1. Overcoming effector T cell exhaustion in ovarian cancer ascites with a novel adenovirus encoding for a MUC1 bispecific antibody engager and IL-2 cytokine.
- Author
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Basnet S, Van der Heijden M, Quixabeira DCA, Jirovec E, Grönberg-Vähä-Koskela SAM, Clubb JHA, Kanerva A, Pakola S, Haybout L, Arias V, Hemminki O, Kudling T, Zafar S, Cervera-Carrascon V, Santos JM, and Hemminki A
- Subjects
- Humans, Female, Animals, Mice, Cell Line, Tumor, Genetic Vectors genetics, Genetic Vectors administration & dosage, Oncolytic Virotherapy methods, Oncolytic Viruses genetics, Oncolytic Viruses immunology, Lymphocyte Activation immunology, T-Lymphocytes immunology, T-Lymphocytes metabolism, Disease Models, Animal, Immunotherapy methods, T-Cell Exhaustion, Ovarian Neoplasms therapy, Ovarian Neoplasms immunology, Ovarian Neoplasms genetics, Antibodies, Bispecific, Adenoviridae genetics, Ascites therapy, Ascites immunology, Interleukin-2 metabolism, Xenograft Model Antitumor Assays, Mucin-1 genetics, Mucin-1 immunology
- Abstract
T cell-focused cancer immunotherapy including checkpoint inhibitors and cell therapies has been rapidly evolving over the past decade. Nevertheless, there remains a major unmet medical need in oncology generally and immuno-oncology specifically. We have constructed an oncolytic adenovirus, Ad5/3-E2F-d24-aMUC1aCD3-IL-2 (TILT-322), which is armed with a human aMUC1aCD3 T cell engager and IL-2. TILT-322 treatment stimulated T cell cytotoxicity through the increased presence of granzyme B, perforin, and interferon-gamma. Additional immune profiling indicated TILT-322 increased gamma delta T cell activation and impacted other cell types such as natural killer cells and natural killer-like T cells that are traditionally involved in cancer immunotherapy. TILT-322 treatment also decreased the proportion of exhausted CD8
+ T cells as demarked by immune checkpoint expression in ovarian ascites samples. Overall, our data showed that TILT-322 treatment led to an enhanced T cell activation and reversed T cell exhaustion translating into high antitumor efficacy when given locally or intravenously. The analysis of blood and tumors isolated from an in vivo patient-derived ovarian cancer xenograft model suggested TILT-322 mediated tumor control through improved T cell functions. Therefore, TILT-322 is a promising novel anti-tumor agent for clinical translation., Competing Interests: Declaration of interests A.H. is a shareholder of Circio Holdings ASA. (Norway). A.H., J.C., J.M.S., and D.Q. are employees and shareholders of TILT Biotherapeutics, Ltd., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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