Poster Presentation Melbourne Immunotherapy Spring Symposium 2025

Enhanced efficacy of FOXO1-expressing CAR T cells in human prostate cancer patient-derived xenografts (#118)

Sophie G Harrison 1 , Laura H Porter 2 , Christina M Scheffler 3 4 , Shelley Hedwards 2 , Meg Magennis 2 , Prue O'Hare 2 , Junming Tong 3 4 , Hong Wang 2 , Phillip K Darcy 3 4 , Gail P Risbridger 2 3 4 , Renea A Taylor 1 2 3 4
  1. Department of Physiology, Monash University, Melbourne, VIC, Australia
  2. Department of Anatomy and Developmental Biology, Monash University , Melbourne, VIC, Australia
  3. Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
  4. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia

Chimeric antigen receptor (CAR) T cell therapy has shown remarkable clinical success in the treatment of haematological malignancies, including acute lymphoblastic leukaemia, B cell lymphoma and multiple myeloma. However, its efficacy, particularly in immunosuppressive and heterogenous cancers like prostate cancer, remains limited.

 

We previously demonstrated that a single dose of carboplatin induces a cascade of immunomodulatory changes within the tumour microenvironment (TME) of a fully responsive patient-derived xenograft (PDX) model (PDX-287R). In this NSG mouse model, carboplatin treatment generated a pro-inflammatory TME that significantly enhanced the anti-tumour activity of retrovirus-transduced Lewis-Y (LeY)-specific CAR T cells, resulting in significant tumour regression in vivo.

 

However, despite inducing several comparable changes within the TME, this combination treatment failed to elicit the same therapeutic response in a different LeY+ PDX line, PDX-224R-Cx. To address this, we investigated whether next-generation CAR T cells, engineered using a lentiviral vector to overexpress the memory-associated transcription factor FOXO1, could synergise with carboplatin-induced TME modulation to reduce tumour burden within PDX-224R-Cx.

 

Here, we demonstrated that FOXO1-expressing CD3+CAR+ T cells effectively infiltrated PDX-224R-Cx tumours as early as 2-weeks following infusion, with the combination treatment significantly altering the composition of these subcutaneous grafts compared to CAR T cells alone. By 3-weeks post-administration, combination-treated tumours significantly reduced in volume, relative to irradiation alone controls. Furthermore, both FOXO1-expressing CAR T cell and combination-treated tissues exhibited a significant increase in intratumoural F4/80+ mouse immune cells, suggesting enhanced recruitment of the host immune system to support an adaptive anti-tumour response. These findings underscore the importance of aligning the use of next-generation CAR T cells with a pro-inflammatory TME to ensure optimal in vivo efficacy. This refined combination approach offers a promising immunotherapeutic strategy for patients with carboplatin-sensitive LeY-positive prostate cancers.