Immuno-Oncology: Integrating innovation into standard of care practice
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28 May 2020
1891 marked one of the first examples of cancer immunotherapy, when William B. Coley used a bacterial broth to shrink malignant tumours in patients with inoperable bone cancers. In today’s remarkable field of Immuno-Oncology, there is still much yet to discover.
The field of Immuno-Oncology (I-O) was revolutionised with the discovery of T-cell immune checkpoints CTLA-4 and PD-1. Blocking these brought about a number of autoimmune adverse events, but with it an enhanced immune response against tumours. These results confirmed that tumours suppress the immune system as a mechanism to ensure their survival, and led to the hypothesis that the immune system could be mobilised to control many cancers affecting a variety of cells and tissues.[3,4]
Ongoing clinical trials are assessing the potential of other immune checkpoints as researchers look for ways to overcome immune checkpoint toxicity. Other active areas of I-O research are searching for new ways to target tumours through understanding their surrounding microenvironment, including investigating the potential of ‘metabolic checkpoints’, and understanding the influence of the patient’s microbiome in response to immunotherapy.
The immune system is now known to recognise and respond to tumours through a process known as immunosurveillance. The immune system uses the recognition of viral or mutated proteins expressed on the tumour surface – tumour antigens – to do this. However, tumours have their own immunosuppressive mechanisms that make these initial immune responses ineffective.
I-O therapies, ranging from monoclonal antibodies to cellular vaccines, stimulate or inhibit particular immune checkpoints in order to boost the patient’s own anti-tumour immune responses.[3,6,7] This method differs from ‘targeted’ therapies, which target the tumour directly or aim to disrupt the tumour blood supply, as well as traditional chemo- and radiation therapies which cause ‘collateral’ damage to healthy cells.[4,8,9]
I-O therapies are the next generation of cancer treatment
In responsive patients, I-O therapy can provide more durable clinical outcomes than traditional therapies such as chemotherapy and radiotherapy and, in some cases contribute to complete tumour regression. I-O therapies also pose less detrimental impact on patients’ quality of life due to a lower incidence of serious adverse events.
However, not all patients respond to I-O therapies. There is the issue of tumour heterogeneity; cancer cells within a tumour that mutate over time into potentially different sub-populations with different levels of sensitivity to anticancer therapies. There are also many naturally occurring pathways in place to prevent autoimmunity in the human body, which can limit the effectiveness of these therapies.
GSK is developing cancer immunotherapies that are designed to target these regulatory pathways as a means of improving response rates in cancer patients.
Solidifying I-O into standard of care practice
Unlike traditional therapies, I-O therapies are able to induce durable immune responses to cancer cells in responsive patients partly due to the mechanism of immunological memory. This means that the immune system can mount a more intense response when encountering a tumour antigen a second time.
The observation that I-O therapies have the potential to extend the lives of patients beyond that of traditional therapies is shifting the focus of clinical trials from improvements in typical measures such as progression-free survival and median overall survival, to the more gold-standard measure of overall survival extension (e.g. 2- or 5-year survival rates).
I-O is becoming increasingly established in standard of care practice as results of combination clinical trials are published. These studies examine strategies to combine synergistic I-O therapies or I-O in combination with traditional and/or ‘targeted’ therapies. The improvements in outcomes may however come at the cost of increased drug-related toxicities.
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