional, Nickols, Nicholas G., additional, Rettig, Matthew, additional, Drakaki, Alexandra, additional, Reiter, Robert E., additional, Spratt, Daniel E., additional, Kupelian, Patrick A., additional, Steinberg, Michael L., additional, and King, Christopher R., additional

Published
2019
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239. Near-Infrared Dye-Labeled Anti-Prostate Stem Cell Antigen Minibody Enables Real-Time Fluorescence Imaging and Targeted Surgery in Translational Mouse Models

Author

Zhang, Mo, primary, Kobayashi, Naoko, additional, Zettlitz, Kirstin A., additional, Kono, Evelyn A., additional, Yamashiro, Joyce M., additional, Tsai, Wen-Ting K., additional, Jiang, Ziyue K., additional, Tran, Chau P., additional, Wang, Chung, additional, Guan, Johnny, additional, Wu, Anna M., additional, and Reiter, Robert E., additional

Published
2019
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240. Preclinical evaluation of PSMA expression in response to androgen receptor blockade for theranostics in prostate cancer

Author

Lückerath, Katharina, primary, Wei, Liu, additional, Fendler, Wolfgang P., additional, Evans-Axelsson, Susan, additional, Stuparu, Andreea D., additional, Slavik, Roger, additional, Mona, Christine E., additional, Calais, Jeremie, additional, Rettig, Matthew, additional, Reiter, Robert E., additional, Herrmann, Ken, additional, Radu, Caius G., additional, Czernin, Johannes, additional, and Eiber, Matthias, additional

Published
2018
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242. Genomic Hallmarks and Structural Variation in Metastatic Prostate Cancer

Author

Quigley, David A., primary, Dang, Ha X., additional, Zhao, Shuang G., additional, Lloyd, Paul, additional, Aggarwal, Rahul, additional, Alumkal, Joshi J., additional, Foye, Adam, additional, Kothari, Vishal, additional, Perry, Marc D., additional, Bailey, Adina M., additional, Playdle, Denise, additional, Barnard, Travis J., additional, Zhang, Li, additional, Zhang, Jin, additional, Youngren, Jack F., additional, Cieslik, Marcin P., additional, Parolia, Abhijit, additional, Beer, Tomasz M., additional, Thomas, George, additional, Chi, Kim N., additional, Gleave, Martin, additional, Lack, Nathan A., additional, Zoubeidi, Amina, additional, Reiter, Robert E., additional, Rettig, Matthew B., additional, Witte, Owen, additional, Ryan, Charles J., additional, Fong, Lawrence, additional, Kim, Won, additional, Friedlander, Terence, additional, Chou, Jonathan, additional, Li, Haolong, additional, Das, Rajdeep, additional, Li, Hui, additional, Moussavi-Baygi, Ruhollah, additional, Goodarzi, Hani, additional, Gilbert, Luke A., additional, Lara, Primo N., additional, Evans, Christopher P., additional, Goldstein, Theodore C., additional, Stuart, Joshua M., additional, Tomlins, Scott A., additional, Spratt, Daniel E., additional, Cheetham, R. Keira, additional, Cheng, Donavan T., additional, Farh, Kyle, additional, Gehring, Julian S., additional, Hakenberg, Jörg, additional, Liao, Arnold, additional, Febbo, Philip G., additional, Shon, John, additional, Sickler, Brad, additional, Batzoglou, Serafim, additional, Knudsen, Karen E., additional, He, Housheng H., additional, Huang, Jiaoti, additional, Wyatt, Alexander W., additional, Dehm, Scott M., additional, Ashworth, Alan, additional, Chinnaiyan, Arul M., additional, Maher, Christopher A., additional, Small, Eric J., additional, and Feng, Felix Y., additional

Published
2018
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245. False positive PSMA PET for tumor remnants in the irradiated prostate and other interpretation pitfalls in a prospective multi-center trial.

Author

Fendler, Wolfgang P., Calais, Jeremie, Eiber, Matthias, Simko, Jeffrey P., Kurhanewicz, John, Santos, Romelyn Delos, Feng, Felix Y., Reiter, Robert E., Rettig, Matthew B., Nickols, Nicholas G., Kishan, Amar U., PSMA PET Reader Group, Shozo, Okamoto, Emmett, Louise, Zacho, Helle D., Ilhan, Harun, Rischpler, Christoph, Wetter, Axel, Schoder, Heiko, and Burger, Irene A.

Subjects
PROSTATE, HOSPITAL central service departments, PROSTATE cancer, TREATMENT effectiveness, EXOCRINE glands
Abstract

Purpose: Readers need to be informed about potential pitfalls of [68Ga]Ga-PSMA-11 PET interpretation. Methods: Here we report [68Ga]Ga-PSMA-11 PET findings discordant with the histopathology/composite reference standard in a recently published prospective trial on 635 patients with biochemically recurrent prostate cancer. Results: Consensus reads were false positive in 20 regions of 17/217 (8%) patients with lesion validation. Majority of the false positive interpretations (13 of 20, 65%) occurred in the context of suspected prostate (bed) relapse (T) after radiotherapy (n = 11); other false positive findings were noted for prostate bed post prostatectomy (T, n = 2), pelvic nodes (N, n = 2), or extra pelvic lesions (M, n = 5). Major sources of false positive findings were PSMA-expressing residual adenocarcinoma with marked post-radiotherapy treatment effect. False negative interpretation occurred in 8 regions of 6/79 (8%) patients with histopathology validation, including prostate (bed) (n = 5), pelvic nodes (n = 1), and extra pelvic lesions (n = 2). Lesions were missed mostly due to small metastases or adjacent bladder/urine uptake. Conclusion: [68Ga]Ga-PSMA-11 PET at biochemical recurrence resulted in less than 10% false positive interpretations. Post-radiotherapy prostate uptake was a major source of [68Ga]Ga-PSMA-11 PET false positivity. In few cases, PET correctly detects residual PSMA expression post-radiotherapy, originating however from treated, benign tissue or potentially indolent tumor remnants. Trial registration number: ClinicalTrials.gov Identifiers: NCT02940262 and NCT03353740. [ABSTRACT FROM AUTHOR]

