Invited Speaker Presentation Eradicate Cancer 2020

Targeting PTPN2 to enhance CAR T cell mediated anti-tumour immunity  (73521)

Florian Wiede 1 2 3 , Kun-Hui Lu 1 2 3 , Xin Du 1 4 , Shuwei Liang 1 2 3 , Garron T Dodd 2 3 , Pei Goh 1 2 3 , Conor Kearney 1 , Deborah Meyran 1 , Paul A Beavis 1 4 , Melissa A Henderson 1 , Sheng Zhang 5 , Zhong-Yin Zhang 5 , Jane Oliaro 1 4 , Phillip K Darcy 1 4 , Tony Tiganis 2 3
  1. Peter MacCallum Cancer Center, Melbourne, Victoria, Australia
  2. Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia
  3. Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia
  4. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia
  5. Department of Medicinal Chemistry and Molecular Pharmacology, Institute for Drug Discovery , Purdue University, West Lafayette, Indiana, USA

Adoptive chimeric antigen receptor (CAR) T cell therapy has emerged as an exciting approach for combating cancer. Although CAR T cell therapy has shown remarkable clinical efficacy in hematological malignancies, its success in combating solid tumours has been limited.  Here we report that PTPN2-deletion/knock-down/inhibition markedly enhanced the therapeutic efficacy of CAR T cells targeting the human orthologue of murine ErbB2/Neu, HER-2, an oncoprotein which is overexpressed in many solid tumours. PTPN2-deficient CAR T cells significantly repressed tumour growth in mice bearing mammary HER-2 overexpressing tumours which was accompanied by increased tumour T cell infiltration. Moreover, PTPN2-deficiency in HER-2- specific CAR T cells increased CAR T cell homing and activation, whereas PTPN2-inhibition increased the cytotoxic potential of human CAR T cells ex vivo. Our findings define PTPN2 as a target for bolstering T cell mediated anti-tumour immunity and CAR T cell therapy and point towards a novel approach for enhancing the efficacy of adoptive T cell therapy in otherwise recalcitrant solid tumours.