Paul Wong, Class of 2021
With the myriad of robust clinical trials that are currently conducted, the road towards finding the cure to cancer seem to be coming to an end as the available treatment options appear to limitless. However, the next question that researchers continue to pursue comes with a sense of irony: Are we better off using one medication than another? In the current repertoire of medication options, ipilimumab and interferon-α2b are the leading candidates for systemic therapy in high-risk melanomas (1).
Ipilimumab, which is commonly known as Yervoy, is a monoclonal antibody that is a type of targeted cancer drug for high-risk melanoma. Along with fighting advanced melanoma, ipilimumab has also been shown to combat renal cell carcinoma (2). The drug fights cancer by enhancing the immune system, more specifically T-cells. On the surface of T-cells, there is a protein called CTLA-4, which functions as an immune checkpoint to downregulate T-cell function (3). In turn, Yervoy acts as a CTLA-4 inhibitor, causing T-cells to be constitutively activated to attack cancer cells.
On the other hand, interferon-α2b is commonly used to treat a variety of cancer, such as leukemia and melanoma, along with treating virus infections like chronic hepatitis B and C (4). The drug is modeled after a class of naturally-occurring proteins that are made and secreted by the immune systems, called interferons. These interferons, like ipilimumab, boosts the function of the immune system to fight viruses and cancer. One major difference, however, between interferon-α2b and ipilimumab is that the mechanism in which interferon stimulates the immune system is not widely understood (5).
Although both treatment options have shown their respective curative effects on advanced melanoma, recent clinical studies have compared the two medications to figure out which option is the best in maximizing overall survival and recurrence-free survival time. Tarhini et al. reports that patients who received ipilimumab 3 mg/kg had 22% lower mortality than in patients on interferon (P=0.044) (6). Despite the effects seen, the researchers sought to further investigate the efficacies of the drugs to ensure optimal treatment of advanced melanoma.
After establishing the efficacies of each individual drug, the research group conducted their randomized study in order to assess two aims: whether interferon-α2b boosts the clinical outcomes of melanoma patients when used in combination with ipilimumab and whether the increased toxicity that arises from a higher dosage of ipilimumab is a justified tradeoff for a greater effect of the drug. In their first aim, their hypothesis was that adding interferon-α2b to ipilimumab would curate a more durable response towards tumors and improve the prognosis of advanced melanoma patients. Their hypothesis in their second aim was that increasing the dosage of ipilimumab would boost the immune response seen in the high-risk melanoma patients and prolong their survival.
To analyze clinical outcomes, the researchers used median progression free survival (PFS) and median overall survival (OS) as their two main metrics. The four treatment arms that they used were ipilimumab 10 mg/kg + high-dose interferon (HDI), ipilimumab 10 mg/kg alone, ipilimumab 3 mg/kg + HDI, and ipilimumab 3 mg/kg alone. In their results, it was noted that there was an increase in both PFS and OS when HDI was added and a higher dose of ipilimumab was give. Despite these increases in PFS and OS, these differences by HDI or by ipilimumab dose did not reach statistical significance.
Although their results did not reach statistical significance, their findings have paved the path for future clinical trials to compare the efficacies of different treatment options, both alone and in combination with one another. This clinical study, and many more like this, has proven that scientists have not fully uncovered the mechanisms that embody cancer progression. Perhaps, the solution for finding the cure to cancer lies in a potential synergy between different medications, instead of a single drug.
References:
Ipilimumab, which is commonly known as Yervoy, is a monoclonal antibody that is a type of targeted cancer drug for high-risk melanoma. Along with fighting advanced melanoma, ipilimumab has also been shown to combat renal cell carcinoma (2). The drug fights cancer by enhancing the immune system, more specifically T-cells. On the surface of T-cells, there is a protein called CTLA-4, which functions as an immune checkpoint to downregulate T-cell function (3). In turn, Yervoy acts as a CTLA-4 inhibitor, causing T-cells to be constitutively activated to attack cancer cells.
