Using immune checkpoint inhibitors to treat cancer

By Cristina Riquelme Vano

There are more than a hundred sixty-six thousand cancer deaths in the UK every year according to Cancer Research UK (Cancer Statistics for the UK. 2021). One of the reasons why cancer is so hard to tackle is that cancer cells are very similar to normal cells. Only a few genetic changes result in their differences and enable them to proliferate uncontrollably.  Due to their similarity, it is extremely difficult to create treatments that kill cancer cells while leaving normal cells unharmed. 

Immunotherapy is an exciting area of research in cancer treatment contrasts to conventional treatments and can target cancer cells while leaving normal cells unharmed. It does so by boosting the body’s immune response against cancer cells. One type of immunotherapy is immune checkpoint therapy (Naing & Hajjar, 2020).

Immune checkpoints are molecules expressed in the surface of cells that act as regulators of the immune system. They can either speed up or slow down the immune system’s response in combating pathogens, such as cancer cells. Immune checkpoint inhibitors target inhibitory immune checkpoints that act as the breaks during the immune response and deliver inhibitory signals to T cells (Hargadon, Johnson & Williams, 2018).

Inhibitory immune checkpoints are critical for maintaining self-tolerance. During normal conditions, inhibitory immune checkpoints expressed in the surface of healthy cells are recognised and bind to the corresponding immune checkpoint receptor on the surface of T-cells. For example, the immune checkpoint receptor Programmed Cell Death Protein 1 (PD-1) in T cells seeks out its ligand, Programmed cell Death-Ligand 1 (PD-L1), which is expressed in the surface of healthy cells  (Naing & Hajjar, 2020; Sharma & Allison, 2015). The binding of these sends an inhibitory signal to the T cells and so T cells don’t react against the healthy cells. This prevents autoimmunity. 

Immune checkpoints are also involved in the anti-tumour immune response. Antigen presenting cells such as dendritic cells in the tumour tissue can take up material from their environment such as tumour associated antigens. Dendritic cells then migrate to the lymph nodes where naïve T cells reside. Dendritic cells present the tumour antigen by MHC Class I molecules to cytotoxic T cells via their tumour antigen specific T cell receptor. This activates cytotoxic T cells that migrate to the tumour tissue where ideally kill cancer cells  (Li et al., 2018).

However, this is not always the case. Cancer cells can take advantage of inhibitory immune checkpoints normally expressed in healthy cells to evade the immune system. In many cancer types, cancer cells or cells within the tumour microenvironment overexpress inhibitory immune checkpoints such as PD-L1 (Sharma & Allison, 2015). This compromises the ability of the immune system to mount an anti-tumour response and leads to immune evasion, one hallmark of cancer. Immune evasion allows cancer cells to circulate through the body untouched making tumour growth and metastasis much less daunting.

The concept of immune checkpoint inhibitors as a cancer treatment focuses on blocking the immune checkpoint or its receptors  (Hargadon, Johnson & Williams, 2018; Sharma & Allison, 2015). In other words, removing the brakes cancer cells or cells within the tumour microenvironment have to inhibit T cells, so the immune system is always at full strength to fight the cancer. 

So far, the most successful method to achieve this has been using another immune system component: antibodies. Antibodies that block either inhibitory immune checkpoints or its receptors. In 2011, ipilimumab, the first antibody blocking an immune checkpoint was authorized by the Food and Drug Administration (FDA). This was rapidly followed by the development of monoclonal antibodies targeting PD1 (pembrolizumab and nivolumab) and PDL1 (atezolizumab and durvalumab)  (Sharma & Allison, 2015).

Ipilimumab is an anti-CTLA-4 antibody that binds to the receptor Cytotoxic T-Lymphocyte-Associated Protein 4 (CTLA-4) on T-cells. During cancer progression, binding of the immune checkpoint B7 of some cells in the tumour microenvironment such as dendritic cells to its receptor CTLA-4 on T-cells prevents the priming of T-cells, which will not kill cancer cells. Ipilimumab can prevent this happening. The anti-CTLA-4 antibody binds and blocks CTLA-4 on T cells so it can no longer bind to its ligand, B7 on dendritic cells, effectively priming naïve T cells that will migrate to the tumour tissue and kill cancer cells. This has been proven to be a successful treatment for melanoma.

