Physical Poster + E-Poster Presentation 34th Lorne Cancer Conference 2022

Targeting mutant HLA-bound cancer peptide demonstrated in vivo efficacy in delaying tumour growth in a low mutational burden aggressive ovarian cancer  (#143)

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

Ovarian carcinosarcoma (OCS) are rare, aggressive cancers with poor prognosis due to limited effective treatments1. OCS tumorigenesis is not driven by somatic mutation, but via reprogramming of gene expression2. Therefore, the tumour mutation burden (TMB) is often low, and they are relatively non-responsive to single agent immunotherapy3.

We have established a paired OCS patient-derived xenograft (PDX) model, SFRC01177 from baseline chemonaïve and post-chemotherapy specimens in Nod-SCID-Gamma (NSG) major histocompatibility complex (MHC)null mice. These mice are deficient in MHC class I/II expression to reduce acute graft-versus-host disease following injection of human peripheral mononuclear cells4. The tumour is refractory to cisplatin and to 1 million human leukocyte antigens (HLA)-match CD8 T-cell injection consistent with expected tumour phenotype.

Whole genome/exome sequencing was performed on the baseline and recurrent tumours. Despite a low TMB of < 4 mutations/Mb, a total of 14,419 variants of mutant peptides ranging from 8 to 16 amino acid length were identified: 13,170 in the baseline and 10,998 in the recurrent tumour with 9,750 shared. Immunoprecipitation of the tumour HLA-complexes with their bound peptides followed by tandem mass spectrometry have identified over 2,300 HLA-bound peptides: 2,215 in the baseline and only 317 in the recurrent tumour with 239 shared. The analysis of the HLA-peptide motifs suggested that down-regulation of tumour cell MHC class I/II may account for this reduction. By combining the genomic and the immunopeptidomic data, a mutant HLA-bound neoepitope was identified. Neuropeptide W E100Q homologous to COSV61585942 (known immunogenic peptide; reported over 5 times in colon cancer) was associated with high areas under the curve in both the baseline and recurrent tumours. Ex vivo pulse neuropeptide W E100Q with HLA-matched dendritic and CD8 T-cells demonstrated delayed in OCS tumour in vivo growth and increased CD8 T-cells intra-tumour infiltration.

In summary, we can identify potential immunogenic mutant neoepitope using an integrated multi-omics approach in a TMB-low tumour. High affinity T-cell receptor discovery against this peptide is currently underway.

  1. Rauh-Hain, J.A., Birrer, M. & Del Carmen, M.G. "Carcinosarcoma of the ovary, fallopian tube, and peritoneum: Prognostic factors and treatment modalities". Gynecol Oncol 142, 248-254 (2016)
  2. Barker, H.E. & Scott, C.L. Genomics of gynaecological carcinosarcomas and future treatment options. Semin Cancer Biol 61, 110-120 (2020).
  3. J, W., et al. T-cell receptor therapy in the treatment of ovarian cancer: A mini review. Front. Immunol. (2021).
  4. Brehm, M.A., et al. Lack of acute xenogeneic graft- versus-host disease, but retention of T-cell function following engraftment of human peripheral blood mononuclear cells in NSG mice deficient in MHC class I and II expression. FASEB J 33, 3137-3151 (2019).