Oral Presentation Asia-Pacific Vaccine and Immunotherapy Congress 2024

Leveraging DC activation to overcome tumour heterogeneity in CAR T cell therapy (#46)

Cheok Weng Chan 1 2 , Junyun Lai 1 2 , Paul A Beavis 1 2 , Ilia Voskoboinik 1 2 , Phillip K Darcy 1 2
  1. Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
  2. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia

Adoptive cell transfer (ACT) 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 CAR-targeted antigen. Previously we demonstrated that CAR T cells engineered to secrete (DC) growth factor Fms-like tyrosine kinase 3 ligand (Flt3L) promote host anti-tumour immunity to effectively eradicate heterogenous tumours by expanding intratumoural conventional type 1 dendritic cells (cDC1) (Lai et al. 2020 Nat Immunol). cDC1 is well-reported to be a critical mediator in activation of anti-tumour cytotoxic responses. A key aspect of this study was that despite the increased population of intratumoral cDC1s, 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 ACT therapy. Engagement of upregulated CD40 on antigen-experienced DC with its ligand CD40L, which is traditionally expressed on activated T cells, induces DC activation. The effect of activation was observed via the upregulation of co-stimulatory molecules, CD80 and CD86, indicating DC maturation and expansion of tumour-antigen specific T cells upon anti-CD40 activation of Flt3L-expanded cDC1 in vivo. To incorporate the CD40 axis activation in adoptive cell therapy, successful engineering of CAR T cells was conducted using a novel construct to induce high CD40L expression constitutively. Improved DC maturation was observed upon CD40 engagement following adoptive transfer of CD40L-expressing T cells, correlated with improved therapeutic efficacy. Based on our results of the synergistic effect between Flt3L and CD40L on cDC1, we are poised to further incorporate this with Flt3L-secreting CAR T cell to achieve cDC1 expansion and activation upon ACT. Our study has demonstrated an enhanced efficacy of CAR T cell treatment in solid cancers by harnessing the endogenous immune responses against tumours.

  1. 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.