Despite recent advances, advanced prostate cancer is suboptimally responsive to current chemotherapeutic agents. Radiolabeled monoclonal antibody therapy that targets prostate specific membrane antigen (PSMA) shows promise and is an area of active investigation. J591 is a deimmunized IgG monoclonal antibody developed to target the extracellular domain of PSMA. Preclinical and early phase clinical studies utilizing radiolabeled J591 have demonstrated efficacy in targeting tumor cells and decreasing levels of prostate-specific antigen. Radiolabeled J591 is well-tolerated, non-immunogenic, and can be administered in multiple doses. The dose limiting toxicity is reversible myelosuppression with little non-hematologic toxicity. Future studies will include approaches to optimize patient selection and incorporate novel strategies to improve the success of anti-PSMA radioimmunotherapy.

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In the fall of 2007, we started the Phase I dose escalation studies with 177Lu-DOTA-huJ591 monoclonal antibodies (mAb) using dose fractionation regimen. In patients with PCa and who have recurrent and/or metastatic disease, 177Lu dose (20-40 mCi/m2) was escalated in 5 different dose levels (3-6 patients at each dose level). So far we have recruited 17 patients in 5 groups. At each dose level, the patients received two doses of 177Lu-J591 mab, 2 weeks apart. The dose of huJ591 MAb remained fixed at 20 mg/dose. We hope to complete this first trial by June 2009 and start the combination therapy protocol almost immediately. The combination therapy protocol was approved by our IRB and was submitted to DOD HSRRB for review and approval. We started recruitment of subjects into the combination therapy protocol. Our goal is to complete the study in by September 2010. The revised SOW is attached.

This book comprehensively covers application of salvage therapy in reccurrent prostate cancer. Chapters focus on specific issues associated with a range of surgical and oncological management techniques and strategies including hormone therapy, lymphnode dissection, robotic prostatectomy and salvage reirradiation after locoregional failure. Learning objectives, and definitions of keywords are provided to aid the reader develop a thorough understanding of the topic and reinforce the key points covered in each chapter. Salvage Therapy for Prostate Cancer provides a detailed practically applicable guide on how salvage therapy can be utilised in the treatment of prostate cancer. It represents a valuable resource for trainee and practicing urologists, oncologists, and specialist nurses.

Prostate specific membrane antigen (PSMA) is the single most well-established, highly restricted prostate epithelial cell membrane antigen expressed by virtually all prostate cancers. PSMA is an ideal target for developing radio labeled monoclonal antibodies (mAbs) for radioimmunotherapy (RIT) of prostate cancer. J591 mAb binds with very high affinity to the extra-cellular domain of PSMA and binds to viable tumor cells. We have previously submitted the final report of the Phase I of the Idea development Award in November 2000.

