Poster Presentation Asia-Pacific Vaccine and Immunotherapy Congress 2023

Flt3L and CD40L-expressing CAR T cell therapy drives activation of antitumour immunity to overcome tumour heterogeneity (#128)

Cheok Weng Chan 1 2 , Junyun Lai 1 2 , Paul A Beavis 1 2 , Phil K Darcy 1 2
  1. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia
  2. Peter MacCallum Cancer Centre, Melbourne, VIC, Australia

Adoptive cell transfer therapy using patient-derived T cells genetically engineered to express a chimeric antigen receptor (CAR) is highly effective in B cell malignancies and is now FDA-approved. However, tumour heterogeneity remains a major challenge in treating solid tumours due to the relapse of tumours negative for the antigen targeted by the CAR. Previously we demonstrated that CAR T cells engineered to secrete dendritic cell growth factor Fms-like tyrosine kinase 3 ligand (Flt3L) promote host anti-tumour immunity by expanding intratumoural conventional type 1 dendritic cells (cDC1)1. A key aspect of this study was that cDC1s required a second activatory stimulus to elicit anti-tumour immunity. Here, we explored the possibility of leveraging the CD40 axis to promote cDC1 function and synergise with Flt3L-secreting CAR T cell therapy. Upregulation of co-stimulatory molecules and expansion of tumour-antigen specific T cells was observed upon anti-CD40 activation of Flt3L-expanded cDC1 in vivo. We subsequently conducted successful engineering of CAR T cells to constitutively express CD40L, as shown on both CD4+ and CD8+ CAR T cells via in vitro evaluation. Improved maturation of DC was observed through elevated expression of co-stimulation molecules upon engaging with CD40L-expressing CAR T cells in vitro. Based on our results of the synergistic effect between Flt3L and CD40L on cDC1, we are now poised to further incorporate this into the Flt3L-secreting CAR T cell system to achieve cDC1 expansion and activation upon adoptive cell transfer treatment in vivo. Our study has demonstrated an enhanced efficacy of CAR T cell treatment in solid cancers by harnessing the endogenous immune responses against tumours.

  1. Lai, J., Mardiana, S., House, I. G., Sek, K., Henderson, M. A., Giuffrida, L., ... & Beavis, P. A. (2020). Adoptive cellular therapy with T cells expressing the dendritic cell growth factor Flt3L drives epitope spreading and antitumor immunity. Nature immunology, 21(8), 914-926.