Immunotherapy is a form of treatment to improve the natural ability of the immune system to fight diseases and infections, with immuno-oncology (IO) focusing on combatting cancer specifically. Novel immunotherapies are a possible solution for cancers that don’t respond to standard cancer treatments, either as standalone or in combination therapy. IO is changing the approach of many research and pharmaceutical companies and merely keeping up with this new, ever changing environment requires a strategy in itself.
Immune checkpoint inhibitors (ICIs) have been a major talking point in the clinical landscape and investment into their development continues to expand since approval of the first compound in 2011. The global ICI market is predicted to exceed $25 billion USD by 2022, and over 940 agents are currently under investigation in clinical trials. Are all these treatment possibilities beneficial or are they simply adding to an already overcrowded market?
Immune checkpoints are regulatory proteins of the immune system that either stimulate or inhibit the functioning of the system. In cancer cells, these proteins are activated to downregulate immune responses and prevent T cells from fighting against them. Immune checkpoint inhibitors target these proteins to block their function and restore that of the immune system to halt further proliferation of cancer cells. Currently approved ICIs target CTL4-A, PD-1, and PD-L1, and have since proved their worth due to their potential use against many types of cancer.
CTLA-4 is expressed by T cells once activated and induces an inhibitory signal to the T cells. This affects the ability of the T cells to destroy cancer cells. However, inhibitors stop this process from occurring and turn off the inhibitory process, allowing cytotoxic T cells to act on the cancerous cells. Ipilimumab (brand name Yervoy) is a monoclonal antibody that was the first CTLA-4 inhibitor to be approved for the treatment of melanoma in 2011, firstly to treat advanced tumours or those that cannot be surgically removed. In 2015, ipilimumab was approved as adjuvant therapy and is currently being investigated in numerous clinical trials for the treatment of other cancer types.
PD-L1 ligands supress the immune system in various clinical scenarios, such as pregnancy and tissue allografts—but their role in cancer progression makes them a viable target for IO treatment. PD-L1 is highly expressed on cancer cells themselves, normally supressing the function of cytotoxic T cells. Blocking the binding of PD-L1 to its receptor, PD-1, removes the brakes from the immune system, hence reducing the growth of tumours. Atezolizumab (Tecentriq) was the first PD-L1 inhibitor to be approved, and granted fast track status by the FDA in 2016 for treatment of urothelial carcinoma after chemotherapy failure.
Combination therapy of both anti-CTL4-A and anti-PD-1 compounds have been shown to be more effective than either in standalone treatment for metastatic melanoma, however this is associated with increased risk and frequency of adverse events, and varying results when resuming therapy. Resistance to ICIs is also becoming an increasing issue and is a threat to their success rate, although more common in patients specifically with renal cell carcinoma and non-small cell lung cancer.
Chimeric antigen receptor T (CAR-T) cell therapy is a key player in the IO game, making significant progress in the oncology field in the last 20 years. T cells are extracted from the patient and modified ex vivo to express a CAR. The engineered new T cells are then reintroduced into the body, allowing them to be able to recognize and bind to specific proteins on the surface of tumour cells, and thus the immune response is boosted.
The function of CAR-T cells can also be supressed by PD-L1 binding to PD-1, just as normal T cells would be. Therefore, additionally blocking PD-1 function may enhance the success of CAR-T cells and combined therapy trials are presently ongoing.
Costing approximately $475,000 USD per patient, this novel treatment is a huge investment, bigger than British health system capacity at present, and so it is only available at a clinical trial level. However, Chief Executive of NHS England Simon Stevens states clearly that this is an area we must embrace and that the benefits are definitely worth the spend.
The scope for immunotherapy to provide precision medicine is growing especially when using multiple treatments in combination with each other. However, the pressure also falls onto ensuring we have the correct diagnostic and informatics tools to correctly and efficiently detect and treat cancers. The emerging treatments on the market need to be correctly supported by clinicians and systems alike to perform to the best of their ability. Regardless, checkpoint inhibitors and CAR T therapy are just a couple of treatments harbouring huge potential within oncology and part of a wider emerging industry to definitely keep an eye on.
Featured image credit: CGRB pipetting robot by Shawn O’Neil. CC-BY-2.0 via Flickr.
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