Best of the Best Oral Presentation Clinical Oncology Society of Australia Annual Scientific Meeting 2020

CHK1 inhibitor + subclinical dose of hydroxyurea selectively kills melanomas and enhances immune responses in the tumour micro-environment that synergise with immune checkpoint inhibitors in vivo.  (#19)

Martina Proctor 1 , Jazmina-Libertad Gonzalez-Cruz 2 , Colm Keane 1 , Nikolas Haass 2 , Bijun Zeng 2 , Riccardo Dolcetti 2 , James Wells 2 , Brian Gabrielli 1
  1. Mater Research Institute, The University of Queensland, Brisbane, Queensland, Australia
  2. University of Queensland Diamantina Institute, Princess Alexandra Hospital, Brisbane, QLD, Australia

Recent progress with the combination of MAPK and immune checkpoint inhibitors has demonstrated the effectiveness of such combination.  The targeted therapy serves the two-fold purpose of gaining immediate control of tumour growth and acting to enhance the immune micro-environment of the tumour, priming it for the immune checkpoint inhibitors.  The downside to MAPK targeted therapies is they can blunt immune responses.  Here we report a similar approach using a different targeted therapy that has demonstrated no adverse effects on the immune response in pre-clinical models.  We have targeted a defect common in melanomas, lung and ovarian cancer, replications tress using a combination of individually subclinical doses of CHK1 inhibitor and hydroxyurea. This combination has demonstrated broad activity in pre-clinical organoid models in vitro and in xenograft and syngeneic mouse models in vivo it readily controls tumor growth.  This drug combination triggers an immunogenic form of apoptosis that can establish a immune memory response.  The combination has no adverse effects on either T cells proliferation in vitro or an immune response in vivo.  This combination also triggers an inflammatory response involves a non-canonical STING pathway activation and cytokine/chemokine expression by the tumour and recruitment of T lymphocytes.   Immune profiling of two syngeneic mouse melanoma models shows that the CHK1 inhibitor combination treatment promoted strong T and NKT cells infiltration into the tumours, alter macrophage and other innate immune cell infiltration and activity, but also increased markers of immunosuppression and T cell exhaustion.  When combined with immune checkpoint inhibition (anti-PD-1), it produced strong anti-tumour immune responses.   This strong pre-clinical data indicates that this combination is likely to establish a strong and durable immune response when extrapolated to treating melanoma, ovarian and NSCLC patients’ tumours.