Therapeutics
Figure 1
Key events in the immuno- oncology timeline. From Coley’s early discoveries
through to some of the recent approvals for melanoma and lung cancer. Timeline adapted from Morrissey et al
employed a strategy of injecting bacteria into a cancer patient with the goal of stimulating the immune system to attack the tumour3, with this successful strategy earning Coley the title of ‘the father of immunotherapy’. We have seen signifi- cant progress since Coley’s early work (Figure 1) and with a wealth of research now being undertak- en in the area of I-O, we are beginning to under- stand the underlying relationships of cancer cells and lymphocytes4. One of the first immunothera- pies to be approved was IL-2 therapy, with the hypothesis that IL-2 cytokines would stimulate T- cell activity against the tumour cells. Unfortunately, treatment regimens were not as suc- cessful as expected with patients experiencing high levels of toxicity4,5, a hurdle that remains with immunotherapies today.
As immunotherapies progress, several modalities within the scope of I-O have been identified and developed, and these can be split into two distinct categories – passive therapies and active therapies. Active therapies include cancer vaccines and oncolytic viruses, while passive therapies include immunomodulatory monoclonal antibodies, with the most well-known examples being checkpoint inhibitors4. Tumours are able to avoid attack from the immune system by hijacking normal immune- suppressive pathways, which in healthy tissue would provide protection against infection but not destroy otherwise healthy tissue3. Upregulation of negative regulators of the immune system can allow malignant cells to defeat the immune surveil- lance system, promoting the formation and pro- gression of tumours3. As immunomodulatory monoclonal antibodies (mAbs), checkpoint inhibitors act by blocking receptors on cells that inactivate host T-cell migration. With hundreds of antibody-based candidates in the development pipeline, the field of I-O represents one of the most promising strategies for cancer treatment, includ-
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ing, for example, the treatment of lung cancer and melanoma. There are already several FDA- approved immunotherapy agents for melanoma and lung cancer, such as Nivolumab and Pembrolizumab, which are anti-PD1 checkpoint inhibitors; and Ipilimumab, an anti-CTLA-4 checkpoint inhibitor3,14,15.
Preclinical safety assessments of novel immunotherapies While the promise of biologics is great, so too are the challenges researchers have come up against. The traditional phased approach of drug develop- ment considers features of a candidate sequentially. However, this approach is neither optimal nor suf- ficiently sophisticated to support the development of immunotherapies, which involves a vast array of combinations of targets, drugs and biomarkers. Taking immunomodulatory monoclonal antibod- ies (mAbs) as an example, the objective of preclin- ical studies is to define the toxicological profile of the mAb. This can include the pharmacological profile, identification of starting dose for human studies and profiling the bio-distribution, on-off target binding and overall toxicity of the molecule3. Unique challenges arise for immunotherapies as these agents are interacting with the tumour microenvironment, and animal models often do not mimic the exact environment found in humans, along with differences in immune response. The importance of assessing off- tumour binding in normal tissues is paramount. Since immunotherapies are, in one way or another, stimulating the immune system to identify and attack cancer cells, so too are normal, otherwise healthy tissues open to attack. This undesirable side-effect of immunotherapies has been well doc- umented, as has the extent to which these effects can cause serious autoimmune complications. A significant proportion of patients receiving
Drug Discovery World Summer 2017
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