Genomic Characteristics and Immune Dynamics of Tumor Progression in Melanoma with In-Transit Metastasis (ITM)

Background: Cellular therapies using the adoptive transfer of T cells, such as patient-derived tumor-infiltrating lymphocytes (TILs), have demonstrated potential in effectively treating various types of cancer.Chemotherapy-based conditioning causes substantial morbidity and mortality, thereby significantly limiting the application of cellular therapies.Methods: Here, we present an alternative to conventional conditioning by replacing chemotherapy and interleukin (IL) 2 with arenavirus-based virotherapy.We use adoptive transfer of T-cell receptor transgenic T cells recognizing the melanocyte differentiation antigen TRP2 and the B16F10 murine melanoma model.Results: Our results demonstrate that arenavirus-based virotherapy has an excellent safety profile and maintains efficacy of cellular therapy.We show complete rejection of established melanomas after conditioning with the replicating lymphocytic choriomeningitis virus carrying TRP2 (artLCMV-TRP2), without prior lymphodepletion or addition of IL-2.We further show that replication of the virotherapy is needed for lasting tumor control.Our data indicate that artLCMV induces activation and expansion of transferred T cells significantly more efficiently than the replicating Pichinde virus (artPICV), translating into complete rejection of established melanomas.artLCMV carrying a non-tumor antigen is unable to control tumor growth.Conclusions: We identify three key factors required for effective conditioning using virotherapy: virus replication, virus type, and antigen identity.Our study establishes virotherapy as a promising alternative to conventional conditioning in cellular immunotherapies.This approach demonstrates significant antitumor efficacy with an improved safety profile.