Poster Presentation 35th Lorne Cancer Conference 2023

A novel multi-omics immunopeptidomics platform to identify immunogenic neoantigens for precision T-cell receptor therapy for cancer (#162)

Gwo Yaw Ho 1 2 , Tu Nguyen-Dumont 2 , Tracy Putoczki 3 , Belinda Lee 3 4 , Janet Chang 2 , Jessica Wu 2 , Holly Barker 3 , Peter Eggenhuizen 2 , Jason Steen 2 , Justin Bedo 3 5 , Sophia Frentzas 1 2 , Cassandra Vandenberg 3 , Paul Hertzog 6 , Sean Grimmond 7 , Tony Papenfuss 3 , Clare Scott 3 4 8 , Eva Segelov 2 9 , Pouya Faridi 2 , Joshua Ooi 2
  1. Monash Health, Clayton, VIC, Australia
  2. School of Clinical Sciences, Monash University, Clayton , Victoria
  3. Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
  4. Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
  5. Department of Computing and Information Systems, University of Melbourne, Parkville
  6. Hudson Institute of Medical Research, Clayton, Victoria, Australia
  7. Centre for Cancer Research, University of Melbourne, Parkville, Victoria
  8. Royal Women’s Hospital, Melbourne, VIC, Australia
  9. University of Bern, Bern, Switzerland

In June 2022, the New England Journal of Medicine published a landmark case report demonstrating T-cell receptor therapy (TCR-T) targeting human leukocyte antigen (HLA) presented tumour neoantigen was very effective, safe and feasible for treatment of a patient with advanced heavily pre-treated pancreatic cancer1. This was achieved by transferring the high-affinity T-cell receptor against a mutant neoantigen from an HLA-matched patient with advanced colorectal cancer, who had identical somatic gene mutations, to another pancreatic cancer patient’s CD8+ T cells. Following a single infusion of neoantigen-TCR CD8+ T cells, most of the pancreatic cancer patient’s metastatic lesions regressed, and continued to shrink over a period of 5 months. 

The crucial components for a successful precision cancer TCR-T are (1) identification of cancer-specific HLA-presented tumour neoantigens, (2) identification of high affinity T-cell receptors against these tumour neoantigens and (3) the ability to transfer high affinity T-cell receptors to cytotoxic CD8+ T cells2.

Our team have developed a novel, integrated multi-omics tumour neoantigen discovery platform at Monash University, combining the use of immunopeptidomics, genomics and immunologic techniques. We present proof-of-concept evidence that we can successfully identify immunogenic mutant HLA-presented TNA in aggressive immunologically "cold" low tumour mutational burden ovarian cancer. Using a cancer vaccine approach by ex vivo pulse HLA-matched CD8+ T cells against the mutant neoantigen, we have demonstrated increased intra-tumoural CD8+ T cell infiltration, and delayed tumour growth in our patient derived xenograft (PDX) model. We are now in the process of identifying high-affinity TCRs against TNAs by using single cell RNA sequencing on healthy HLA-matched donor blood. We aim to genetically engineer a precision TCR-T for in vivo tumour cytocidal testing. We plan to expand this study into a cohort of well curated pancreatic PDX and organoid biospecimens, with matched genomic and clinical data. This novel work has the potential to change the oncology treatment landscape, and its success will likely improve the outcome of many people with incurable cancers.

  1. Leidner, R., et al. Neoantigen T-Cell Receptor Gene Therapy in Pancreatic Cancer. N Engl J Med 386, 2112-2119 (2022)
  2. J, W., et al. T-cell receptor therapy in the treatment of ovarian cancer: A mini review. Front. Immunol. (2021)