On the other hand, interferon-α2b is commonly used to treat a variety of cancer, such as leukemia and melanoma, along with treating virus infections like chronic hepatitis B and C (4). The drug is modeled after a class of naturally-occurring proteins that are made and secreted by the immune systems, called interferons. These interferons, like ipilimumab, boosts the function of the immune system to fight viruses and cancer. One major difference, however, between interferon-α2b and ipilimumab is that the mechanism in which interferon stimulates the immune system is not widely understood (5).
Although both treatment options have shown their respective curative effects on advanced melanoma, recent clinical studies have compared the two medications to figure out which option is the best in maximizing overall survival and recurrence-free survival time. Tarhini et al. reports that patients who received ipilimumab 3 mg/kg had 22% lower mortality than in patients on interferon (P=0.044) (6). Despite the effects seen, the researchers sought to further investigate the efficacies of the drugs to ensure optimal treatment of advanced melanoma.
After establishing the efficacies of each individual drug, the research group conducted their randomized study in order to assess two aims: whether interferon-α2b boosts the clinical outcomes of melanoma patients when used in combination with ipilimumab and whether the increased toxicity that arises from a higher dosage of ipilimumab is a justified tradeoff for a greater effect of the drug. In their first aim, their hypothesis was that adding interferon-α2b to ipilimumab would curate a more durable response towards tumors and improve the prognosis of advanced melanoma patients. Their hypothesis in their second aim was that increasing the dosage of ipilimumab would boost the immune response seen in the high-risk melanoma patients and prolong their survival.
To analyze clinical outcomes, the researchers used median progression free survival (PFS) and median overall survival (OS) as their two main metrics. The four treatment arms that they used were ipilimumab 10 mg/kg + high-dose interferon (HDI), ipilimumab 10 mg/kg alone, ipilimumab 3 mg/kg + HDI, and ipilimumab 3 mg/kg alone. In their results, it was noted that there was an increase in both PFS and OS when HDI was added and a higher dose of ipilimumab was give. Despite these increases in PFS and OS, these differences by HDI or by ipilimumab dose did not reach statistical significance.
Although their results did not reach statistical significance, their findings have paved the path for future clinical trials to compare the efficacies of different treatment options, both alone and in combination with one another. This clinical study, and many more like this, has proven that scientists have not fully uncovered the mechanisms that embody cancer progression. Perhaps, the solution for finding the cure to cancer lies in a potential synergy between different medications, instead of a single drug.
References:
- Rotte, Anand, et al. “Immunotherapy of Melanoma: Present Options and Future Promises.” SpringerLink, Springer US, 15 Jan. 2015, link.springer.com/article/10.1007%2Fs10555-014-9542-0.
- George, Daniel. “Immunotherapy of Renal Cell Carcinoma.” UpToDate, 2019, www.uptodate.com/contents/immunotherapy-of-renal-cell-carcinoma.
- Rowshanravan, Behzad, et al. “CTLA-4: a Moving Target in Immunotherapy.” Blood, U.S. National Library of Medicine, 4 Jan. 2018, www.ncbi.nlm.nih.gov/pmc/articles/PMC6317697/.
- Yu, E., et al. “Immunotropic Properties of Immobilized Interferon-α2b.” SpringerLink, Springer US, 5 Oct. 2016, link.springer.com/article/10.1007%2Fs10517-016-3487-y.
- Hao, Junli, et al. “Inhibition of Alpha Interferon (IFN-α)-Induced MicroRNA-122 Negatively Affects the Anti-Hepatitis B Virus Efficiency of IFN-α.” Journal of Virology, American Society for Microbiology, Jan. 2013, www.ncbi.nlm.nih.gov/pmc/articles/PMC3536426/.
- Tarhini, Ahmad, et al. “Neoadjuvant Ipilimumab (3 Mg/Kg or 10 Mg/Kg) and High Dose IFN-α2b in Locally/Regionally Advanced Melanoma: Safety, Efficacy and Impact on T-Cell Repertoire.” Journal for Immunotherapy of Cancer, BioMed Central, 23 Oct. 2018, www.ncbi.nlm.nih.gov/pmc/articles/PMC6199801/.
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