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Identification of a high-risk immunogenic prostate cancer patient subset as candidates for T-cell engager immunotherapy and the introduction of a novel albumin-fused anti-CD3 × anti-PSMA bispecific design

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Background: Cancer immunotherapies such as bispecific T-cell engagers have seen limited adoption in prostate cancer (PC), possibly due to differing levels of cancer receptor expression and effector T-cell infiltration between patients and inherent defects in T-cell engager design. Methods: CD8+ T-cell infiltration and PSMA expression were determined by RNA sequencing of primary PC tissue samples from 126 patients with localised PC and 17 patients with metastatic PC. Prognostic value was assessed through clinical parameters, including CAPRA-S risk score. A panel of albumin-fused anti-CD3 × anti-PSMA T-cell engagers with different neonatal Fc receptor (FcRn) affinity were characterised by flow cytometry, Bio-Layer Interferometry and functional cellular assays. Results: A subset of patients with localised (30/126 = 24%) and metastatic (10/17 = 59%) PC showed both high PSMA expression and high CD8+ T-cell enrichment. The High/High phenotype in localised PC associated with a clinically high-risk cancer subtype, confirmed in an external patient cohort (n = 550, PRAD/TCGA). The T-cell engagers exhibited tunable FcRn-driven cellular recycling, CD3 and PSMA cellular engagement, T-cell activation and PSMA level-dependent cellular cytotoxicity. Conclusion: This work presents an albumin-fused bispecific T-cell engager with programmable FcRn engagement and identifies a high-risk PC patient subset as candidates for treatment with the T-cell engager class of immuno-oncology biologics.

Original languageEnglish
JournalBritish Journal of Cancer
Volume127
Issue12
Pages (from-to)2186-2197
Number of pages12
ISSN0007-0920
DOIs
Publication statusPublished - Dec 2022

Bibliographical note

© 2022. The Author(s).

    Research areas

  • Albumins, Humans, Male, Prostatic Neoplasms/therapy, T-Lymphocytes

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