Enhancing Efficacy of TCR-engineered CD4+ T Cells Via Coexpression of CD8α. Issue 4 (27th May 2023)

• Record Type: Journal Article
• Authors: Anderson, Victoria E.; Brilha, Sara S.; Weber, Anika M.; Pachnio, Annette; Wiedermann, Guy E.; Dauleh, Sumaya; Ahmed, Tina; Pope, George R.; Quinn, Laura L.; Docta, Roslin Y.; Quattrini, Adriano; Masters, Siobhan; Cartwright, Neil; Viswanathan, Preetha; Melchiori, Luca; Rice, Louise V.; Sevko, Alexandra; Gueguen, Claire; Saini, Manoj; Tavano, Barbara; Abbott, Rachel J.M.; Silk, Jonathan D.; Laugel, Bruno; Sanderson, Joseph P.; Gerry, Andrew B.
• Is Part Of: Journal of immunotherapy. Volume 46:Issue 4(2023)
• Page Start: 132
• Page End: 144
• Publication Date: 2023-05-27
• Subjects: adoptive T-cell therapy -- cancer -- MAGE-A4 -- T-cell receptor; Immunotherapy -- Periodicals; Immunotherapy -- Periodicals; Neoplasms -- therapy -- Periodicals; Electronic journals; Electronic journals; 615.37
• DOI: 10.1097/CJI.0000000000000456
• Languages: English
• ISSNs: 1524-9557

Abstract

Abstract : Adoptive cell therapy with T cells expressing affinity-enhanced T-cell receptors (TCRs) is a promising treatment for solid tumors. Efforts are ongoing to further engineer these T cells to increase the depth and durability of clinical responses and broaden efficacy toward additional indications. In the present study, we investigated one such approach: T cells were transduced with a lentiviral vector to coexpress an affinity-enhanced HLA class I–restricted TCR directed against MAGE-A4 alongside a CD8α coreceptor. We hypothesized that this approach would enhance CD4 + T-cell helper and effector functions, possibly leading to a more potent antitumor response. Activation of transduced CD4 + T cells was measured by detecting CD40 ligand expression on the surface and cytokine and chemokine secretion from CD4 + T cells and dendritic cells cultured with melanoma-associated antigen A4 + tumor cells. In addition, T-cell cytotoxic activity against 3-dimensional tumor spheroids was measured. Our data demonstrated that CD4 + T cells coexpressing the TCR and CD8α coreceptor displayed enhanced responses, including CD40 ligand expression, interferon-gamma secretion, and cytotoxic activity, along with improved dendritic cell activation. Therefore, our study supports the addition of the CD8α coreceptor to HLA class I–restricted TCR-engineered T cells to enhance CD4 + T-cell functions, which may potentially improve the depth and durability of antitumor responses in patients.