Oral Presentation Melbourne Immunotherapy Network Winter Symposium 2021

New approaches for refuelling” CAR T cell therapy for the effective treatment of cancer (#10)

Junyun Lai 1 2 , Sherly Mardiana 1 2 , Imran G House 1 2 , Kevin Sek 1 2 , Melissa A Henderson 1 2 , Lauren Giuffrida 1 2 , Amanda X. Y Chen 1 2 , Kirsten L. Todd 1 2 , Emma V Petley 1 2 , Jack D Chan 1 2 , Emma Carrington 3 4 , Andrew M Lew 3 4 , Benjamin J Solomon 1 2 , Joseph A Trapani 1 2 , Katherine Kedzierska 5 , Maximilien Evard 5 , Stephin J Vervoort 1 2 , Jason Waithman 6 , Paul A Beavis 1 2 , Phil Darcy 1
  1. Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia
  2. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville
  3. Department of Medical Biology, University of Melbourne, Melbourne
  4. The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria
  5. Department of Microbiology and Immunology, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne
  6. Telethon Kids Institute, University of Western Australia, Perth, WA

Adoptive cell therapy (ACT) using chimeric antigen receptor (CAR) T cells is a specialized form of immunotherapy that involves the genetic engineering and re-infusion of a patient’s own T cells to specifically target cancer. While CAR T cells have had a significant impact in some haematological malignancies, its efficacy in solid cancers have been limited to date. Major factors limiting its success is the immunosuppressive nature of the tumor microenvironment and the heterogeneous expression of antigen on tumors leading to immune escape. We have shown that combination therapies using checkpoint blockade targeting immunosuppressive pathways or using CRISPR/Cas9 gene-editing technology can significantly enhance CAR T cell responses. For addressing the problem of antigen heterogeneity, we engineered CAR T cells to secrete Fms-like tyrosine kinase 3 ligand (FL), a growth factor critical for the development of DCs. Mice treated with FL-secreting T cells showed expanded DC and precursor populations, and an increased recruitment of host T cells to the tumor and draining lymph nodes (dLN). Strikingly, combination of FL-secreting CAR T cells with adjuvants resulted in inhibition of tumor growth and improved survival in two mouse models of ACT for breast and colorectal tumors. This was associated with an increased number of activated DCs and functional host T cells in the dLN following combination therapy, suggesting that this therapy is capable of inducing epitope spreading and eliminating tumors that are negative for the antigen targeted by the CAR. Our data suggest that employing these combination approaches can augment the efficacy of CAR T cells in solid cancers and may help combat the clinical problem of tumor induced immunosuppression and antigen negative tumor escape following therapy.