Abstract
Background – Preferentially expressed Antigen in Melanoma (PRAME) is a cancer-testis antigen broadly expressed in solid tumors. PRAME-targeting T cell therapy has already demonstrated deep and durable clinical responses in melanoma and is currently being evaluated across a broader range of solid tumor indications. This study investigates the expression of PRAME in advanced/metastatic solid tumors to help prioritize indications with the greatest potential for clinical responses to PRAME-targeting immunotherapy.
Methods – Analysis of PRAME mRNA expression in cancer was performed (1) on 4,622 stage III/IV patient samples across 10 solid tumor indications using the Tempus de-identified real-world database, and (2) using The Cancer Genome Atlas. PRAME protein expression was assessed by immunohistochemistry using tumor microarrays (TMAs) comprising individual samples from 1284 patients across multiple solid tumor indications, and in ‘multi-lesion’ TMAs comprising up to 18 samples from different regions of the primary tumor and corresponding metastases, derived from 220 ovarian, 49 lung and 38 melanoma patients.
Results – PRAME prevalence was highest in melanoma, endometrial cancer, ovarian epithelial cancer, lung squamous cell carcinoma and triple negative breast cancer, closely followed by head & neck squamous cell carcinoma and esophageal cancer. Indications with high prevalence were also characterized by high PRAME expression levels. Protein expression data using TMAs from melanoma, ovarian carcinoma and lung squamous cell carcinoma confirmed expression homogeneity within primary tumors and across matched metastases. Importantly, PRAME expression levels were highly consistent between primary tumors and metastases, as well as between first-line and later lines of treatment, with no apparent impact of prior exposure to anti-PD1/PD-L1 therapies on PRAME expression across indications. These results suggest that patients may be eligible for and benefit from PRAME-targeting therapy irrespective of disease stage, tumor location or prior treatments.
Conclusions – Our findings provide a comprehensive characterization of PRAME expression across clinically relevant patient populations and emphasize the value of real-world data in evaluating cancer targets. This work highlights the unique expression characteristics of PRAME and supports its potential as a broadly applicable therapeutic target for immunotherapy across multiple solid tumor indications with high unmet medical need. Notably, the data suggest the potential for deep and durable responses, with low risk for antigen-negative relapses.
Acknowledgements – The results are in part based upon data generated by the TCGA Research Network: https://www.cancer.gov/tcga.
Ethics Approval – The Tempus study was conducted on de-identified health information subject to an IRB exempt determination (Advarra Pro00072742) and did not involve human subjects research. The use of archived remnants of diagnostic tissues for manufacturing of TMAs and their analysis for research purposes as well as patient data analysis at University Medical Center Hamburg-Eppendorf has been approved by local laws (HmbKHG, §12) and by the local ethics committee (Ethics commission Hamburg, WF-049/09). All work has been carried out in compliance with the Helsinki Declaration.
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