Similar approaches are used for the anti-PD1 or anti-PD-L1 antibodies. If PD-L1 is blocked in cancer cells, then cancer cells do no longer send inhibitory signals to T cells which kill them. The same thing happens with the anti-PD1 monoclonal antibody which binds to PD-1 on T cells so they cannot longer bind to PD-L1 on cancer cells and so cancer cells cannot evade the immune system, being recognised and killed by activated cytotoxic T cells  (Sharma & Allison, 2015). For the related discoveries, James P. Allison and Tasuku Honjo won the Nobel Prize in Physiology or Medicine in 2018  (Guo, 2018).

However immune checkpoint therapy has one main drawback: some cancers are more susceptible than others, and it has been recently discovered a possible reason why. Cancers with a high tumour mutational burden such as non-small cell lung cancer and melanoma have a higher response rate than cancers with fewer genetic mutations like breast cancer. A high tumour mutational burden in cancer cells elevates their probability of producing neoantigens with a strong immunogenicity that flag the tumour as non-self, thus eliciting a strong immune response (Campesato et al., 2015). 

Overall, immune checkpoint inhibitors have been developed and authorized for several cancer types with an unprecedented speed over the last decade. Since then, they have improved the prognosis for thousands of patients and many researchers believe that this is just the tip of the iceberg of what these therapies might be able to achieve. 

References:

Cancer Statistics for the UK. (2021) Available from: https://www.cancerresearchuk.org/health-professional/cancer-statistics-for-the-uk[Accessed 23 February 2021].

Naing, A. & Hajjar, J. (2020) Immunotherapy. 3rd edition. Cham, Springer International Publishing. 14-21.

Hargadon, K. M., Johnson, C. E. & Williams, C. J. (2018) Immune checkpoint blockade therapy for cancer: An overview of FDA-approved immune checkpoint inhibitors. International Immunopharmacology; Int Immunopharmacol. 62 29-39. Available from: doi: 10.1016/j.intimp.2018.06.001.

Sharma, P. & Allison, J. P. (2015) Immune Checkpoint Targeting in Cancer Therapy: Toward Combination Strategies with Curative Potential. Cell (Cambridge); Cell. 161 (2), 205-214. Available from: doi: 10.1016/j.cell.2015.03.030.

Li, J., Lee, Y., Li, Y., Jiang, Y., Lu, H., Zang, W., Zhao, X., Liu, L., Chen, Y., Tan, H., Yang, Z., Zhang, M. Q., Mak, T. W., Ni, L. & Dong, C. (2018) Co-inhibitory Molecule B7 Superfamily Member 1 Expressed by Tumor-Infiltrating Myeloid Cells Induces Dysfunction of Anti-tumor CD8+ T Cells. Immunity (Cambridge, Mass.); Immunity. 48 (4), 773-786.e5. Available from: doi: 10.1016/j.immuni.2018.03.018.

Guo, Z. S. (2018) The 2018 Nobel Prize in medicine goes to cancer immunotherapy (editorial for BMC cancer). BMC Cancer; BMC Cancer. 18 (1), 1086. Available from: doi: 10.1186/s12885-018-5020-3.

Campesato, L. F., Barroso-Sousa, R., Jimenez, L., Correa, B. R., Sabbaga, J., Hoff, P. M., Reis, L. F. L., Galante, P. A. F. & Camargo, A. A. (2015) Comprehensive cancer-gene panels can be used to estimate mutational load and predict clinical benefit to PD-1 blockade in clinical practice. Oncotarget; Oncotarget. 6 (33), 34221-34227. Available from: doi: 10.18632/oncotarget.5950.