Enhancing chimeric antigen receptor T‐cell immunotherapy against cancer using a nanoemulsion‐based vaccine targeting cross‐presenting dendritic cells

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 OVA _323‐339 (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.

Abstract

Clec9A‐targeting tailored nanoemulsion (Clec9A‐TNE) induced extensive proliferation, persistence and activation of chimeric antigen receptor (CAR) T cells, leading to the eradication of solid tumours in murine models. This novel approach could lead to the development of new CAR T‐cell therapies against some common solid tumour types in patients.