We have recently determined that more than 90% of melanomas overexpress the receptor tyrosine kinase(RTK) EphA2, with the EphA2 level of overexpression associated with metastic phenotype and an adverseclinical prognosis. Cross-linking of tumor cell-expressed EphA2 molecules using either ligand Ephrin A1-lgfusion proteins or activating anti-EphA2 antibodies results in RTK phosphorylation, followed by receptorinternalization, c-Cbl-dependent ubiquitination and proteasome-dependent degradation. As a consequence,agonist-treated tumor cells acquire a more benign phenotype, and based on our preliminary data, theyconditionally up-regulate their expression of EphA2-derived epitopes presented in MHC class I complexes.Using EphA2-specific CTL lines and clones, wehave shown in preliminary data that treatment with theseEphA2 ligand agonists results in improved recognition and killing of tumor cells by anti-EphA2 CD8+ T cellsin vitro and in vivo in Hu-SCID models. We have also recently observed that pharmacologic inhibition ofprotein tyrosine phosphatases (PTP) or HSP90 function also serves to increase EPhA2 preteasomalprocessing, theoretically making EphA2 peptides accessible to the MHC class I biosynthetic pathway. Wehypothesize that EphA2 ligand agonists and PTP/HSP90 inhibitors may act synergistically in promotingenhanced tumor cell recognition by CTLs. As a consequence, we hypothesize that combinationalimmunotherapies consisting of 1) EphA2-based vaccines designed to elicit specific CTLs and 2) theconditional activation of EphA2 degradation and proteasomal processing via locoregional administration ofEphA2 ligand agonists or PTP/HSP90 inhibitors will result in improved ani-melanoma efficacy.
Our SpecificAims are to' Evaluate the ability of 'agonists' that promote EphA2 proteasomal processing to sensitizemelanoma cells to anti-EphA2 CD8+ T cell recognition in vitro (AIM 1); Test the hypothesis thatcombinational immunotherapies targeting the conditional proteasomal processing of EphA2 are safe andmore effective than single modality therapies in mouse models in vivo (AIM 2); and Design and perform aphase I clinical trial of a combinational therapy involving DC1/EphA2 peptide immunization and conditionalaugmentation of tumor presentation of EphA2-derived epitopes in HLA-A2+ patients with advanced-stagemelanoma (AIM 3).
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