Oral Presentation 8th Australasian Vaccines & Immunotherapeutics Development Meeting 2020

Overcoming tumour heterogeneity by engaging host immunity to enhance chimeric antigen receptor (CAR) T cell therapy of solid cancers (#15)

Junyun Lai 1 , Sherly Mardiana 1 , Imran House 1 , Kevin Sek 1 , Melissa Henderson 1 , Lauren Giuffrida 1 , Amanda Chen 1 , Kirsten Todd 1 , Emma Petley 1 , Jack Chan 1 , Emma Carrington 2 , Andrew Lew 2 , Benjamin Solomon 1 , Joseph Trapani 1 , Katherine Kedzierska 3 , Maximilien Evrard 3 , Stephin Vervoort 1 , Jason Waithman 4 , Phillip Darcy 1 , Paul Beavis 1
  1. Peter MacCallum Cancer Centre, Melbourne, VICTORIA, Australia
  2. The Walter and Eliza Hall Institute of Medical Research, Melbourne, VICTORIA, Australia
  3. The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, VICTORIA, Australia
  4. Telethon Kids Institute , Perth, WA, Australia

Adoptive cell therapy (ACT) using chimeric antigen receptor (CAR) T cells is a form of immunotherapy where T cells are genetically modified to recognise tumour antigens and specifically target cancer. While CAR-T cells have achieved remarkable therapeutic efficacy for some blood cancers, its effect in solid cancers has remained limited. One confounding issue is the variable expression of target antigens on solid tumours (i.e. tumour heterogeneity). CAR-T cells may eliminate antigen-expressing but not antigen-negative tumour cells, which can consequently lead to disease relapse involving the latter. Dendritic cells (DCs) are professional antigen-presenting cells specialised in the priming and activation of T cells. We hypothesised that engaging the host immune system by enhancing DCs will improve host T cell anti-tumour responses and overcome tumour heterogeneity in ACT. To this end, we engineered T cells to secrete DC growth factor Fms-like tyrosine kinase 3 ligand (FL). Mice treated with FL-secreting T cells showed expanded host DC and T cell numbers in tumours. Combination of FL-secreting T cells with immune-stimulatory adjuvants further inhibited tumour growth in models of ACT and CAR-T cell therapy in a host DC and T cell-dependent manner. Importantly, combination therapy was associated with a significant increase in host anti-tumour T cells recognising antigens beyond those targeted by the CAR (epitope spreading). Our data suggest that enhancing host anti-tumour immunity represents a promising strategy to improve the overall efficacy of CAR-T cell therapy against solid tumour heterogeneity, which may help combat the clinical problem of antigen-negative tumour relapse following therapy.