Spurthi Tarugu

 Introduction. Melanoma is a deadly form of skin cancer that occurs when melanocytes become cancerous. In early stages, the 5-year survival rate is over 98%; metastasis reduces it to 17%– making melanoma the deadliest type of skin cancer1. Studies have shown that melanomas produce Programmed Death-Ligand 1 (PD-L1). PD-L1 helps tumors evade the immune system via a number of mechanisms, including suppression of TH1 and TH2 cells, apoptosis of antigen- specific T-cells, and inhibition of T-cell proliferation2,3. These findings suggest a potential drug target in the treatment of Melanoma. Methods. A study researching the safety and activity of anti-PD-L1 antibodies conducted a multicenter phase 1 trial in which IV anti–PD-L1 antibody was regularly administered to patients with advanced cancers until the patient had a complete response or confirmed disease progression4. Another study researched the mechanism behind resistance to anti-PD1 antibodies by conducting whole exon sequencing of biopsy samples from lesions in four patients with metastatic melanoma who had an initial objective tumor regression during anti-PD-1 therapy followed by disease progression 5. A 2017 study researched the efficacy of CD80-Fc molecules to overcome PDL1-mediated suppression by culturing human tumor cells PDL1+ C8161 with allogeneic human PBMC plus PHA in the presence or absence of CD80-Fc. Restoration of T-cell function was assessed using IFN-γ levels which were measured using ELISA6. Results.  In the anti-PD-L1 antibody study, a total of 207 patients (55 with melanoma) received anti–PD-L1 antibody with a median duration of 12 weeks; Grade 3 or 4  toxic effects related to treatment occurred in 9% of patients, and an objective response was observed in 9 of 52 patients with melanoma4. The Resistance to Anti-PD-L1 Antibodies study found mutations in the genes encoding interferon-receptor-associated JAK1 or JAK25. The CD80-Fc study found that CD80 prevents binding of some PDL1 mAb to CD80+PDL1+ human tumor cells and restores activation of CD4+ and CD8+ T lymphocytes6. Conclusions. These studies show that antibody-mediated blockade of PD-L1 induced durable tumor regression and prolonged stabilization of melanoma. Administration of antibody to PD-L1 was also found to be safe, with instances of severe, non-reversible adverse events in 5% of patients4. In patients who acquired resistance to anti-PD-L1 antibodies, the JAK1/JAK2 truncating mutations led to insensitivity to IFN-γ, creating a pro-proliferative state for cancer cells5. Finally, CD80-Fc combined with PDL1 antibodies is more effective than solely anti-PD-L1 antibody via the dual mechanism of PDL1-PD1 inhibition and CD28 costimulation6.

1. Melanoma Tests and Mayo Clinic. http://www.mayoclinic.org/diseases- conditions/melanoma/basics/tests-diagnosis/con-20026009. Accessed  March  24,  2017.
2. Dolan DE, Gupta PD-1 pathway inhibitors: changing the landscape of cancer immunotherapy. Cancer control : journal of the Moffitt Cancer Center. https://www.ncbi.nlm.nih.gov/pubmed/24955707. Published July 2014. Accessed April 20, 2017.
3. Merelli B, Massi D, Cattaneo L, Mandalà Targeting the PD1/PD-L1 axis in melanoma: Biological rationale, clinical challenges and opportunities. Critical Reviews in Oncology/Hematology. 2014;89(1):140-165.  doi:10.1016/j.critrevonc.2013.08.002.
4. Brahmer JR, Tykodi SS, Chow LQM, et Safety and Activity of Anti–PD-L1 Antibody in Patients with Advanced Cancer. The New England journal of medicine. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3563263/. Published  June  28,  2012. Accessed April 24, 2017.
5. Zaretsky JM, Garcia-Diaz A, Shin DS, et Mutations Associated with Acquired Resistance to PD-1 Blockade in Melanoma. The New England Journal of Medicine.https://www.ncbi.nlm.nih.gov/pubmed/27433843. Published  September 1, 2016.Accessed April 20, 2017.
6. Haile ST, Dalal SP, Clements V, Tamada K, Ostrand-Rosenberg Soluble CD80 Restores T Cell Activation and Overcomes Tumor Cell Programmed Death Ligand 1- Mediated Immune Suppression. The Journal of Immunology. 2013;191(5):2829-2836. doi:10.4049/jimmunol.1202777.