Abstract: Purpose of Review [177Lu]Lu-PSMA-617 is a radiopharmaceutical that emits beta-minus radiation and targets prostate-specific membrane antigen (PSMA)-positive prostate cancer. Despite its clinical success, there are still patients not showing sufficient response rates. This review compiles latest studies aiming at therapy improvement in [177Lu]Lu-PSMA-617-naïve and -resistant patients by alternative or combination treatments. Recent Findings A variety of agents to combine with [177Lu]Lu-PSMA-617 are currently under investigation including alpha radiation-emitting pharmaceuticals, radiosensitizers, taxane chemotherapeutics, androgen receptor pathway inhibitors, immune checkpoint inhibitors, and external beam radiation. Actinium-225 (225Ac)-labeled PSMA-targeting inhibitors are the most studied pharmaceuticals for combination therapy or as an alternative for treatment after progression under [177Lu]Lu-PSMA-617 therapy. Summary Alpha emitters seem to have a potential of achieving a response to PSMA-targeting radionuclide therapy in both initial non-responders or responders to [177Lu]Lu-PSMA-617 later developing treatment resistance. Emerging evidence for immunostimulatory effects of radiopharmaceuticals and first prospective studies support the combination of [177Lu]Lu-PSMA-617 and immune checkpoint inhibition for late-stage prostate cancer. Introduction The lutetium-177 (177Lu)-labeled radiopharmaceutical [177Lu]Lu-PSMA-617 (market name PluvictoTM) has been approved by the US Food and Drug Administration (FDA) [1] and European Medicines Agency (EMA) [2] in 2022 as a last-line therapy for metastatic castration-resistant prostate cancer (mCRPC). Patients can be treated with [177Lu]Lu-PSMA-617 after progression on anti-hormonal therapy with androgen receptor pathway inhibitors (ARPIs) and taxane chemotherapy. The mode of action of [177Lu]Lu-PSMA-617 begins with specific binding of the compound to the prostate-specific membrane antigen (PSMA) [3], a transmembrane protein that is overexpressed in prostate cancer with expression levels rising with higher progression [4, 5]. Upon binding, the pharmaceutical is internalized by PSMA-expressing cells leading to its accumulation and dispersion throughout the cytoplasm [6]. The radiation emitted from 177Lu damages the DNA and other macromolecules, ultimately causing cell death. 177Lu predominantly emits beta-minus particle radiation which has a relatively low linear energy transfer (LET: amount of energy deposited across a unit of traveled particle track) of 0.2 keV/μm [7]. Still, compared to gamma radiation, beta particles emitted from 177Lu have very low tissue penetration ability traveling a mean distance of 0.67 mm [8], thereby damaging only tumor cells in their proximity with limited off-target irradiation of neighboring healthy tissues. The radiation causes single-strand breaks (SSBs) and double-strand breaks (DSBs) in the DNA, either by direct ionization of DNA or indirectly via the formation of highly reactive hydroxyl radicals [9, 10]. These properties render beta-emitting radiopharmaceuticals valuable for the specific targeting of extensively metastasized prostate cancer. The international, randomized, prospective phase III VISION trial completed the clinical testing phase of [177Lu]Lu-PSMA-617, which led to its FDA and EMA approval for mCRPC. The trial assessed the efficacy of the novel treatment comparing [177Lu]Lu-PSMA-617 plus standard of care (SOC) and SOC only ([11]; NCT03511664). Permitted SOC included ARPIs (e.g., abiraterone, enzalutamide) and excluded, e.g., chemotherapy and immunotherapy due to unknown risks in combination with [177Lu]Lu-PSMA-617. In the radioligand therapy (RLT) arm, patients received a median of five cycles, each at a dose of 7.4 gigabecquerel (GBq) at 6-week intervals. The median overall survival (OS) was significantly better in the RLT arm as compared to SOC only (15.3 months vs. 11.3 months). Patients treated with RLT had a median progression-free survival (PFS) of 8.7 months and those treated with SOC 3.4 months. Of note, a substudy of the trial characterized outcomes depending on the patients' baseline PSMA expression intensity according to positron emission tomography/ computed tomography (PET/CT) imaging. Patients in the highest quartile (whole-body mean standard uptake value (SUV) ≥ 10.2) had a PFS of 14.1 months and those in the lowest quartile (whole body mean SUV 6.0) 5.8 months. This analysis shows that with low-PSMA expression patients do still benefit from PSMA-targeting RLT with 177Lu ([177Lu]Lu-PSMA RLT) [12].brbrThe Australian multicenter, randomized, phase II trial "TheraP" ([13]; NCT03392428) enrolled patients previously receiving docetaxel and in most cases ARPIs. The study compared the efficacy of cabazitaxel, one of the standard subsequent treatment regimens, to [177Lu]Lu-PSMA-617. RLT was administered every 6 weeks for up to six cycles and cabazitaxel once every 3 weeks for up to ten cycles. The primary endpoint was prostate-specific antigen response (PSA: serum marker for biochemical response) and was defined as the proportion of patients achieving a ≥ 50% PSA decline. The response rates were 66% in the RLT arm and 37% in the cabazitaxel arm.br

Prostate cancer is the commonest male cancer with over 5 million survivors in US alone. Worldwide, the problem is staggering and has attracted significant attention by media, scientists and cancer experts. Significant research, discoveries, innovations and advances in treatment of this cancer have produced voluminous literature which is difficult to synthesize and assimilate by the medical community. Prostate Cancer: A Comprehensive Perspective is a comprehensive and definitive source which neatly resolves this problem. It covers relevant literature by leading experts in basic science, molecular biology, epidemiology, cancer prevention, cellular imaging, staging, treatment, targeted therapeutics and innovative technologies. Prostate Cancer: A Comprehensive Perspective, is a valuable and timely resource for urologists and oncologists.