Oral - Virtual Presentation 33rd Lorne Cancer Conference 2021

The Ins and Outs of Cancer Therapy: Modifying Endocytosis Reversibly in Clinical Applications (#7)

Hui Yi Chew 1 , Priscila O De Lima 1 , Jzamina L Gonzalez Cruz 1 , Blerida Banushi 1 , Godwins Echejoh 1 , Lingbo Hu 1 , Shannon R Joseph 1 , Benedict Lum 1 , James Rae 2 3 , Jake S O'Donnell 1 , Lilia Merida de Long 1 , Satomi Okano 1 , Brigid King 1 , Rachael Berry 1 , Davide Moi 1 , Roberta Mazzieri 1 , Ranjeny Thomas 1 , Fernando Souza-Fonseca-Guimaraes 1 , Matthew Foote 4 , Adam McCluskey 5 , Phillip J Robinson 6 , Ian H Frazer 1 , Nicholas A Saunders 1 , Robert G Parton 2 3 , Riccardo Dolcetti 1 , Katharine Cuff 7 8 , Jennifer H Martin 5 7 , Benedict Panizza 7 9 , Euan Walpole 7 , James W Wells 1 , Fiona Simpson 1
  1. University of Queensland Diamantina Institute, Woolloongabba, QLD, Australia
  2. Cell Biology and Molecular Medicine Division, Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Victoria
  3. Australia Centre for Microscopy and Microanalysis, University of Queensland, Brisbane, QLD, Australia
  4. Princess Alexandra Hospital, Brisbane, QLD, Australia
  5. Centre for Chemistry, Biology and Clinical Pharmacology, The University of Newcastle, Newcastle, NSW, Australia
  6. Cell Signaling Unit, Children’s Medical Research Institute, The University of Sydney, Sydney, NSW, Australia
  7. Princess Alexandra Hospital, Woolloongabba, QLD, Australia
  8. Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
  9. Faculty of Medicine, University of Queensland, St Lucia, Australia

A safe and controlled manipulation of endocytosis in vivo may have disruptive therapeutic potential. We demonstrate that the anti-emetic/anti-psychotic prochlorperazine can be repurposed to reversibly inhibit the in vivo endocytosis of membrane proteins targeted by therapeutic monoclonal antibodies, as directly demonstrated by our human tumor ex-vivo assay. Temporary endocytosis inhibition results in enhanced target availability and improved efficiency of natural killer cell-mediated antibody-dependent cellular cytotoxicity (ADCC), a mediator of clinical responses induced by IgG1 antibodies, demonstrated here for cetuximab, traztuzumab and avelumab. Extensive analysis of downstream signalling pathways ruled out on-target toxicities. By overcoming the heterogeneity of drug target availability that frequently characterizes poorly responsive or resistant tumors, clinical application of reversible endocytosis inhibition may considerably improve the clinical benefit of ADCC-mediating therapeutic antibodies. In this presentation we expand the discussion to discuss our Phase IB safety trial outcomes and new targets for therapeutic intervention.