Flash Talk & E-Poster Presentation 33rd Lorne Cancer Conference 2021

Systematic analysis of chemo-immunotherapy combinations that lead to durable anti-tumour responses in murine mesothelioma (#25)

Wayne J Aston 1 , Nicola Principe 1 2 , Danika E Hope 1 , Scott A Fisher 1 2 , Wee Loong Chin 1 3 4 , Caitlin M Tilsed 1 2 , Ian M Dick 1 , Richard A Lake 1 2 , Anna K Nowak 1 3 , Jonathan Chee 1 2 , Willem J Lesterhuis 1 2 4
  1. National Centre for Asbestos Related Diseases, Institute for Respiratory Health, University of Western Australia, Nedlands, WA, Australia
  2. School of Biomedical Science, University of Western Australia, Crawley, WA, Australia
  3. School of Medicine, University of Western Australia, Crawley, WA, Australia
  4. Telethon Kids Institute, Perth, WA, Australia

Recent clinical trials investigating combination immune checkpoint blockade (ICPB) with chemotherapy have shown promising results with increased overall survival in patients with non-small cell lung cancer. Combining chemotherapy with ICPB is attractive option for mesothelioma treatment, and is currently being assessed by different groups including our own. Certain classes of chemotherapeutics have been found to enhance anti-tumour immune responses. Therefore, chemotherapy may prime an immune response that is further enhanced by ICPB, with the potential to convert non-responding patients into those that have an effective, durable anti-tumour response. However, it is unclear which classes of chemotherapeutics provide the most benefit in combination with ICPB. The underlying cellular and immune mechanisms also need to be investigated to understand why some chemo-immunotherapy combinations work well together, while others do not.

We investigated 12 chemotherapeutics from the main canonical classes dosed once at maximum tolerated dose in combination with ICPB (anti-CTLA-4 and anti-PD-L1) in two murine mesothelioma models. We identified combinations that were additive, provided no benefit or were antagonistic compared to monotherapy. In particular, fluorouracil (5-FU) or cisplatin was additive when combined with ICPB. Both 5-FU and cisplatin in combination with ICPB induced profound expansion of lymphocytes within tumour draining lymph nodes. The proportion of intratumoural, activated CD8+ T lymphocytes increased in 5-FU+ICPB compared to chemotherapy or ICPB monotherapies. Cisplatin+ICPB increased the proportion of activated intratumoral CD4+ T helper lymphocytes compared to monotherapy. Anti-tumour responses in both combinations were CD8+ dependent. 5-FU+ICPB treated tumours upregulated immune related and downregulated hypoxia and glycolysis gene signatures compared to monotherapies. In particular, 5-FU+ICPB significantly enhanced IL-1 and TNFa signaling. We are currently performing further analysis to validate if blocking these individual pathways abrogates the additive effect of combination therapy.

We present a systematic assessment of responses to multiple chemo-immunotherapy combinations in murine mesothelioma, and identified that effective chemo-immunotherapy is associated with increased anti-tumour responses, particularly enhanced activation of T lymphocytes and proinflammatory signalling pathways.