Folate hydrolase-1 (FOLH1) is a novel target for antibody-based brachytherapy in Merkel cell carcinoma.

BACKGROUNDS: Folate Hydrolase-1 (FOLH1; PSMA) is a type II transmembrane protein, luminally expressed by solid tumour neo-vasculature. Monoclonal antibody (mAb), J591, is a vehicle for mAb-based brachytherapy in FOLH1+ cancers. Brachytherapy is a form of radiotherapy that involves placing a radioactive material a short distance from the target tissue (e.g., on the skin or internally); brachytherapy is commonly accomplished with the use of catheters, needles, metal seeds and antibody or small peptide conjugates. Herein, FOLH1 expression in primary (p) and metastatic (m) Merkel cell carcinoma (MCC) is characterized to determine its targeting potential for J591-brachytherapy. MATERIALS & METHODS: Paraffin sections from pMCC and mMCC were evaluated by immunohistochemistry for FOLH1. Monte Carlo simulation was performed using the physical properties of conjugated radioisotope lutetium-177. Kaplan-Meier survival curves were calculated based on patient outcome data and FOLH1 expression. RESULTS: Eighty-one MCC tumours were evaluated. 67% (54/81) of all cases, 77% (24/31) pMCC and 60% (30/50) mMCC tumours were FOLH1+. Monte Carlo simulation showed highly localized ionizing tracks of electrons emitted from the targeted neo-vessel. 42% (34/81) of patients with FOLH1+/- MCC had available survival data f or analysis. No significant differences in our limited data set were detected based on FOLH1 status (p = 0.4718; p = 0.6470), staining intensity score (p = 0.6966; p = 0.9841) or by grouping staining intensity scores (- and + vs. ++, +++, +++) (p = 0.8022; p = 0.8496) for MCC-specific survival or recurrence free survival, respectively. CONCLUSIONS: We report the first evidence of prevalent FOLH1 expression within MCC-associated neo-vessels, in 60-77% of patients in a large MCC cohort. Given this data, and the need for alternatives to immune therapies it is appropriate to explore the safety and efficacy o f FOLH1-targeted brachytherapy for MCC.

Acquired cancer resistance to combination immunotherapy from transcriptional loss of class I HLA.

Understanding mechanisms of late/acquired cancer immunotherapy resistance is critical to improve outcomes; cellular immunotherapy trials offer a means to probe complex tumor-immune interfaces through defined T cell/antigen interactions. We treated two patients with metastatic Merkel cell carcinoma with autologous Merkel cell polyomavirus specific CD8+ T cells and immune-checkpoint inhibitors. In both cases, dramatic remissions were associated with dense infiltration of activated CD8+s into the regressing tumors. However, late relapses developed at 22 and 18 months, respectively. Here we report single cell RNA sequencing identified dynamic transcriptional suppression of the specific HLA genes presenting the targeted viral epitope in the resistant tumor as a consequence of intense CD8-mediated immunologic pressure; this is distinguished from genetic HLA-loss by its reversibility with drugs. Transcriptional suppression of Class I loci may underlie resistance to other immunotherapies, including checkpoint inhibitors, and have implications for the design of improved immunotherapy treatments.

Serum estrogenicity and biological responses in African catfish raised in wastewater ponds in Ghana.

Reuse of wastewater for aquaculture improves the efficient use of water and promotes sustainability but the potential effects of endocrine disrupting compounds including estrogens in wastewater are an emerging challenge that needs to be addressed. We examined the biological effects of wastewater-borne estrogens on African catfish (Clarias gariepinus) raised in a wastewater stabilization pond (WSP) of a functioning municipal wastewater treatment plant, a wastewater polishing pond (WWP) of a dysfunctional treatment plant, and a reference pond (RP) unimpacted by wastewater, located in Ghana. Measurements of estrogen concentrations in pond water by liquid chromatography/tandem mass spectrometry showed that mean 17 ß-estradiol concentrations were higher in the wastewater ponds (WWP, 6.6 ng/L±2.7 ng/L; WSP, 4.9 ng/L±1.0) than the reference (RP, 3.4±1.1 ng/L). Estrone concentrations were found to be highest in the WSP (7.8 ng/L±1.7) and lowest in the WWP (2.2 ng/L±2.4) with the RP intermediate (4.7±5.0). Fish serum estrogenicity assayed by E-SCREEN was significantly higher in female vs. male catfish in the RP and WSP but not in the WWP (p≤0.05). Histological examination of liver and gonad tissue showed no apparent signs of intersex or pathology in any ponds. The similarities in various measures of body indices between fish of this study and African catfish from freshwater systems suggest that aquaculture may be a suitable reuse option for treated municipal wastewater.