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Targeting metastatic prostate cancer with radiolabeled monoclonal antibody J591 to the extracellular domain of prostate specific membrane antigen
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Mark P. Ritter / Urologic Oncology: Seminars and Original Investigations 22 (2004) 378 –385
of biochemical and clinical outcomes in 4,839 prostate cancer patients treated with radiotherapy and constructed from results from 9 institutions. These definitions were tested with respect to their abilities to predict clinical failure. Furthermore, the impact of backdating the failure date, one of the most controversial features of the current ASTRO definition, was explored in detail. Results indicated that while the original ASTRO definition has very usefully provided a standardized outcomes assessment method that has reasonable accuracy, there are several alternate definitions that provide superior sensitivity and specificity for predicting clinical failure and that avoid an overestimation of failure rates that backdating produces, particularly at earlier follow-up intervals. Included with these superior definitions were three rises scored at the time of the last rise (call date) and PSA nadir plus 2 ng/mL increase. Importantly, low absolute PSA failure thresholds such as 0.2 or 0.5 ng/mL, which would be considered more appropriate in a postprostatectomy setting, suffered from very poor specificity and were deemed inadequate for this group of patients treated with external beam radiotherapy. In contrast, as in the case of surgery, it has been suggested that very low thresholds might be superior for prostate brachytherapy-treated patients. The findings of the above analyses will likely play a role in future modifications of the post-radiation definition of biochemical failure—modifications that will hopefully further improve the ability to counsel patients and compare outcomes of different treatment strategies and modalities. doi:10.1016/j.urolonc.2004.04.022 Mark P. Ritter, M.D., Ph.D.
Targeting metastatic prostate cancer with radiolabeled monoclonal antibody J591 to the extracellular domain of prostate specific membrane antigen. Bander NH, Trabulsi EJ, Kostakoglu L, Yao D, Vallabhajosula S, Smith-Jones P, Joyce MA, Milowsky M, Nanus DM, Goldsmith SJ, Department of Urology, Division of Nuclear Medicine, New York-Presbyterian Hospital/Weill Medical College of Cornell University, New York, NY. J Urol 2003;170:1717–21 Purpose: We performed an interim analysis of imaging data collected in 2 Phase I radioimmunotherapy trials to determine the ability of monoclonal antibody (mAb) J591 directed to the extracellular domain of prostate specific membrane antigen (PSMA) to target sites of known metastatic prostate cancer accurately. Materials and Methods: Patients with progressing hormone independent prostate cancer were entered in 2 Phase I dose finding trials with radiolabeled mAb J591. J591 is the first mAb targeting the extracellular domain of PSMA as well as the first de-immunized (humanized) mAb to PSMA to be tested in humans. These trials were primarily designed to assess dose limiting toxicity, maximum tolerated dose, pharmacokinetics and organ dosimetry. Planar gamma camera imaging studies obtained on the first 53 patients were reviewed and compared to sites of metastatic prostate cancer visualized on conventional imaging studies including bone scan, computerized tomography and/or magnetic resonance imaging. In 1 trial 29 patients received 111indium-J591 for imaging followed by 90yttrium-J591 for therapy. In the parallel trial 24 patients were treated with 177lutetium-J591, an isotope that can be imaged directly. Results: Of 53 patients reviewed 46 (87%) had evidence of metastatic disease on conventional scans. Overall, of the 43 evaluable patients J591 accurately targeted bone and/or soft tissue lesions in 42 (98%). J591 accurately targeted bone lesions in 32 of 34 (94%) and soft tissue lesions in 13 of 18 (72%) evaluable patients. Conclusions: Radiolabeled J591 accurately targets bone and soft tissue metastatic prostate cancer sites, and may be useful for targeting therapeutic and/or diagnostic imaging agents.
Commentary Bander et al. report on the ability of J591, an antibody to the extracellular domain of prostate specific membrane antigen (PSMA), to localize to known sites of metastatic prostate cancer. PSMA could be an ideal diagnostic and therapeutic target since it is expressed in all prostate cancers and its expression level increases in more poorly differentiated and hormone refractory tumors. A previous PSMA antibody (7E11) targeted the intracytoplasmic site of PSMA and localized to only two-thirds of known soft tissue masses and to very few bone metastases. It was speculated that, because of the intracellular nature of its binding site, 7E11 would only bind when cell destruction was present, such as from necrosis. Contrary to this previous antibody, J591 is reported here to accurately target 32 of 34 (98%) known bone lesions and 13 of 18 (72%) soft tissue lesions. The results reported here have much potential. With appropriate radioactive tagging for diagnostic purposes, J591 could prove to be an extremely useful imaging agent capable of delineating both soft tissue and bone metastases. Radiolabeled for therapeutic purposes, this nonimmunogenic antibody could prove to be a highly specific therapeutic agent in the treatment of metastatic prostate cancer. In addition, the antibody itself could prove to have anti-tumor activity. doi:10.1016/j.urolonc.2004.04.025 Mark P. Ritter, M.D., Ph.D.
