Overcoming effector T cell exhaustion in ovarian cancer ascites with a novel adenovirus encoding for a MUC1 bispecific antibody engager and IL-2 cytokine

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Author: Hemminki, Otto ; Basnet, Saru ; Arias, Victor ; Quixabeira, Dafne C A ; Haybout, Lyna ; Van der Heijden, Mirte ; Grönberg-Vähä-Koskela, Susanna A M ; Clubb, James H A ; Santos, Joao M ; Kudling, Tatiana ; Hemminki, Akseli ; Pakola, Santeri ; Jirovec, Elise ; Kanerva, Anna ; Zafar, Sadia ; Cervera-Carrascon, Victor

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.

01 Sep 2024·Molecular Therapy

An oncolytic adenovirus co-expressing a bi-specific T cell engager and IL-2 for the treatment of ovarian cancer

Article

Author: Wakimoto, Hiroaki ; Ayele, Kalkidan ; Saha, Dipongkor

A review.Advanced ovarian cancer is a difficult-to-treat disease and frequently associated with malignant ascites, a condition characterized by abnormal peritoneal accumulation of fluid containing cellular (tumor, immune, and other cell types) and acellular (cytokines and metabolites) factors and an immunosuppressive tumor microenvironment (TME) with reduced effector activity of T cells.In issue of Mol. Therapy, Basnet et al. explore one such promising approach.To utilize the therapeutic T cell-promoting antitumor potential of both BsTEs and IL-2, Basnet et al. developed a novel oAd co-expressing a BsTE plus human IL-2, referred to as Ad5/3-E2F-d24-BsTE(aMUC1aCD3)-IL2, or TILT-322.The BsTE in TILT-322 carries a single-domain antibody against human mucin 1 (MUC1), a TAA dysregulated in 95%-100% of ovarian cancers and associated with promoting metastasis and dismal clin. outcome, linked to a single-domain antibody against human CD3.Basnet et al. previously demonstrated that TILT-321 (Ad5/3-E2F-d24-BsTE), the control oAd used in this study, secretes functional BsTEs that induce T cell activation.The combination of TILT-322 with immune checkpoint blockade, such as anti-PD-1, also warrants investigation, as PD-L1 expression on cancer and other cells is likely to be upregulated by interferon-γ following TILT-322 treatment.This underscores the need for further research and preclin. studies on TILT-322.

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Indication	Highest Phase	Country/Location	Organization	Date
Solid tumor	Discovery	Finland	TILT Biotherapeutics Oy	19 Apr 2024

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