If you’ve ever traveled internationally, you know you need a passport. This document is your access pass to the world. What you might not know is that this rather plain looking document is filled with a variety of different checkpoints to ensure authenticity. Some passports have biometric chips, others have incorporated images only visible under UV light, and others may have microprinting, making it almost impossible to duplicate.
The incorporation of checkpoints is a necessary part of national security to ensure individuals entering a country only have good intentions and are not attempting to undermine or thwart the normal function of the environment. However, at times, the efforts to keep a nation safe may encounter unforeseen troubles. This could come in the form of mistaken identity, inadvertent damages to the passport such as a water drop, or the rather inconvenient association between a country name and an undeserved stigma.
Should any of these issues come up, innocent individuals may end up becoming snared into a policing system for which they have no place. Delays will occur but this might be the least of the concerns. Some may find themselves denied the ability to continue on their journey while others may end up being detained and even facing prosecution.
In the human body, a similar process occurs in which our tissues are being subjected to a constant passport review by our immune system. The process is somewhat different as paper and electronics are replaced by what is known as ligand-receptor interactions. Much like a jigsaw puzzle, two molecules find a common area where they can fit into one another. This leads to a shift in the structure of one or both of the members. This allows other interactions to occur, informing the rest of the cell of the event. If the signal is considered to be acceptable, the cell passes the checkpoint and is left alone. If however, the interaction leads to a molecular red flag, the cell may find itself facing increased scrutiny and possibly an unfortunate demise.
Over the last few decades, a number of these immune checkpoints have been discovered. Each one is a tool used by the enforcers of the immune system, T-cells, to provide them with the knowledge needed to properly assess the cell. The list is rather long and yet each one can help to ensure the right action is taken, even if it means leaving the cells in a specific environment alone.
Under normal conditions, this process is required to ensure inadvertent problems such as overzealous reactions leading to systemic inflammation and autoimmunity do not occur. Only when there is a problem, such as an infection, are defensive plans – such as segregation, incarceration, and attack – put into action. The process is smooth and efficient and rarely encounters any problems.
However, when tumorigenesis occurs, something nefarious can result. The cancer cells do their best to evade detection and/or the initiation of an immune attack (Beatty & Gladney, 2015). In doing so, they may take advantage of several checkpoints (Table 1) to ensure the immune system does not recognize trouble is brewing. Should this happen, the T-cell is tricked into believing nothing is wrong and the tumor is allowed to continue growing without incident (Farkona, Diamandis, & Blasutig, 2016; Marshall & Djamgoz, 2018).
|Checkpoints Used By Cancer Cells To Evade Immune Attack|
|CTLA-4||Cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4)|
|LAG-3||Lymphocyte activation gene 3|
|PD-1||Programmed death 1|
|TIGIT||T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domains|
|Tim3||T-cell immunoglobulin and mucin domain 3|
|VISTA||V-domain immunoglobulin suppressor of T-cell activation|
In order to deal with this evasive measure by cancer cells, researchers have focused on a therapeutic intervention known as checkpoint inhibition. Pharmacological agents are used to ensuring cancer’s ability to neutralize checkpoints is halted thus triggering an immune reaction. A variety of these agents now exist (Marshall & Djamgoz, 2018) and their effectiveness has been shown both when used alone or in combination with other therapies. Not surprisingly, a significant amount of attention has been devoted to this process – as is evidenced by the inclusion of several articles in this blog – in the hopes of to help reduce the pathogenesis of cancer and possibly act as part of a path towards remission.
Unfortunately, there is a drawback to this process. The body may mistake the use of these inhibitors as a massive incursion on its corporeal security. In essence, the checkpoints are triggered throughout the body and the immune system is triggered on a large scale. A few years ago, this was identified as a potential problem due to toxicity associated with having too many active immune soldiers (Weber, Yang, Atkins, & Disis, 2015). The investigation has grown to include a variety of other adverse events such as the potentially lethal cytokine-release syndrome (Shimabukuro-Vornhagen et al., 2018). Other effects have been seen on non-immune aspects of the body, such as the development of endocrine disorders such as thyroid dysfunction, and insulin-dependent diabetes mellitus (Girotra et al., 2018).
