mart-1-antigen and trametinib

Limited data are available to assist the selection between immune checkpoint inhibitors and BRAF/mitogen-activated protein kinase kinase inhibitors as first-line treatment for patients with BRAF-mutant advanced malignant melanoma.. To investigate the outcomes associated with first-line pembrolizumab or dabrafenib/trametinib treatment for advanced melanoma with activating BRAF V600 mutation.. Data of patients with BRAF V600-mutant melanoma who were treated with first-line pembrolizumab (n = 40) or dabrafenib/trametinib (n = 32) were analyzed. Tumor response, progression-free survival, and overall survival were evaluated. Immune evasion accompanied with emerging resistance to BRAF/mitogen-activated protein kinase kinase inhibitors was assessed.. A longer overall survival was observed after first-line pembrolizumab treatment than after first-line dabrafenib/trametinib treatment (hazard ratio = 2.910, 95% CI: 1.552-5.459), although there were no significant differences in progression-free survival (P = .375) and response rate (P = .123). Emergence of resistance to dabrafenib/trametinib co-occurred with immune evasion, enabling melanoma cells to escape recognition and killing by Melan-A-specific CD8. Analysis was conducted in a retrospective manner.. Pembrolizumab may be recommended over BRAF/mitogen-activated protein kinase kinase inhibitors as the first-line treatment in patients with advanced BRAF V600-mutant melanoma.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; CD8-Positive T-Lymphocytes; Humans; Imidazoles; Immune Checkpoint Inhibitors; MART-1 Antigen; Melanoma; Mitogen-Activated Protein Kinase Kinases; Mutation; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Retrospective Studies; Skin Neoplasms

Most tumor-associated proteins are located inside tumor cells and thus are not accessible to current marketed therapeutic monoclonal antibodies or their cytotoxic conjugates. Human leukocyte antigen (HLA) class I can present peptides derived from intracellular tumor-associated proteins and somatically mutated proteins on the cell's surface, forming an HLA/peptide complex as tumor-specific antigens for T cell receptor (TCR) recognition. Therefore, HLA-mediated presentation of intracellular tumor antigen peptides provides a viable way to distinguish tumor cells from normal cells, which is important for broadening antigen selection, especially for antibody-drug conjugates (ADCs) regarding their highly cytotoxic payload. We applied sortase A-mediated conjugation to develop TCR-like ADCs (i.e., EA1 HL-vcMMAE) targeting intracellular MART-1 protein, a melanocyte-differentiating antigen specific for metastatic melanomas, via the cell surface HLA-A2/MART-1

Topics: Aminoacyltransferases; Animals; Antibody Specificity; Antigen Presentation; Antineoplastic Agents; Bacterial Proteins; Cell Line, Tumor; Cysteine Endopeptidases; Endocytosis; Female; Histocompatibility Antigens Class I; Immunoconjugates; Intracellular Space; MART-1 Antigen; Melanoma; Mice, SCID; Peptides; Protein Binding; Pyridones; Pyrimidinones; Receptors, Antigen, T-Cell