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Cancer is a multifaceted and intricate disease that poses a significant global health burden and impacts millions of individuals worldwide. Among the diverse subtypes of cancer, sarcoma stands out as a rare yet highly aggressive malignancy originating from connective tissues such as bone, cartilage, and muscle, and presents challenges in diagnosis and treatment. Despite remarkable progress in cancer research and therapy, the prognosis for sarcoma patients remains low, requiring development of novel therapeutic avenues. Cancer immunotherapies focused on generating tumor-specific responses are emerging as promising alternatives to traditional cancer treatments. T cell-based immunotherapies, such as cancer vaccines and CAR-T cells, are designed to target tumor antigens and generate long term immune memory capable of constant surveillance against recurrence. Therefore, the objective of this study is to establish the groundwork for a novel T cell-based immunotherapeutic approach tailored specifically to sarcoma. Throughout the study, we explored various critical aspects associated with the development of immunotherapy. First, we conducted a proof-of-concept study, evaluating a novel prime-boost vaccine combination employing anti-DEC205 and oncolytic rhabdoviruses targeting a model antigen in a pre- clinical model of melanoma. This study showed that using the DEC205 dendritic cell-targeting antibody as a vector for antigen delivery is a promising alternative to other prime-boost strategies being evaluated in the clinic (NCT02285816). To facilitate the translation of this therapeutic approach to clinical applications, a comprehensive understanding of the human sarcoma tumor immune microenvironment and the identification of a suitable target antigen are essential. Therefore, we conducted an in-depth immune profiling of a high grade and aggressive dedifferentiated liposarcoma (DDLS) using gene expression profiling and immunohistochemistry. We gained valuable insights into the tumor biology and the complex immunological mechanisms within the tumor immune microenvironment. Notably, we identified a novel antigen that is highly expressed in human DDLS and absent in normal tissues, that could be used as a potential antigenic target for immunotherapy. Finally, we evaluated a range of prime and boost vaccine vectors targeting the newly discovered target antigen in pre-clinical murine sarcoma models. Ultimately, we found that an oncolytic rhabdovirus prime and a modified vaccinia Ankara virus boost targeting the sarcoma antigen generates strong antigen specific cellular and humoral responses and protects against tumor growth in a prophylactic model of sarcoma. Altogether, this study lays the foundations for the development of a T cell-based immunotherapy employing an oncolytic rhabdovirus and targeting a novel antigen for the treatment of sarcoma.

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