How Immunotherapy Treatments May Change the Face of Cancer Treatment

In 2012 alone, cancer accounted for an estimated 15% of all deaths worldwide, according to the World Health Organization  (World Health Organization, 2014). The lack of a cure is certainly not from lack of trying; investigated by high school students and tenured professors alike, purported cures for cancer seem to arise regularly and predictably as research conducted around the world searches for a panacea for this debilitating and terrible disease. Of course, a complete solution has proven elusive and difficult to find; cancer is still quite prevalent and continues to impact societies on a global level. The past two decades have, however, seen much progress as new treatments have been developed to complement medical staples like surgery, chemotherapy and radiation therapy. Targeted therapies, hormonal therapies and angiogenesis inhibitors have all demonstrated the potential to seek out and disrupt tumors, stymie growth, or even kill cancerous cells. At the forefront of cancer treatment research today, however, is immuno-oncology, a subset of immunotherapy, which relies on the simple premise of using and enhancing the human body’s existing immune response to fight cancer. In particular, immuno-oncology treatments targeting the programmed cell death 1 (PD-1) and programmed death-ligand 1 (PD-L1) proteins have been identified as among the most promising potential future sources for cancer treatment today.

Immuno-oncology, a subset of immunotherapy, relies on the simple premise of using and enhancing the human body’s existing immune response to fight cancer.

In retrospect, it seems fairly obvious that using the human body’s natural immune response may be a good approach to fighting cancer. The reality is, though, that many of the developments and discoveries necessary to facilitate the rise in immuno-oncology only came relatively recently. Most notably, a process for producing pure monoclonal antibodies was developed in 1975, and, even now, the realm of immunology with its complex web of gene and protein interactions is still not well understood. In contrast, radiation therapy, chemotherapy and hormonal therapy have all had nearly a century to develop into viable treatments, and, moreover, they rely on mechanisms that are perhaps less complex. For the current vanguard of anti-PD-1 and anti-PD-L1 therapies, the road took researchers from cDNA identification in 1992, down a decade-long discovery of the PD-1 structure, to eventual discovery of its function and its interactions with the PD-L1 and PD-L2 ligands (Okazaki & Honjo, 2007). The approval and release of the anti-PD-1 drug ipilimumab by Bristol-Myers Squibb in 2011 and the recent release of Merck’s anti-PD-1 drug pembrolizumab in September 2014 were received with much excitement (Garde, 2014).  These two drugs are the first available treatments; however, the anticipation surrounding other anti-PD-1 and anti-PD-L1 drugs in development by companies such as Bristol-Myers Squibb, Roche and other pharmaceutical giants continues to signify the potential of these therapies to revolutionize cancer treatment and perhaps cap off the quixotic quest for a simple cure for cancer.

Though the PD-1, PD-L1 and PD-L2 proteins were discovered relatively recently and remain relatively poorly understood, they hold some of the greatest promise as cancer treatments for several reasons. Simply put, PD-1 is a membrane protein, a protein that sits on the surface of the cells of the immune system (Okazaki & Honjo, 2007). Of these immune cells, T cells, which help organize the immune response and also directly attack infections, are the main focus of anti-PD-1 and anti-PD-L1 treatments  (Science Museum). PD-L1 and PD-L2 are ligands, molecules that can bind to the PD-1 protein and inhibit T cells and the rest of the immune response (Okazaki & Honjo, 2007). Under normal circumstances, these mechanisms likely function by preventing excessive and unnecessary immune responses. Thus, evidence suggests that a lack of PD-1 or ligand expression can limit this type of regulation, in turn contributing to autoimmune diseases like rheumatoid arthritis and lupus (Okazaki & Honjo, 2007). At the other extreme, however, diseases can also exploit this pathway, often by expressing an abundance of PD-L1 to suppress the body’s natural immune response; in this way, they can avoid detection and reproduce unchecked. Numerous studies have demonstrated that the expression of PD-L1 by tumor cells does just that — it essentially masks these cells from the body’s immune response (Okazaki & Honjo, 2007).  However, the new array of anti-PD-1 and anti-PD-L1 drugs are meant to target this particular hiding mechanism of cancer cells.

