Every four minutes someone in the UK will die from cancer, equating to almost 170,000 deaths annually (1). However, a new chapter has started in the treatment of cancer, one that could rapidly increase the number of people that are cured.
What is cancer? The human body is made up of cells, as are all living things. These cells can divide into two, a process known as cell division, allowing the continual renewal and repair of the organism. However, cancer cells behave abnormally, dividing in an uncontrolled manner to form tumours as they become unable to respond to the signals instructing them that new cells are not yet needed. This is due to changes in genes, the instructions that tell each cell how to behave, that occur throughout a person’s lifetime.
Inside the body, there is a never ending battle between self and non-self. This is orchestrated by the immune system, which is capable of recognising and killing invading germs (called pathogens) and cancer cells whilst leaving healthy cells alone. This is carried out by killer T cells, which have proteins on their surface called T cell receptors that can recognise foreign or abnormal substances. In the bodies of many people with cancer, there are already killer T cells that have receptors capable of recognising the cancer cells. Why then are they not capable of killing them?
T cells have additional proteins on their surface, called checkpoint proteins, which function as ON and OFF switches to turn on or turn off their ability to kill their targets. The OFF switches, an example being PD-1, prevent killer T cells from becoming overly active and destroying healthy cells. However, cancer cells often camouflage themselves from the killer T cells by producing proteins that can push these OFF switches. An example of one of these proteins is PD-L1, which can press PD-1. Seminal work by James Allison and Tasuku Honjo, co-recipients of the 2018 Nobel Prize in Physiology or Medicine, demonstrated that preventing cancer cells from being able to access these OFF switches blows their cover, allowing them to be killed by the killer T cells (2,3). This strategy is called checkpoint inhibition. It has led to the development of lifesaving drugs that can, in certain cases, shrink tumours far more effectively than chemo- and radiotherapy and with milder side effects. In a clinical trial, a drug that blocks PD-1 called pembrolizumab was given to 135 patients with melanoma, a type of cancer that usually develops in the skin. This cured or significantly shrunk the tumour in 38% of patients (4).
What about other OFF and ON switches? The surface of a killer T cell is covered in proteins, but the function of most of them is not known. Scientists are hard at work trying to discover which of these proteins are switches in order to identify new drug targets. In addition, it is hoped that by understanding the underlying wiring of the switches, in other words how pressing the switch tells the killer T cell to attack or not to attack, drugs can be developed that disconnect multiple OFF switches or lock multiple ON switches into the ON position that are wired in a similar way. With intense research in the past decade, the immunotherapy field has exploded rapidly with over 2500 trials now listed worldwide as of March 2019. This is opening an exciting new chapter in cancer treatment, one that could rapidly expand the number of people being cured.
Who will respond, who won’t respond and why? As more cancer patients are prescribed checkpoint inhibitors, it is essential to fully understand why some patients respond exceptionally whereas others do not respond at all. It is becoming increasingly clear that this boils down to the characteristics of the tumour itself. Scientists are actively searching for differences in these characteristics in order to identify biomarkers, which are measurable factors that help doctors choose the most appropriate treatment for each patient. An example is the ability to detect, from biopsy samples, which proteins the cancer cells are producing in order to toggle OFF switches on killer T cells and therefore which OFF switches need to be blocked using a drug.
Tumours that are surrounded by killer T cells are highly responsive to checkpoint inhibitors, since the cancer cells are killed once their cover is blown. However, other tumours do not have killer T cells nearby. This is because the tumour is physically inaccessible or the killer T cells have not been able to learn to tell the difference between the appearance of healthy cells and these cancer cells. These differences can be subtle, which the killer T cells have a difficult time spotting.
For patients with cancer cells that blend in, a different type of immunotherapy has been developed in which killer T cells are taught to recognise the subtle differences. This is achieved by taking the patient’s own killer T cells, designing a new T cell receptor for them in the lab and putting them back into the patient to kill the cancer cells. Steve Rosenberg used this approach to teach killer T cells to recognise cancer cells that have a single change in a protein called KRas (5). However, the challenge now facing scientists is to identify the targets that best differentiate cancer cells from healthy cells so that the healthy cells are not also attacked. The ultimate goal would be to have engineered killer T cells that can be used off-the-shelf in a number of patients.
Other differences between patients that respond and those that do not are more subtle and difficult for scientists to understand. The gut microbiota, which refers to the plethora of bacteria found in our guts, is the hottest scientific topic of the decade and has been implicated in a number of conditions with a high societal burden, including obesity, inflammatory bowel disease and dementia. It has recently also been linked to the success of immunotherapy! Melanoma patients that respond to PD-1 blockers have a higher number of ‘good’ bacteria in their guts (6). It is currently thought that this is due to the essential role that our gut microbiota plays in educating our immune system. This raises the exciting possibility that the microbiota could be manipulated in order to improve the response to immunotherapy, or possibly even as a preventative measure to help the body destroy cancer cells before they get the chance to form tumours.
With the impressive portfolio of immunotherapy drugs that are currently in clinical trials, which have been built upon decades of research by scientists exploring fundamental questions on how killer T cells target cancer cells, the future for the treatment of cancer looks bright. As scientists learn more about which switches on killer T cells should be targeted, and the best biomarkers to guide decision making in the clinic, the number of cancer survivors should continue to steadily increase.
(1) Cancer Research UK. (2016) Cancer statistics for the UK. Available from: https://www.cancerresearchuk.org/health-professional/cancer-statistics-for-the-uk.
(2) Hodi, F. S., Mihm, M. C., Soiffer, R. J., Haluska, F. G., Butler, M., Seiden, M. V., Davis, T., Henry-Spires, R., MacRae, S., Willman, A., Padera, R., Jaklitsch, M. T., Shankar, S., Chen, T. C., Korman, A., Allison, J. P. & Dranoff, G. (2003) Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients. Proceedings of the National Academy of Sciences of the United States of America. 100 (8), 4712-4717.
(3) Iwai, Y., Terawaki, S. & Honjo, T. (2005) PD-1 blockade inhibits hematogenous spread of poorly immunogenic tumor cells by enhanced recruitment of effector T cells. International Immunology. 17 (2), 133-144.
(4) Burns, M. C., O’Donnell, A. & Puzanov, I. (2016) Pembrolizumab for the treatment of advanced melanoma. Expert Opinion on Orphan Drugs. 4 (8), 867-873.
(5) Rosenberg, S. A., Tran, E. & Robbins, P. F. (2017) T-Cell Transfer Therapy Targeting Mutant KRAS. The New England Journal of Medicine. 376 (7), e11.
(6) Matson, V., Fessler, J., Bao, R., Chongsuwat, T., Zha, Y., Alegre, M. L., Luke, J. J. & Gajewski, T. F. (2018) The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science (New York, N.Y.). 359 (6371), 104-108.