Prostate-specific membrane antigen (PSMA) is a cell membrane glycoprotein that is selectively expressed in prostate cells, with expression levels increasing dramatically in prostatic adenocarcinoma. PSMA-based radioligand therapy (RLT) has emerged as a viable therapeutic modality for the treatment of progressive metastatic prostate cancer. One commonly employed combination involves lutetium-177 conjugated to the ligand PSMA-617 (177 Lu-PSMA-617). In this meta-analysis, we examine therapeutic responses in patients with metastatic disease who have received 177 Lu-PSMA-617 therapy. We conducted a literature search with the following inclusion criteria: clinical trials involving more than 10 patients and solely utilizing 177 Lu-PSMA-617. Seventeen studies were included in the final analysis. Variables documented included the number of patients, the total therapeutic dose administered, the percentage of any prostate-specific antigen (PSA) decline, the percentage with PSA decline exceeding 50% baseline, and toxicities. Overall, a majority of patients responded to therapy, and in the prospective studies, survival was found to be upwards of one year. Significant toxicities included cytopenias, which were infrequent. Patients who had PSA declines in response to therapy had longer survival. Performance status and tumor grade were also key predictors of outcome.

BackgroundProstate-specific membrane antigen (PSMA) imaging has been suggested as highly sensitive modality for detection of metastases in patients with biochemically recurrent or advanced prostate cancer (PCa). PSMA expression is associated with grade and stage and has a relationship with androgen receptor signaling. The aim of this study was to evaluate the prognostic utility of radiographic PSMA expression in men with metastatic castration-resistant prostate cancer (mCRPC).MethodsPatients with mCRPC and available baseline PSMA imaging were studied. Images by planar/single-photon emission computed tomography (SPECT) or positron emission tomography (PET)/CT were reviewed. Planar/SPECT images were scored semi-quantitatively and PET/CT scored quantitatively with comparison of tumor uptake to liver uptake on a scale of 0–4 in order to determine an imaging score (IS). The IS (high: 2–4 versus low: 0–1), subsequent receipt of life-prolonging systemic therapies (taxane chemotherapy, potent androgen receptor pathway inhibitors, sipuleucel-T, and radium-223), and the CALGB prognostic risk stratification of patients were analyzed according to overall survival (OS) in univariate and multivariate Cox’s proportional hazards models.ResultsHigh PSMA expression (IS 2–4) was found in 179 (75.21%) patients, and 59 (24.79%) patients had low PSMA uptake. The median OS of the entire cohort was 16.8 (95%CI: 14.9–19.3) months. Patients with a high IS had a significantly shorter OS of 15.8 (95%CI 13.0–18.1) months compared to those with low expression [22.7 (95%CI: 17.7–30.7) months, p = 0.002]. After accounting for use of life-prolonging therapies (p<0.001) and CALGB prognostic groups (p = 0.001), high PSMA IS emerged as an independent prognostic factor for OS [HR(95%CI): 1.7 (1.2–2.2); p = 0.003].ConclusionPresence of high radiographic PSMA expression on SPECT or PET/CT may portend a poor prognosis in patients with mCRPC treated with standard systemic therapies. This provides implications for therapeutic targeting of PSMA-avid disease as a means to improve outcomes.

In a phase 1 trial involving patients with refractory lymphoid cancer, an antibody-drug complex directed against ROR1 had no unexpected toxicities. About half of the patients with mantle cell lymphoma and diffuse large B-cell lymphoma had clinically meaningful responses.