Published
2021
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246. Impact of 68Ga-PSMA-11 PET on the Management of recurrent Prostate Cancer in a Prospective Single-Arm Clinical Trial.

Author

Fendler, Wolfgang P., Ferdinandus, Justin, Czernin, Johannes, Eiber, Matthias, Flavell, Robert R., Behr, Spencer C., Wu, I-Wei K., Lawhn-Heath, Courtney, Pampaloni, Miguel H., Reiter, Robert E., Rettig, Matthew B., Gartmann, Jeannine, Murthy, Vishnu, Slavik, Roger, Carroll, Peter R., Herrmann, Ken, Calais, Jeremie, and Hope, Thomas A.

Published
2020
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248. Evaluation of [131I]I- and [177Lu]Lu-DTPA-A11 Minibody for Radioimmunotherapy in a Preclinical Model of PSCA-Expressing Prostate Cancer.

Author

Tsai, Wen-Ting K, Zettlitz, Kirstin A, Dahlbom, Magnus, Reiter, Robert E, and Wu, Anna M

Subjects
RADIOIMMUNOTHERAPY, ANIMAL models in research, PROSTATE cancer, TUMOR growth, STEM cells, CYTOTOXIC T cells
Abstract

Purpose: Radioimmunotherapy uses tumor-specific antibodies to deliver therapeutic radionuclides, but hematological toxicity due to the long serum half-life of intact antibodies remains a challenge. We evaluated a smaller antibody fragment, the minibody, with faster kinetics and a potentially improved therapeutic index. Procedures: The anti-prostate stem cell antigen (PSCA) minibody (A11 Mb) was radiolabeled with iodine-124 ([124I]I-A11 Mb) or conjugated with deferoxamine (DFO) and labeled with zirconium-89 ([89Zr]Zr-DFO-A11 Mb) for surrogate immunoPET to profile pharmacokinetics in a human prostate cancer xenograft model. Subsequently, minibodies labeled with two therapeutic beta emitters, directly iodinated [131I]I-A11 Mb (non-residualizing) and 177Lu chelated using DTPA ([177Lu]Lu-DTPA-A11 Mb) (residualizing), were compared for in vitro antigen-specific cytotoxicity. Full biodistribution studies (in 22Rv1-PSCA tumor bearing and hPSCA knock-in mice) were conducted for dosimetry calculations. Finally, the lead candidate [131I]I-A11 Mb was evaluated in a radioimmunotherapy experiment. Escalating single doses (3.7, 11, or 37 MBq) and saline control were administered to 22Rv1-PSCA tumor bearing mice and anti-tumor effects (tumor volume) and toxicity (body weight) were monitored. Results: Minibodies radiolabeled with therapeutic beta emitters [131I]I-A11 Mb and [177Lu]Lu-DTPA-A11 Mb exhibited comparable tumor cell growth inhibition in vitro. In vivo surrogate immunoPET imaging using [89Zr]Zr-DFO-A11 Mb showed activity retention in liver and kidney up to 72 h, while [124I]I-A11 Mb cleared from liver, kidney, and blood by 48 h. Based on full biodistribution and dosimetry calculations, administering 37 MBq [131I]I-A11 Mb was predicted to deliver a favorable dose to the tumor (35 Gy), with a therapeutic index of 22 (tumor:bone marrow). For [177Lu]Lu-DTPA-A11 Mb, the kidneys would be dose-limiting, and the maximum tolerated activity (7.4 MBq) was not predicted to deliver an effective radiation dose to tumor. Radioimmunotherapy with a single dose of [131I]I-A11 Mb showed dose-dependent tumor inhibition with minimal off-target toxicity and improved median survival (19 and 24 days, P < 0.001) compared with untreated mice (12 days). Conclusions: These findings show the potential of the anti-PSCA minibody for targeted radioimmunotherapy with minimal toxicity, and the application of immunoPET and dosimetry for personalized treatment. [ABSTRACT FROM AUTHOR]

Published
2020
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249. Impact of 68Ga-PSMA-11 PET on the Management of recurrent Prostate Cancer in a Prospective Single-Arm Clinical Trial.

Author

Fendler, Wolfgang P., Ferdinandus, Justin, Czernin, Johannes, Eiber, Matthias, Flavell, Robert R., Behr, Spencer C., Wu, I-Wei K., Lawhn-Heath, Courtney, Pampaloni, Miguel H., Reiter, Robert E., Rettig, Matthew B., Gartmann, Jeannine, Murthy, Vishnu, D, Roger Slavik, Carroll, Peter R., Herrmann, Ken, Calais, Jeremie, and Hope, Thomas A.

Published
2020
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