Cytotoxic T-lymphocyte-associated Protein 4: Treating Melanomas
A promising field of cancer therapy is blockading immune checkpoints, which looks at using the body’s own immune system to identify and eliminate cancer. One such immune checkpoint being targeted is CTLA-4. It functions by outcompeting CD28 and inhibiting T-cell activation. Therefore, blockade of CTLA-4 by the drug ipilimumab prevents it from sending its inhibitory signal allowing for T-cell proliferation in the presence of tumor cells. Monitoring treatment effectiveness uses various biomarkers such as values of cell types and surface markers.
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Cytotoxic T-lymphocyte-associated Protein 4: Treating Melanomas
The field of cancer research has made great progress as newer, more advanced technology has become available. One such field of cancer therapy is blockading immune checkpoints, which uses the body’s own immune system to identify and eliminate cancer. Most immune checkpoints are regulated via ligand receptor interactions, which, in turn, can be regulated by blockade with select antibodies. This is the main difference from other types of cancer therapies that focus primarily on targeting tumor cells directly. One such immune checkpoint being targeted is the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). CTLA-4 blockade is approved for treatment of metastatic melanomas by the FDA as the drug Ipilimumab (Ventola, 2017).
Owing to its aggressive behavior and diagnostic difficulties, melanomas are responsible for most skin-related cancer mortalities and one of the most common cancers (Ward, Lambreton, Goel, Yu, & Farma, 2017). Metastatic melanoma develops in the melanocytes, the pigment producing cells found in the epidermis. Exposure to UV light causes DNA mutations in the melanocytes leading to uncontrolled cell growth. In the early stage of the cancer, growth spreads out radially and if detected early enough can be removed surgically. Later stages show an ability to penetrate the deeper layers of the skin accompanied by the potential to spread through the blood or lymph systems. Most often the typical discolored patches on the skin are detected via a routine examination at a doctor’s office following the ABCDE system (asymmetry, border, color, diameter, and evolution) (Ward et al., 2017).
CTLA-4 is expressed on regulatory T-cells where it serves to inhibit the early stages of T-cell activation (Park, Kuen, & Chung, 2018). CTLA-4 has a similar structure to the CD28 protein, and both bind to CD80/CD86. In the presence of CD80/CD86, CTLA-4 can outcompete CD28 and transmit an inhibitory signal to T-cells (Pardoll, 2012). Using this interaction, the drug ipilimumab (an IgG human monoclonal antibody) functions by binding to CTLA-4 and preventing it from sending its inhibitory signal for T-cell activation before the T-cells are able to destroy the tumor (Rausch & Hastings, 2017).
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Monitoring the effectiveness of CTLA-4 blockade can be gauged in several different methods, using various biomarkers (a substance that is linked to the existence of cancer). The frequency of specific cell populations in the tumor or peripheral blood can be measured; the results of which show that an absolute lymphocyte count of greater than 1000/mL point towards an increased benefit to patients (Callahan, Wolchok, & Allison, 2010). Another method of monitoring looks at identifying cells based on surface markers present, specifically using flow cytometry to find CD8+ T-cells. These tumor infiltrating cells are associated with more desirable patient outcomes being that they are directly linked to tumor destruction. Ipilimumab treatment has been shown to produce a significant increase in these CD8+ T-cells present in tumors (Tunger et al., 2018).
There is substantial interest being generated in the field of cancer treatment regarding immune checkpoint blockades. Blockade of CTLA-4 has been shown to improve patient outcomes in many cases. However, timely detection of early melanomas is still needed in order to limit mortality rates. In addition, more biomarkers need to be identified that allow for precise monitoring of immune checkpoint therapy. Furthermore, research is needed into blockade therapy and how it can be combined with other cancer therapies including radiation and chemotherapy in order to achieve the best possible patient outcome. Answers gleaned from this research will enable future immune checkpoint therapies to be more effective moving forward.
- Callahan, M. K., Wolchok, J. D., & Allison, J. P. (2010). Anti-CTLA-4 antibody therapy: immune monitoring during clinical development of a novel immunotherapy. Semin Oncol, 37(5), 473-484. doi:10.1053/j.seminoncol.2010.09.001
- Pardoll, D. M. (2012). The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer, 12(4), 252-264. doi:10.1038/nrc3239
- Park, Y. J., Kuen, D. S., & Chung, Y. (2018). Future prospects of immune checkpoint blockade in cancer: from response prediction to overcoming resistance. Exp Mol Med, 50(8), 109. doi:10.1038/s12276-018-0130-1
- Rausch, M. P., & Hastings, K. T. (2017). Immune Checkpoint Inhibitors in the Treatment of Melanoma: From Basic Science to Clinical Application. In W. H. Ward & J. M. Farma (Eds.), Cutaneous Melanoma: Etiology and Therapy. Brisbane (AU).
- Tunger, A., Kiessler, M., Wehner, R., Temme, A., Meier, F., Bachmann, M., & Schmitz, M. (2018). Immune Monitoring of Cancer Patients Prior to and During CTLA-4 or PD-1/PD-L1 Inhibitor Treatment. Biomedicines, 6(1). doi:10.3390/biomedicines6010026
- Ventola, C. L. (2017). Cancer Immunotherapy, Part 2: Efficacy, Safety, and Other Clinical Considerations. P T, 42(7), 452-463. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/28674473
- Ward, W. H., Lambreton, F., Goel, N., Yu, J. Q., & Farma, J. M. (2017). Clinical Presentation and Staging of Melanoma. In W. H. Ward & J. M. Farma (Eds.), Cutaneous Melanoma: Etiology and Therapy. Brisbane (AU).
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