ePoster Presentation 49th Annual Scientific Meeting of the Australian and New Zealand Society for Immunology 2021

Assessing the efficacy of immune agonist immunotherapies in a preclinical model of microsatellite-stable colorectal cancer (#120)

Stephen J Blake 1 , Yee Chern Tee 1 , Susan L Woods 1 2 , David J Lynn 1 3 , Jarrad Goyne 1 , Krystyna Gienec 1 2 , Daniel L Worthley 1
  1. South Australian Health and Medical Institute, Adelaide, SA, Australia
  2. School of Medicine, University of Adelaide, Adelaide, SA, Australia
  3. College of Medicine & Public Health, Flinders University, Adelaide, SA, Australia

Intro/Aims: Colorectal cancer (CRC) is the second leading cause of cancer related mortality in Australia and worldwide. This is partly due to the lack of effective therapies for most CRC patients. While the microsatellite instable form of CRC (MSI-CRC) has been shown to be sensitive to immune checkpoint inhibitors (ICI), the more common (>70%), microsatellite stable form of colorectal cancer (MSS-CRC) is not. Patients with advanced MSS-CRC have limited treatment options and are likely to exhaust standard care chemo(radio)therapy and targeted approaches, highlighting the need for new therapies. Immune agonist immunotherapies (IAIs) have shown to enhance anti-tumour responses when used alone or in conjunction with other treatments such as ICIs, by inducing immune responses in the tumour. Hence, we aimed to investigate the efficacy of IAIs in a pre-clinical model of

 

Method/Approach: Using a novel, organoid derived, orthotopic, mouse model of AKP (ApcΔ/Δ;KrasG12D;Trp53 Δ/Δ) MSS-CRC inoculated into immunocompetent mice, we evaluated various immune agonist immunotherapies to evaluate their anti-tumour responses. Timmune cell infiltration after treatment was assessed by flow cytometry and the efficacy of immune agonist treatment was evaluated by monitoring survival and tumour growth by colonoscopy.

 

Results: We found that anti-CD40, but not other immune agonists, was able to induce a significant increase in activated lymphocytes in the tumours, especially CD8+ T cells, and significantly increased PD1 expression on these lymphocytes. Treatment with anti-CD40 led to significantly increased survival of MSS-CRC tumour bearing mice. Interestingly, we also found that antibiotic co-treatment significantly reduced the toxicity induced by anti-CD40, without impacting its anti-tumour efficacy.

 

Conclusion: Our preclinical data suggests that anti-CD40 may a promising treatment approach for MSS-CRC. Further assessment of anti-CD40 immunotherapy in combination with other treatments (e.g. chemotherapy, radiotherapy and ICIs) is now being investigated to further enhance responses.