Mark P. Ritter / Urologic Oncology: Seminars and Original Investigations 22 (2004) 378 –385
of biochemical and clinical outcomes in 4,839 prostate cancer patients treated with radiotherapy and constructed from results from 9 institutions. These definitions were tested with respect to their abilities to predict clinical failure. Furthermore, the impact of backdating the failure date, one of the most controversial features of the current ASTRO definition, was explored in detail. Results indicated that while the original ASTRO definition has very usefully provided a standardized outcomes assessment method that has reasonable accuracy, there are several alternate definitions that provide superior sensitivity and specificity for predicting clinical failure and that avoid an overestimation of failure rates that backdating produces, particularly at earlier follow-up intervals. Included with these superior definitions were three rises scored at the time of the last rise (call date) and PSA nadir plus 2 ng/mL increase. Importantly, low absolute PSA failure thresholds such as 0.2 or 0.5 ng/mL, which would be considered more appropriate in a postprostatectomy setting, suffered from very poor specificity and were deemed inadequate for this group of patients treated with external beam radiotherapy. In contrast, as in the case of surgery, it has been suggested that very low thresholds might be superior for prostate brachytherapy-treated patients. The findings of the above analyses will likely play a role in future modifications of the post-radiation definition of biochemical failure—modifications that will hopefully further improve the ability to counsel patients and compare outcomes of different treatment strategies and modalities. doi:10.1016/j.urolonc.2004.04.022 Mark P. Ritter, M.D., Ph.D.
Targeting metastatic prostate cancer with radiolabeled monoclonal antibody J591 to the extracellular domain of prostate specific membrane antigen. Bander NH, Trabulsi EJ, Kostakoglu L, Yao D, Vallabhajosula S, Smith-Jones P, Joyce MA, Milowsky M, Nanus DM, Goldsmith SJ, Department of Urology, Division of Nuclear Medicine, New York-Presbyterian Hospital/Weill Medical College of Cornell University, New York, NY. J Urol 2003;170:1717–21 Purpose: We performed an interim analysis of imaging data collected in 2 Phase I radioimmunotherapy trials to determine the ability of monoclonal antibody (mAb) J591 directed to the extracellular domain of prostate specific membrane antigen (PSMA) to target sites of known metastatic prostate cancer accurately. Materials and Methods: Patients with progressing hormone independent prostate cancer were entered in 2 Phase I dose finding trials with radiolabeled mAb J591. J591 is the first mAb targeting the extracellular domain of PSMA as well as the first de-immunized (humanized) mAb to PSMA to be tested in humans. These trials were primarily designed to assess dose limiting toxicity, maximum tolerated dose, pharmacokinetics and organ dosimetry. Planar gamma camera imaging studies obtained on the first 53 patients were reviewed and compared to sites of metastatic prostate cancer visualized on conventional imaging studies including bone scan, computerized tomography and/or magnetic resonance imaging. In 1 trial 29 patients received 111indium-J591 for imaging followed by 90yttrium-J591 for therapy. In the parallel trial 24 patients were treated with 177lutetium-J591, an isotope that can be imaged directly. Results: Of 53 patients reviewed 46 (87%) had evidence of metastatic disease on conventional scans. Overall, of the 43 evaluable patients J591 accurately targeted bone and/or soft tissue lesions in 42 (98%). J591 accurately targeted bone lesions in 32 of 34 (94%) and soft tissue lesions in 13 of 18 (72%) evaluable patients. Conclusions: Radiolabeled J591 accurately targets bone and soft tissue metastatic prostate cancer sites, and may be useful for targeting therapeutic and/or diagnostic imaging agents.
Commentary Bander et al. report on the ability of J591, an antibody to the extracellular domain of prostate specific membrane antigen (PSMA), to localize to known sites of metastatic prostate cancer. PSMA could be an ideal diagnostic and therapeutic target since it is expressed in all prostate cancers and its expression level increases in more poorly differentiated and hormone refractory tumors. A previous PSMA antibody (7E11) targeted the intracytoplasmic site of PSMA and localized to only two-thirds of known soft tissue masses and to very few bone metastases. It was speculated that, because of the intracellular nature of its binding site, 7E11 would only bind when cell destruction was present, such as from necrosis. Contrary to this previous antibody, J591 is reported here to accurately target 32 of 34 (98%) known bone lesions and 13 of 18 (72%) soft tissue lesions. The results reported here have much potential. With appropriate radioactive tagging for diagnostic purposes, J591 could prove to be an extremely useful imaging agent capable of delineating both soft tissue and bone metastases. Radiolabeled for therapeutic purposes, this nonimmunogenic antibody could prove to be a highly specific therapeutic agent in the treatment of metastatic prostate cancer. In addition, the antibody itself could prove to have anti-tumor activity. doi:10.1016/j.urolonc.2004.04.025 Mark P. Ritter, M.D., Ph.D.