Invited Speaker Melbourne Immunotherapy Spring Symposium 2025

The Role of Regulated Cell Death in OSCC Development and in Therapeutic Approaches for Combinative Immunotherapy for Late-Stage Disease (129816)

Lorraine O'Reilly 1 , A. Sakthianandeswaren 1 , R. Cross 1 , A. Celentano 2 , J. Rickard 3 , N. Silke 1 , J. Dong 1 , T. Yap 2 , T. Iseli 4 , P. Gibbs 1 , M. Jenkins 1 , O. Sieber 1 , J. Silke 1
  1. Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
  2. Melbourne Dental School, The University of Melbourne, Melbourne, Victoria, Australia
  3. Dorevitch Pathology, Heidelberg West, VIC, Australia
  4. Royal Melbourne Hospital, Parkville, VIC, Australia

The approximately 50%, 5-year overall survival rate for advanced oral squamous cell carcinoma (OSCC) has not improved for over 30 years due to lack of targeted combinative and personalised treatments. OSCC genomic studies indicate key TNF controlled cell death pathway genes and Smac Mimetic (SM) targets are frequently amplified or mutated in OSCC (IAPs, FADD, CASP8). This highlights the therapeutic potential for SM cell death inhibitors (IAP antagonists) which regulate immunomodulatory properties within immune cells, stimulate anti-tumour immunity and sensitise to TNF-induced killing.

Dissecting how these cell death pathways contribute to OSCC in preclinical models is required to identify clinically relevant molecular indicators. To assess this, we used a murine model of oral carcinogenesis (4-NQO) combined with genetic deletions of cell death/NF-kB pathway components. Our studies indicate that cell death pathways and inflammation do play a role in OSCC development and underly the hypothesis that reducing the impact of this signalling pathway with SMs could be beneficial therapeutically.

B7-H3/CD276 and EGFR are also highly expressed on the surface of HNSCC/OSCC indicating that their targeting with CAR T cells also has therapeutic potential, but in its infancy for this cancer. SMs have been shown to synergize with immunotherapies, therefore combining SMs with CAR T cells may enhance CAR T cell anti-tumour efficacy to overcome tumour antigen heterogeneity and reduce immunosuppression, but for which pre-clinical data is lacking.

We have developed a patient-derived OSCC tumour organoid high-throughput platform to test personalised combination SM therapies in vitro. We have shown that human OSCC organoids express SM targets and are killed by SMs, with SMs also enhancing the killing of EGFRhi OSCC organoids with novel functionally validated EGFR targeting CAR T cells. To determine if B7-H3 or EGFR CAR T-cells are robust therapies against B7-H3hi/mid or EGFRhi/mid OSCC in combination with SMs in vivo we also developed a novel orthotopic sublingual tongue NSG mouse PDX preclinical model with tumour growth monitored by virtual biopsy.