5015 Background: Antibodies and small molecule ligands target PSMA with different kinetics and biodistribution, with certain sites of PSMA expression such as salivary/lacrimal glands, kidneys, and small bowel less accessible to large antibodies. Alpha emitters such as 225Ac have high potency, but short range. We report dose-escalation plus expansion cohort results of a first in human study of 225Ac-J591. Methods: Men with progressive mCRPC following at least 1 potent AR-pathway inhibitor (ARPI, e.g. abi/enza) and chemo (or unfit/refuse chemo) without limit of # prior therapies (including Ra-223 or prior 177Lu-PSMA) provided adequate organ function were eligible. Baseline 68Ga-PSMA11 PET was performed, but not used for eligibility. Dose-escalation was in single-subjects x4 followed by 3+3 with a single infusion of 225Ac-J591 (13.3 KBq/kg with planned escalation up to 93.3 KBq/kg). Dose-limiting toxicity (DLT) was defined as attributable grade (Gr) 4 heme toxicity or Gr 3/4 non-heme tox. Imaging, genomic, patient-reported outcomes (PRO), and immune correlates embedded. Results: 32 men were treated with a single dose of 225Ac-J591 on 7 dose levels with expansion at the highest dose level (n = 16). Median age 69.5 (range 52-89), PSA 149.1 (4.8-7168.4); 75% with >2 prior ARPI, 62.5% chemo, 28% Ra-223, 43.7% 177Lu-PSMA. One (3.1%) CALGB (Halabi) good prognostic risk, 8 (25%) intermediate, and 23 (71.9%) poor risk. While PSMA uptake was not a prerequisite for treatment, of 28 with pre-treatment PSMA PET, none had tumor SUVmax < liver, 5 (17.8%) with tumor SUVmax 1-2.5x liver, 2 (7.2%) with tumor SUVmax 2.5-5x liver, and 21 (75%) with tumor SUVmax > 5x liver SUVmean. 1 of 6 in cohort 6 (80 KBq/kg) had DLT (Gr 4 anemia and platelets) with 0 of 6 at the highest dose level (93.3 KBq/Kg) and this dose was expanded. High Gr AEs were restricted to hematologic: In addition to DLT, 4 (12.5%) Gr 3 platelets and 2 (6.2%) with Gr 3 neutropenia. Non-heme AE’s were restricted to Gr 1/2 and included: 10 (31.2%) fatigue, 5 (15.6%) pain flare, 14 (43.7%) nausea, 8 (25%) with Gr 1 xerostomia (of which 5 received prior 177Lu-PSMA), 12 (37.5%) AST elevation. Despite prior treatment including 177Lu-PSMA and no selection for PSMA expression, 22 (68.7%) with any PSA decline, 12 (37.5%) with > 50% PSA decline. Of 21 with paired baseline and 12-wk CTC counts, 12 declined (5 converting from unfavorable to favorable and 5 converting detectable to 0), 5 remained 0, 4 increased. In the subset with PRO data, pain scores by BPI-SF tended to improve by wk 12. Following a single dose of 225Ac-J591, median PFS 7.2 months [95% CI 4.6-NR], median OS 10.9 months [7.6-21.1]. Conclusions: PSMA-targeted alpha-emitter 225Ac utilizing intact antibody J591 is tolerable with early evidence of clinical activity. Based upon these results, a follow up study [NCT04506567] testing multiple and fractionated dosing of 225Ac-J591 is underway. Clinical trial information: NCT03276572.

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Cancer cells can be selectively targeted by identifying and developing antibodies to specific antigens present on the cancer cell surface. Cytotoxic agents can be conjugated to these antibodies that bind to these cell surface antigens in order to significantly increase the therapeutic index of whichever cytotoxic agent is utilized. This approach of conjugating the cytotoxic drugs to antibodies to target specific surface antigens enhances the anti-tumor activity of antibodies and improves the tumor-to-normal tissue selectivity of chemotherapy. Critical parameters in the development of these antibody-drug conjugates include: 1) selection of most appropriate antigen, 2) the ability of an antibody to be internalized after binding to the antigen, 3) cytotoxic drug potency and 4) stability of the antibody-drug conjugate. For prostate cancer, prostate-specific membrane antigen (PSMA, also known as folate hydrolase-1) is the most validated theragnostic target to date. PSMA is overexpressed on the prostate cancer cell surface, which makes it an even better target for selective drug delivery through conjugated antibodies. Here, we review the PSMA-based antibody-drug conjugates for metastatic castration-resistance prostate cancer (mCRPC).

Fear conditioning models key processes related to the development, maintenance and treatment of anxiety disorders and is associated with group differences in anxiety. However, laboratory administration of tasks is time and cost intensive, precluding assessment in large samples, necessary for analysis of individual differences. This study introduces a newly developed smartphone app that delivers a fear conditioning paradigm remotely. Three groups of participants (total n=152) took part in three studies involving a differential fear conditioning experiment to assess the reliability and validity of a smartphone administered fear conditioning paradigm. This comprised of fear acquisition, generalisation, extinction, and renewal phases. We show that smartphone app delivery of a fear conditioning paradigm results in a pattern of fear learning comparable to traditional laboratory delivery, and is able to detect individual differences in performance that show comparable associations with anxiety to the prior group differences literature.

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