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Objectives: Nivolumab (anti-PD-1) plus ipilimumab (anti-CTLA-4) is a new first-line treatment combination for patients with pleural mesothelioma. Nivolumab-ipilimumab improved the survival, however, 30.3% of the patients suffered from grade 3–4 treatment related adverse events (TRAE's) and TRAE's led to discontinuation in 23.0% of all patients. Here, we present the first real-world data of nivolumab plus ipilimumab in patients with malignant mesothelioma treated in two mesothelioma expert centers. Methods: Clinical data of patients with mesothelioma treated with nivolumab and ipilimumab were prospectively collected. Clinical parameters were obtained every visit, CT scans were evaluated every 12 weeks and adverse events were assessed continuously during the treatment. Data on grade 2–5 TRAE's and activity (overall response rate (ORR), duration of response (DOR), disease control rate (DCR), median progression-free survival (mPFS) and median overall survival (mOS) were reported. Results: Between January 2021 and August 2022, 184 patients were treated with nivolumab plus ipilimumab. The median follow-up was 12.1 months (95 %CI 11.1 – 13.1). Grade 3–4 TRAEs were seen in 27.7 % of the patients and 25.0 % discontinued immunotherapy treatment early because of TRAE's. ORR was 21.7 % (95 % CI 15.7–27.7), median DOR was 5.7 months (IQR 3.2–8.7) and DCR at 12 weeks 56.0 % (95 % CI 48.8–63.2). The mPFS was 5.5 months (95 %CI 4.1–6.9), mOS was 14.1 months (95 % CI 11.1–18.2). Conclusions: Nivolumab plus ipilimumab had an equal efficacy in a real-world comparable population but also a high risk of TRAE's, leading to discontinuation of treatment in 25% of the patients.

BACKGROUND: Prostate-specific membrane antigen (PSMA) is overexpressed in the neovasculature of renal cell carcinoma (RCC). However, there remains limited evidence regarding the use of PSMA positron emission tomography/computed tomography (PET/CT) in RCC. OBJECTIVE: To assess the impact of PSMA PET/CT in the management of metastatic RCC. DESIGN SETTING AND PARTICIPANTS: This was a retrospective review of patients who underwent PSMA PET/CT from 2014 to 2020 for restaging or suspected metastatic RCC in a tertiary academic setting. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Management plans before and after PSMA PET/CT were recorded. Impact was classified as high (change of treatment intent, modality, or site), medium (change in treatment method), or low. Secondary outcomes included the patient-level detection rate, PSMA PET/CT parameters, sensitivity, and comparison to CT and, if available, fluorodeoxyglucose (FDG) PET/CT. RESULTS AND LIMITATIONS: Sixty-one patients met the inclusion criteria, of whom 54 (89%) had clear cell RCC. PSMA-positive disease was detected in 51 patients (84%). For 30 patients (49%) there was a change in management due to PSMA PET/CT (high impact, 29 patients, 48%). In 15 patients (25%), more metastases were detected on PSMA PET/CT than on CT. The sensitivity of combined PSMA PET/CT and diagnostic CT was 91% (95% confidence interval 77-98%). In a subcohort of 40 patients, the detection rate was 88% for PSMA and 75% for FDG PET/CT (p = 0.17). The maximum standardised uptake value (SUVmax) was higher for PSMA than for FDG PET/CT (15.2 vs 8.0; p = 0.02). Limitations include selection bias due to the retrospective design, and a lack of corresponding histopathology for all patients. CONCLUSIONS: PSMA PET/CT is a promising imaging modality in metastatic RCC and led to a change in management in 49% of patients. PSMA PET/CT detected additional metastases compared to CT in 25% of patients and registered a significantly higher SUVmax than FDG PET/CT

Chimeric antigen receptor T (CAR T) cell therapy is an adoptive immunotherapy that has led to new treatments for lymphoma, leukemia, and other blood cancers; however, its efficacy for prostate cancer remains unproven. Here we report pre-clinical evidence of the efficacy of CAR T cell therapy against the Lewis Y antigen (LeY) using patient-derived models of prostate cancer. To assess the expression of LeY on prostate tumours, we performed immunohistochemistry on a cohort of 41 patient-derived xenografts (PDXs). Cytoplasmic and membrane expression were separately assessed and quantified, for each patient. Overall, 61% (25/41) of PDXs were positive for membrane LeY expression, of which 18 PDXs had greater than 50% membrane-positive cells, and considered most suitable to detection and stable binding by anti-LeY CAR T’s. To determine the in vitro sensitivity to CAR T cytotoxicity, we selected 4 PDXs with high and 2 PDXs with low LeY expression using 3 androgen receptor (AR)-positive adenocarcinomas and 3 AR-negative tumors expressing neuroendocrine markers. Next we established organoids for in vitro co-culture assays where organoids were co-incubated with an equal number of anti-LeY+ CAR T cells or Empty vector control CAR T cells (Ev CAR T). Using time-lapse microscopy we reported destruction of organoids by LeY+ CAR T cells as indicated by their morphological collapse and uptake of propidium iodide from the culture medium; control Ev CAR T cells produced no cytotoxicity. Over the 48h assay, the level of target cell death of the LeY+ organoids was correlated to the intensity LeY surface expression. Target cell death mediated by the CAR T cells required perforin and granzyme B, as potent and highly specific small molecule inhibitors of perforin (SN34960) and granzyme B (C20) applied alone or in combination greatly decreased PI uptake, indicating organoid survival. Neither inhibitor adversely affected CAR T cell viability as measured by PI and Annexin V staining.

Prostate-specific membrane antigen (PSMA) is highly expressed on the membrane of most prostate cancer cells and to a lesser extent in normal tissues. Many vectors targeting this protein have been created over the past decade and numerous clinical studies have positively demonstrated the tolerance and efficacy of radiolabeled prostate-specific membrane antigen ligands for PSMA radioligand therapy (PRLT). Preliminary results are encouraging that PRLT will become an important addition to the current therapeutic options in a number of settings. Improvement in radiopharmaceutical targeting and combination with other oncological agents are under investigation to further improve its therapeutic efficacy. These encouraging results have led to the development of other therapies using PSMA as a target, such as PSMA-targeted chimeric antigen receptor T-cells, PSMA-targeted antibody drug conjugates, and PSMA-targeted bi-specific T-cell-directed therapy. This narrative review details the current state and advancements in prostate-specific membrane antigen targeting in prostate cancer treatment.