Oral Presentation Clinical Oncology Society of Australia Annual Scientific Meeting 2017

Predictive markers of response and resistance to immunotherapies (#60)

Richard Scolyer 1 2 3
  1. Sydney Medical School, The University of Sydney, NSW
  2. Royal Prince Alfred Hospital, Sydney, NSW
  3. Melanoma Institute Australia, Wollstonecraft, NSW, Australia

The survival of patients with advanced stage metastatic melanoma have greatly improved in recent years. Enhanced understanding of both the pathogenesis of melanoma and its molecular drivers as well the importance and regulation of antitumoural immune responses have provided new therapeutic opportunities for melanoma patients. The immune checkpoint inhibitor therapies antiCTLA4 and antiPD1, which act to enhance the antitumoural immune response by blocking negative regulators that inhibit recognition of the tumour by immune cells, have revolutionised the treatment of patients with advanced stage melanoma and many other cancers. Biomarkers can assist in identifying patients who are most likely to respond to such therapies and those that are unlikely to respond. Initial studies reported a positive correlation between IHC expression of PD-L1 on tumour cells in the pre-treatment biopsy of patients and objective response with no patients responding in the “PD-L1 negative” group. However, it is clear that tumoural PD-L1 expression is not an ideal predictive biomarker as the level of heterogeneity in PD-L1 expression is high and PD-L1 expression is also potentially inducible nature with cytokines such as IFN-γ, released by activated lymphocytes. Nevertheless, in clinical trials assessing responses to PD-1 inhibitors, the expression of PD-L1 still remained the most significant predictor of outcome in these patients. There are currently no known  predictive biomarkers for the selection of patients  likely to have durable and long term responses to ipilimumab. A few studies have attempted to characterize the subpopulations of T cells that are present in pre-treatment biopsies of patients treated with ipilimumab and demonstrated associations between the expression of various regulatory markers such as FOXP3 and transcription factors such as EOMES and Gata3 but these do not have a role in routine clinical practice at present.  Recent research findings suggest that pathological assessment of immune cell subsets and the tumour are likely to be important in selecting which patients are most likely to derive benefit from immune checkpoint inhibitors. Similarly, pathological observations of on-treatment tumour tissue biopsies has provided new insights not only into the mechanisms of action of targeted therapies and immune check point inhibitors but have also contributed to the identification of resistance mechanisms and provided a rational biological basis for the exciting prospect of combining them to further improve survival rates and this is currently being investigated in clinical trials.