Cancer Immunotherapy: Immune Checkpoint Blockade

By Clarice Tse

The immune system is the human body’s greatest defense, therefore, scientists eagerly research new ways of manipulating immune mechanisms to combat diseases, for example cancer. 

As scientists have learned more about the immune system, they have been able to integrate their knowledge with cancer biology to develop immunotherapy. The importance of immunotherapy was affirmed when James P Allison and Tasuku Honjo were awarded the 2018 Nobel Prize in Physiology or Medicine for the discovery of Programmed cell death-1 (PD-1), Programmed cell death ligand-1 (PD-L1) and CTLA . These are immune checkpoint proteins involved in the suppression of the immune system. In this article, the major approach of immunotherapy – immune checkpoint blockade (ICB) is highlighted.

Under normal conditions, the immune system carries out anti-cancer immune response through the cancer immunity cycle. First, a type of immune cell called dendritic cell captures mutated antigens on tumour cells. T cells are attracted and primes with tumour antigens, which stimulates the activation of killer T cells. Finally, killer T cells recognizes and binds to cancer cells to release cytotoxins which induce apoptosis (cell death) of cancer cells.  

However, immune checkpoints provide cancer cells a way to escape the immune response.,  The checkpoints are proteins on cell surfaces that negatively regulates the immune response by inhibiting immune response. Cancer cells evade the immune system through the interaction between immune checkpoint proteins of the tumour cells and the immune cells. By inhibiting immune checkpoints, the inhibition to immune response caused by the checkpoints would be reversed, leading to the activation of the immune system, and in turn boosting the immune system to attack on cancer cells. This is why immune checkpoint inhibition is a major pillar in cancer immunotherapy. 

The PD-1/PD-L1 checkpoint pathway is the most meticulously researched and prevalently used in immunotherapy. PD-1 is a transmembrane protein expressed on activated T, natural killer and B lymphocytes, macrophages, dendritic cells, and monocytes, particularly in tumour-specific T-cells. Therefore, it is an inhibitor of both adaptive and innate immune response. PD-L1 is a type of transmembrane glycoprotein expressed on tumour cells, macrophages, some activated T and B cells, DCs and some epithelial cells. When binding to its receptor (PD-1), intracellular signalling pathways are activated and the activation of immune cells are inhibited, thereby reducing the secretion of cytokines and antibodies by immune cells. 

Normally, this would mediate immune tolerance in tissues. However, if cancer cells are involved, the immune suppression would instead dampen the anti-tumour immunity. The immune response against tumour cells will be reduced due to the interaction. Use of a PD-1/ PD-L1 inhibitor binds on PD-1/ PD-L1  to block the interaction between PD-1  receptor and PD-L1 to remove its subsequent inhibition on the immune system and re-initiate the anti-tumour immune response. As this therapeutic approach aims to boost the body’s immune response rather than targeting particular molecules of cancer cells, the escape of cancer cells by the mutation of targeted molecules of the tumour cells can be avoided. This also allows targeted PD-1/PD-L1 immunotherapy to treat various types of cancer (Han, Liu & Li, 2020; Jiang et al., 2019).

Albeit its advantages, only a small proportion of patients are sensitive to immunotherapy. The desired effects in the treatment of different types of cancers has not been fully reached, especially for solid tumours due to individual differences between patients and tumour heterogeneity as different tumours have different PD-L1 expression levels (Jiang et al. , 2019). Therefore biomarkers are needed to identify responders and non-responders of the inhibitors. 