When events such as this happen on an international scale, security experts from all over the world gather to determine how to deal with such problems. In the cancer world, that onus falls on the American Society for Clinical Oncology (ASCO). Earlier this year, they released the incredibly valuable document, “Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline.” (Brahmer et al., 2018)
The ASCO decided to ask over two dozen clinicians, researchers, and patient advocates on the best way to approach the problem. The aim – much as one might expect from an international security council – was to determine the risk of an inadvertent reaction and how to manage it. As the lead author, Julie Brahmer pointed out,
“Patient and family caregivers should receive timely and up-to-date education about immunotherapies, their mechanism of action, and the clinical profile of possible immune-related adverse events prior to initiating therapy and throughout treatment and survivorship.”
To accomplish this task, the team performed literature searches on the intervention and examined the different levels of care as well as the overall outcomes. They found 38 systematic reviews and 166 primary studies, which gave them an excellent overview of the security environment in the tumor zone and the rest of the body. They assessed the impact of checkpoint inhibition on the skin, gastrointestinal tract, lungs, kidneys, eyes, blood, as well as the immune, cardiovascular, nervous and endocrine systems. The document was then reviewed and approved by the ASCO. The end result was a set of guidelines on the management of side effects due to the use of immune checkpoint inhibition.
The guideline is long and is directed primarily at oncologists and clinicians. Yet, due to the widespread publicity of immune checkpoint inhibition, this document should be read by anyone who has an interest in cancer therapy. After all, the best way to approach this treatment is not through rose-colored glasses, but rather, through the same perspective as an international security expert.
Without this all-encompassing approach, problems may arise leading to issues far worse than a bag check at passport security. Any consequences arising from the potential risks associated with altering checkpoints could lead to a loss of trust and faith in the system. As we have learned in the past, when this occurs, the impact can be severe and hinder progress.
Research continues to find ways to reduce the potential for adverse events, such as improved therapeutic accumulation and retention in target areas and reduced effects on non-cancerous tissues (Francis & Thomas, 2017). In the meantime, these guidelines will provide professionals with a means to improve the quality of life of a patient and ensure any problems can be identified and mitigated properly. After all, whether one is talking about a nation of three hundred and fifty million or a body comprised of thirty-seven trillion cells, security is a difficult and imperfect task. With these guidelines, we can know the benefits and the risks associated with immune checkpoints therapy. This ultimately will help identify the best way to travel safely through the perilous journey of cancer treatment.
Beatty, G. L., & Gladney, W. L. (2015). Immune escape mechanisms as a guide for cancer immunotherapy. Clin Cancer Res, 21(4), 687-692. doi:10.1158/1078-0432.ccr-14-1860
Brahmer, J. R., Lacchetti, C., Schneider, B. J., Atkins, M. B., Brassil, K. J., Caterino, J. M., . . . Thompson, J. A. (2018). Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline. Journal of Clinical Oncology, 36(17), 1714-1768. doi:10.1200/JCO.2017.77.6385
Farkona, S., Diamandis, E. P., & Blasutig, I. M. (2016). Cancer immunotherapy: the beginning of the end of cancer? BMC Med, 14, 73. doi:10.1186/s12916-016-0623-5https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4858828/
Francis, D. M., & Thomas, S. N. (2017). Progress and opportunities for enhancing the delivery and efficacy of checkpoint inhibitors for cancer immunotherapy. Adv Drug Deliv Rev. 15(114), 33-42. doi: 10.1016/j.addr.2017.04.011. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5581991/
Girotra, M., Hansen, A., Farooki, A., Byun, D. J., Min, L., Creelan, B. C., . . . Gravell, A. E. (2018). The Current Understanding of the Endocrine Effects From Immune Checkpoint Inhibitors and Recommendations for Management. JNCI Cancer Spectr, 2(3), pky021. doi:10.1093/jncics/pky021 https://academic.oup.com/jncics/article/2/3/pky021/5056360
Marshall, H. T., & Djamgoz, M. B. A. (2018). Immuno-Oncology: Emerging Targets and Combination Therapies. Front Oncol, 8, 315. doi:10.3389/fonc.2018.00315 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6115503/
Pardoll, D. M. (2012). The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer, 12(4), 252-264. doi:10.1038/nrc3239
Shimabukuro-Vornhagen, A., Godel, P., Subklewe, M., Stemmler, H. J., Schlosser, H. A., Schlaak, M., . . . von Bergwelt-Baildon, M. S. (2018). Cytokine release syndrome. J Immunother Cancer, 6(1), 56. doi:10.1186/s40425-018-0343-9
Weber, J. S., Yang, J. C., Atkins, M. B., & Disis, M. L. (2015). Toxicities of Immunotherapy for the Practitioner. J Clin Oncol, 33(18), 2092-2099. doi:10.1200/jco.2014.60.0379 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4881375/