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In fact, the results of numerous clinical trials of these drugs on cancer patients have been extremely promising; patient response rates and rates of tumor shrinkage ranged from 30% to as high as 80%, and the application of the drugs led to even higher rates of slowed tumor growth (Fierce Biotech, 2013). In another promising test, 9% of melanoma patients in a Merck trial experienced a “complete response,” while other treated patients generally exhibited improved survival rates (Fierce Biotech, 2013). The recent approval of drugs like Merck’s pembrolizumab in the US and Bristol-Myers Squibb’s nivolumab in Japan point to the viability and promise of these drugs given their ability to pass through clinical trials and rigorous regulatory processes, earning the relatively rare FDA “breakthrough therapy” designation along the way. Additionally, major concern regarding the potential side effect creation of an autoimmune response by inhibiting the PD-1/PD-L1 pathway has not materialized in trials (Garde, 2014). All signs seem to point in the direction of a cure for cancer on the horizon as more and more time and research is committed to immuno-oncology, especially to anti-PD-1 and anti-PD-L1 therapies.

Given all the excitement among the scientific community and promise surrounding these novel treatments, the amount of media coverage seems underwhelming. Perhaps the writers and reporters in other establishments are not as well-informed, intelligent or attractive as the writers here. While that may certainly be likely, the reality is that many of these results are taken from the relatively early phase I and phase II trials for these drugs, where the patient sample is generally small, in contrast to the large and extensive phase III trials (Fierce Biotech, 2013). Additionally, many of these treatments are not unique in their applicability — they are only as effective as promised when used in concert with a host of other drugs. Furthermore, many have only demonstrated usefulness in targeting specific cancer types. For example, Merck’s FDA-approved pembrolizumab treatment is only licensed for use in conjunction with Bristol-Myers Squibb’s ipilimumab to treat melanoma (Food and Drug Administration, 2014). Other treatments that are currently in development follow a similar paradigm (Fierce Biotech, 2013). Most importantly, true demonstrated viability and success for these treatments can only come with extensive use in hospitals and patients on a scale far greater than that of any clinical trial.

Immuno-oncology is, therefore, a still relatively nascent avenue of cancer treatment, and more time and testing will be needed to prove its efficacy. However, it is unlikely that even these promising treatments can be the “silver bullet” that represents a comprehensive cure for cancer. Nevertheless, the potential of these anti-PD-1 and anti-PD-L1 treatments along with other immunotherapies to significantly improve cancer treatment is undeniable. The success in clinical trials along with the ability to pair these with other strategies for cancer treatment and leverage them for use on other oncologic indications paints an optimistic future. With only two major anti-PD-1/PD-L1 treatments on the market now in the US and many, many more in the pipeline, it is still too early to discover and reap the benefits of immunotherapies in treating cancer. This line of inquiry can be expected to continue to produce innovative treatments for cancer and perhaps other diseases, too. Furthermore, the fight against cancer has been successful in many respects, by improving awareness of the causes, encouraging prevention and early detection, providing valuable treatments for cancer patients and producing declines in cancer death rates. Even if the anti PD-1 and PD-L-1 drugs aren’t the definitive cure-all treatment we would all like, they still represent a huge step in improving cancer treatment and a small part of the larger fight to ensure that cancer patients and their families can materially enhance their prospects for recovery.

References

Fierce Biotech. (2013, May 30). Top 10 experimental cancer drugs – 2013. Retrieved from Fierce Biotech: http://www.fiercebiotech.com/special-reports/top-10-experimental-cancer-drugs-2013?page=full

Food and Drug Administration. (2014, September 4). FDA approves Keytruda for advanced melanoma. Retrieved from Food and Drug Administration: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm412802.htm

Garde, D. (2014, September 4). Merck wins breakthrough FDA approval for blockbuster cancer contender pembrolizumab. Retrieved from Fierce Biotech: http://www.fiercebiotech.com/story/merck-wins-breakthrough-fda-approval-cancer-contender-pembrolizumab/2014-09-04

Okazaki, T., & Honjo, T. (2007). PD-1 and PD-1 ligands: from discovery to clinical application. International Immunology, 813-824.

Science Museum. What do T-cells and B-cells do? Retrieved from Science Museum: http://www.sciencemuseum.org.uk/whoami/findoutmore/yourbody/whatdoesyourimmunesystemdo/howdoesyourimmunesystemwork/whatdot-andb-cellsdo.aspx

World Health Organization. (2014, May). Fact sheet N°310. Retrieved from World Health Organization: http://www.who.int/mediacentre/factsheets/fs310/en/

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Ben Huang
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