Search

Abstract Objectives Vaccines that prime Wilms' tumor 1 (WT1)‐specific CD8+ T cells are attractive cancer immunotherapies. However, immunogenicity and clinical response rates may be enhanced by delivering WT1 to CD141+ dendritic cells (DCs). The C‐type lectin‐like receptor CLEC9A is expressed exclusively by CD141+ DCs and regulates CD8+ T‐cell responses. We developed a new vaccine comprising a human anti‐CLEC9A antibody fused to WT1 and investigated its capacity to target human CD141+ DCs and activate naïve and memory WT1‐specific CD8+ T cells. Methods WT1 was genetically fused to antibodies specific for human CLEC9A, DEC‐205 or β‐galactosidase (untargeted control). Activation of WT1‐specific CD8+ T‐cell lines following cross‐presentation by CD141+ DCs was quantified by IFNγ ELISPOT. Humanised mice reconstituted with human immune cell subsets, including a repertoire of naïve WT1‐specific CD8+ T cells, were used to investigate naïve WT1‐specific CD8+ T‐cell priming. Results The CLEC9A‐WT1 vaccine promoted cross‐presentation of WT1 epitopes to CD8+ T cells and mediated priming of naïve CD8+ T cells more effectively than the DEC‐205‐WT1 and untargeted control‐WT1 vaccines. Conclusions Delivery of WT1 to CD141+ DCs via CLEC9A stimulates CD8+ T cells more potently than either untargeted delivery or widespread delivery to all Ag‐presenting cells via DEC‐205, suggesting that cross‐presentation by CD141+ DCs is sufficient for effective CD8+ T‐cell priming in humans. The CLEC9A‐WT1 vaccine is a promising candidate immunotherapy for malignancies that express WT1.

Abstract Objectives Adoptive transfer of chimeric antigen receptor (CAR)‐modified T cells is a form of cancer immunotherapy that has achieved remarkable efficacy in patients with some haematological cancers. However, challenges remain in CAR T‐cell treatment of solid tumours because of tumour‐mediated immunosuppression. Methods We have demonstrated that CAR T‐cell stimulation through T‐cell receptors (TCRs) in vivo can generate durable responses against solid tumours in a variety of murine models. Since Clec9A‐targeting tailored nanoemulsion (Clec9A‐TNE) vaccine enhances antitumour immune responses through selective activation of Clec9A+ cross‐presenting dendritic cells (DCs), we hypothesised that Clec9A‐TNE could prime DCs for antigen presentation to CAR T cells through TCRs and thus improve CAR T‐cell responses against solid tumours. To test this hypothesis, we used CAR T cells expressing transgenic TCRs specific for ovalbumin (OVA) peptides SIINFEKL (CAROTI) or OVA323‐339 (CAROTII). Results We demonstrated that the Clec9A‐TNEs encapsulating full‐length recombinant OVA protein (OVA‐Clec9A‐TNE) improved CAROT T‐cell proliferation and inflammatory cytokine secretion in vitro. Combined treatment using the OVA‐Clec9A‐TNE and CAROT cells resulted in durable responses and some rejections of tumours in immunocompetent mice. Tumour regression was accompanied by enhanced CAROT cell proliferation and infiltration into the tumours. Conclusion Our study presents Clec9A‐TNE as a prospective avenue to enhance CAR T‐cell efficacy for solid cancers.