Use of a Foamy-Virus Vector System to Produce an 'Off-the-Shelf' Fcγ-CR-T Cell Product for the Treatment of Haematological and Solid Tumour Malignancies.

Abstract

The emergence of chimeric antigen receptor (CAR)-T cells has revolutionised the therapeutic landscape of hematologic malignancies, with limited translation only to solid organ malignancies. Furthermore, safety concerns have recently been raised, in terms of tumorigenesis, relating to the viral vector systems used for gene transduction, underlying the need for alternative, safer gene therapy delivery systems. In this study, we investigated the use of foamy virus (FV) vectors, known for their favourable integration profile and reduced genotoxicity, to generate Fcγ (CD16)-chimeric receptor (CR) T cells. Our aim was to provide T cells with the capacity to recognise and bind to tumour cells, opsonised with commercially available monoclonal antibodies (mAbs), enhancing the antibody-dependent cell cytotoxicity (ADCC). The high-affinity F158V polymorphism of the CD16, previously shown to mediate superior ADCC, was utilised for the generation of Fcγ (CD16)-CR T cells. Results showed that FV-derived CD16-CR T cells exhibited robust CD16 expression and demonstrated potent functional activity, including: (i) high mAb-binding capacity, (ii) formation of T-cell tumour cell aggregates in the presence of mAbs, (iii) significant degranulation and proinflammatory cytokine production upon tumour engagement and (iv) potent, dose-dependent cytotoxic activity against target cells in the presence of mAbs. This is the first study, to our knowledge, demonstrating that FV vectors can be used to generate potent CD16-CR T cells, providing a safer and more versatile platform for antibody-based immunotherapy. This approach enables the expansion of engineered T cell therapies beyond hematologic malignancies and towards solid tumours, using clinically approved mAbs.