In recent years, mismatch repair deficiency (dMMR), and microsatellite instability-high (MSI-H) were found to be predictive biomarkers of ICB therapies. DNA mismatch repair (MMR) is a highly conserved process in DNA repair. When there is a functional error or defect in the MMR system, a specific phenotype called microsatellite instability-high (MSI) will develop, characterized by the deletion or insertion of short, repetitive sequences of DNA resulting in mutations in cancer-related genes. This causes an increase in newly formed antigens that have not been previously identified on tumour cells, triggering a greater anti-tumour response and providing important targets for checkpoint blockade therapies (Zhao et al., 2019). In short, tumours with  dMMR and MSI-H are sensitive to ICB, particularly PD-1/PD-L1 inhibitors. Regardless of which type and location of tumour, the expression of dMMR and MSI-H is enough to identify whether a patient responds to ICB. The effectiveness of this biomarker has been validated by the FDA as seen through the granted accelerated approval to pembrolizumab – a PD-1 antibody that acts as an inhibitor targeting the PD-1/PD-L1 pathway treating solid tumours with MSI-H and dMMR. Another one is nivolumab which has been approved for colorectal cancer patients with MSI-H/ dMMR (Jia, Zhang & Zhang, 2018).

In addition to monotherapy, checkpoint inhibitors are used in combination therapies. For instance, pembrolizumab was combined with chemotherapy for the treatment of non-small cell lung cancer (NSCLC).  The proportion of patients who have a partial or complete response to therapy was 55% for combination therapy while that of chemotherapy alone group was only 29%. This substantial increase demonstrates the effectiveness of combining checkpoint inhibitors with chemotherapy (Jia, Zhang & Zhang, 2018; Kruger et al., 2019). The success of this combination therapy has spurred more research and clinical trials of different combinational therapies now and in the future. Immunotherapy is surely a strong force in cancer treatment, and its great potential in improving the prognosis of a broad variety of cancers would make it a game changer  for cancer therapy. 

References:

Gong, J., Chehrazi-Raffle, A., Reddi, S. & Salgia, R. (2018) 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. 6 (1), 8. Available from: https://search.datacite.org/works/10.1186/s40425-018-0316-z. Available from: doi: 10.1186/s40425-018-0316-z.

Han, Y., Liu, D. & Li, L. (2020) PD-1/PD-L1 pathway: current researches in cancer. American Journal of Cancer Research. 10 (3), 727. Available from: https://www.ncbi.nlm.nih.gov/pubmed/32266087.

Jia, L., Zhang, Q. & Zhang, R. (2018) PD-1/PD-L1 pathway blockade works as an effective and practical therapy for cancer immunotherapy. Cancer Biology & Medicine. 15 (2), 116-123. Available from: https://www.openaire.eu/search/publication?articleId=od_______267::f93b7c00d5d90f63fbbb8336ed33e803. Available from: doi: 10.20892/j.issn.2095-3941.2017.0086.

Jiang, X., Wang, J., Deng, X., Xiong, F., Ge, J., Xiang, B., Wu, X., Ma, J., Zhou, M., Li, X., Li, Y., Li, G., Xiong, W., Guo, C. & Zeng, Z. (2019) Role of the tumor microenvironment in PD-L1/PD-1-mediated tumor immune escape. Molecular Cancer. 18 (1), 10. Available from: https://search.datacite.org/works/10.1186/s12943-018-0928-4. Available from: doi: 10.1186/s12943-018-0928-4.

Kruger, S., Ilmer, M., Kobold, S., Cadilha, B. L., Endres, S., Ormanns, S., Schuebbe, G., Renz, B. W., D’Haese, J. G., Schloesser, H., Heinemann, V., Subklewe, M., Boeck, S., Werner, J. & von Bergwelt-Baildon, M. (2019) Advances in cancer immunotherapy 2019 – latest trends. Journal of Experimental & Clinical Cancer Research. 38 (1), 268. Available from: https://search.datacite.org/works/10.1186/s13046-019-1266-0. Available from: doi: 10.1186/s13046-019-1266-0.

Zhao, P., Li, L., Jiang, X. & Li, Q. (2019) Mismatch repair deficiency/microsatellite instability-high as a predictor for anti-PD-1/PD-L1 immunotherapy efficacy. Journal of Hematology and Oncology. 12 (1), 54. Available from: https://search.datacite.org/works/10.1186/s13045-019-0738-1. Available from: doi: 10.1186/s13045-019-0738-1.

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