The (R)evolution and Success(ion) of Immuno-Oncology
The (r)evolution of immunotherapy as anticancer treatment option represents one of the most successful approaches in cancer drug discovery in the past few years (Couzin-Frankel, 2013). Cancer treatment has been transformed by the emergence of immune checkpoint blockers (ICB) as the frontline treatment for multiple cancers, such as metastatic melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma (RCCs), and bladder or urothelial cancer: The first immune checkpoint inhibitor (ipilimumab as an anti-CTLA-4 antibody) was approved by the FDA in 2011 for the treatment of melanoma (Lipson and Drake, 2011; Sondak et al., 2011; Barbee et al., 2015). Since, the two classes of immunotherapy that have been FDA approved for clinical use are (1) inhibitors of either the programmed death receptor 1 (PD-1) or its ligand (PD-L1), or (2) cytotoxic T-cell lymphocyte-associated protein 4 (CTLA-4) (Michot et al., 2016) and they are presently being assessed in numerous other cancer types, including breast cancer, head and neck cancer, and some advanced solid and hematological malignancies.
New agents that target other aspects of the immune system are currently under development - 940 agents are in clinical stages and 1,064 in preclinical stages (Figure 2), with the top targets being unspecified tumor-associated antigens (TAA), PD-1/PDL-1, CD19, HER2, Ido1, Stat3, CTLA4, CD40, CSF1R, ADORA2A, GD2, NY-ESO1, CD20, EGFR, LAG-3, TLR7, MUC-1. Cancer Research Insititute — which specializes in immunotherapies — established a bird’s eye view of the entire immunotherapy landscape (Tang et al., 2017).
Figure 2. The overview of 2,004 immuno-oncology (IO) agents. Six classes of IO agents are identified on the basis of different mechanisms of actions.
While there are 164 anti-PD-1/L1 agents currently in development (50 of which are in clinical stages), the majority of combination trials with unprecedented number of new investigational IO agents, targeted therapies, and chemotherapies focus on the 5 approved agents (Pembrolizumab, Nivolumab, Durvalumab, Atezolizumab, Avelumab) as the top common strategy.
However, with only a minority of patients enjoying a durable benefit from approved immunotherapies the unmet medical need for cancer patients remains high. Although CPB with Ipilimumab (anti-CTLA4), Pembrolizumab and Nivolumab (anti-PD1), and Atezolizumab (anti-PDL-1), leads to prolonged responses in 15–40% of patients with metastatic melanoma, treatment refractory disease, and progression after initial response remain major causes of mortality (Robert et al., 2015; Weber et al., 2015; Herbst et al. 2014).
The future of cancer immunotherapy will need to focus on addressing the following main questions: [see the blog of 05th Jan 2018]
Establish integrated, multidimensional biomarker to predict response to immunotherapy and drive patient selection.
Understand the patterns of immune responsiveness and resistance to immunotherapy.
Evaluate tumor immunogenicity.
How to best develop immunotherapy combinations to reinstate immunosurveillance in immune-refractory tumours?
Primary and acquired resistance to I-O agents remain incompletely characterized and have yet to be validated in large patient cohorts.
Figure 3. Mechanisms operating in the establishment of immunoresistant niches (Syn et al., 2017).
Scientific progress in emerging novel disciplines
Managing side-effects of CAR T cell therapy
Pre-clinical models of efficacy and tolerability.
How and which new approaches in cancer research and development must we adapt to overcome the obstacles to advancement of the most effective clinical trials ?
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