Immune evasion

Immune surveillance is the mechanism by which the body detects potentially malignant tumour cells, which have developed genetic abnormalities disrupting the cell cycle, creating "amortal" cells with the potential to become clinically malignant. T-Cell activity is then required to initiate and propagate an immune response in order to eradicate potentially cancerous tumour cells. To develop a tumour, malignant cells must evolve immune escape mechanisms. These anti-immune response capabilities consist of any genetic aberration that allows the tumour cells to disrupt either T-cell generation, t-cell infiltration or tumour killing activities, such as recognition and initiation of cytotoxicity at tumour sites [1].

Different tumour types evolve differentiated immune escape strategies creating genetically unique targets for the development of cancer specific immunotherapeutic treatment options, which can enable the immune system to detect and destroy tumour cells more effectively. These treatments are of particular interest in aggressive metastatic stages of cancer (by which time drug resistance can develop); classical forms of chemotherapy (ie platinum or taxane-based) provide poor clinical outcomes resulting in a high unmet need.

PD-L1 and PD-1 Inhibitors

Programmed death ligand 1 (PD-L1) is a cell surface protein which can be expressed by mutated tumour cells. PD-L1 binds with the PD-1 (Programmed Death Protein 1) surface protein on T-cells to inhibit immune response. In the early 2000s investigation  began into the efficacy of monoclonal antibodies being utilised as inhibitors of these two immune checkpoint proteins, in order to enhance the ability of the immune system to destroy malignant tumour cells (see fig 1).

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Figure 1. PD-1 and PD-L1 inhibition. A: Tumour cell expressing PD-L1 binds to T-cell PD-1 to inhibit immune response. B: PD-L1 or PD-1 inhibitor binds to either PD-1 or PD-L1 to inhibit tumour cell immune evasion. (MHC = Major Histocompatibility complex; PD-1 = Programmed Death Protein 1; PD-L1 = Programmed Death Ligand 1) [2]

PD-L1 and PD-1 inhibitors are a class of biologic therapies which have been gaining major traction in the treatment of multiple cancers since 2014 with the FDA approval of Keytruda (PD-1 inhibitor, pembrolizumab) and Opdivo (PD-1 inhibitor, nivolumab) both with an indication for melanoma. Since this date Keytruda has been approved in NSCLC (Non-small cell lung cancer, 2015), HNSCC (Head and neck squamous cell carcinoma,2016), Hodgkin Lymphoma (2017), Urothelial Carcinoma (2017) and Gastric cancer (2017) to name but a few. Several other PD-1/PD-L1 targeted drugs have been approved in other indications in the past 3 years including Tecentriq (atezolizumab, 2016), Bavencio (Avelumab, 2017) and Imfinzi (durvalumab, 2017) [3].

As PD-L1 inhibitors are targeted against the expression of specific proteins on the tumour cell surface, their efficacy is variable between patients within the same indication. To identify patients in which PD-L1 inhibitors could be more efficacious, companion diagnostic (CDx) tests have been developed to test for the expression of PD-L1s on a patient by patient basis. FDA approval has been granted for CDx testing for Keytruda, Opdivo, Tecentriq, Bavencio and Imfinzi as of 2017. However, therapies may still prove somewhat efficacious even in the event of a negative indication of a CDx test; in real world scenarios PD-1/PD-L1 inhibitors are often given as treatment regardless of CDx testing results [3].

PD-L1/PD-1 therapies are gaining oncological indications at a lightning pace year on year and are set to potentially revolutionise the treatment of cancer, which has remained largely unchanged in the past two decades; relatively broad platinum/taxane based therapies have been used to treat a multitude of indications. The dawn of a new era of personalised therapies is fast approaching, potentially promising a paradigm shift in the way we view and treat some of the most aggressive forms of cancer.  

References

[1] Vinay, D. Immune evasion in cancer: Mechanistic basis and therapeutic strategies. Seminars in Cancer Biology. 2015; 35:S185-S198.

[2] Bellmunt, J. A review on the evolution of PD-1/PD-L1 immunotherapy for bladder cancer: The future is now. Cancer Treatment Review. 2017;54:58-67.

[3] Gong, J. Development of PD-1 and PD-L1 inhibitors as a form of cancer immunotherapy: a comprehensive review of registration trials and future considerations. Journal for Immunotherapy of Cancer. 2018; 6:8.