Intratumoral Immunotherapy for Melanoma that Utilizes PD-1 Checkpoint Inhibitors
Introduction. Melanoma is a rare form of skin cancer in which melanocytes develop into malignant cells that can spread to other parts of the body. While melanoma’s 5-year survival rate is around 98.4% when found in the first stage, the statistics drop significantly with stage IV being around 15-20%1. The most important cause for melanoma is considered to be intense intermittent UV exposure, which causes damage to the melanocyte’s genome as well as damage to the DNA repair system2. Genetic risk factors have shown a link to melanoma, including mutations in CDKN2A, CDK4 and chromosome 1 (1p22)3. The normal immune response to cancerous melanocytes is through cytotoxic T lymphocytes attacking melanosomal proteins presented on MHC class I, resulting in apoptosis4. This discussion focuses on the effects of the immunoinhibitory receptor, programmed death receptor 1 (PD-1) which is expressed on many adaptive and innate immune cells as well as the melanocytes themselves. PD-1/PD-L1 interaction controls immune hyperactivity by inhibiting the T cell from undergoing activation4. Studies have found that PD-1/PD-L1 interactions not only play a role in limiting the adaptive immune response to melanoma, but promote cancer survival outside of this response due to upregulation of mTOR signaling pathway in the melanocytes5. Current advances show antibodies targeting this receptor/ligand interaction can suppress tumor growth. Methods. Articles from 2014-2018 were analyzed and compiled into this review to study the PD-1/PD-L1 interaction, specifically outside of the adaptive immune response. Strains of immunodeficient mice with melanoma were utilized to demonstrate tumor growth inhibition of PD-L1 antibody independently of adaptive immunity. Biopsies were stained for the PD-1 surface protein and then checked for the presence of CD-45, the pan-lymphocytic marker, and CD-31, the endothelial marker. The melanoma tumors were then injected with anti-PD-L1 and biopsied to compare the effect of the antibody on tumor growth5. Results. Presence of PD-1 on the tumor without CD-31 or CD-45 indicates that melanoma cells can express this receptor. Following the biopsy, immunohistochemical stains revealed a decrease in p-S6 expression (part of the mTOR signaling pathway), as well as a decrease in tumor volume5. Conclusions. The first in-human immunoglobulin G4 (IgG4) PD-1 immune checkpoint inhibitor antibody that disrupts the interaction of PD-1 receptor with its ligand PD-1 and PD-2 was created, Nivolumab6. Patients with stage iV melanoma were treated with this antibody and reduction of the tumor was shown in 31% of patients with adverse effects being minimal and minor7.
- Types of Melanoma. Skin Cancer Foundation. https://www.skincancer.org/skin-cancerinformation/melanoma/types-of-melanoma. Accessed May 11, 2018.
- Khan AQ, Travers JB, Kemp MG. Roles of UVA radiation and DNA damage responses in melanoma pathogenesis. Environmental and Molecular Mutagenesis. 2018. doi:10.1002/em.22176. – UV DAMAGE
- Testa U, Castelli G, Pelosi E. Melanoma: Genetic Abnormalities, Tumor Progression, Clonal Evolution and Tumor Initiating Cells. Medical Sciences. 2017;5(4):28. doi:10.3390/medsci5040028. – GENETICS
- Passarelli A, Mannavola F, Stucci LS, Tucci M, Silvestris F. Immune system and melanoma biology: a balance between immunosurveillance and immune escape. Oncotarget. 2017;8(62). doi:10.18632/oncotarget.22190. – TYPICAL IMMUNE RESPONSE
- Kleffel S, Posch C, Barthel S, et al. Melanoma Cell-Intrinsic PD-1 Receptor Functions Promote Tumor Growth. Cell. 2015;162(6). – RESEARCH
- Selby MJ, Engelhardt JJ, Johnston RJ, et al. Correction: Preclinical Development of Ipilimumab and Nivolumab Combination Immunotherapy: Mouse Tumor Models, In Vitro Functional Studies, and Cynomolgus Macaque Toxicology. Plos One. 2016;11(11). doi:10.1371/journal.pone.0167251. – NIVOLUMAB
- Topalian S, Sznol M, McDermott D, et al.. Survival, Durable Tumor Remission, and Long-Term Safety in Patients With Advanced Melanoma Receiving Nivolumab. J Clin Oncol. 2014;32(10):1020-1030.