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Oncolytic adenovirus coding for bispecific T cell engager against human MUC-1 potentiates T cell response against solid tumors.

ABSTRACT: Immunotherapy with bispecific T cell engagers has shown efficacy in patients with hematologic malignancies and uveal melanoma. Antitumor effects of bispecific T cell engagers in most solid tumors are limited due to their short serum half-life and insufficient tumor concentration. We designed a novel serotype 5/3 oncolytic adenovirus encoding a human mucin1 antibody and the human CD3 receptor, Ad5/3-E2F-d24-aMUC1aCD3 (TILT-321). TILT-321 is engineered to replicate only in cancer cells, leading to a high concentration of the aMUC1aCD3 molecule in the tumor microenvironment. Infection and cell viability assays were performed to determine the oncolytic potential of the novel construct. The functionality of the virus-derived aMUC1aCD3 was evaluated in vitro. When TILT-321 was combined with allogeneic T cells, rapid tumor cell lysis was observed. TILT-321-infected cells secreted functional aMUC1aCD3, as shown by increased T cell activity and its binding to MUC1 and CD3. In vivo, TILT-321 treatment led to effective antitumor efficacy mediated by increased intratumoral T cell activity in an A549 and patient-derived ovarian cancer xenograft mouse model humanized with peripheral blood mononuclear cells (PBMC). This study provides a proof of concept for an effective strategy to overcome the key limitations of recombinant bispecific T cell engager delivery for solid tumor treatment.

SUBMITTER: Basnet S

PROVIDER: S-EPMC9842968 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Oncolytic adenovirus coding for bispecific T cell engager against human MUC-1 potentiates T cell response against solid tumors.

Basnet Saru S Santos Joao M JM Quixabeira Dafne C A DCA Clubb James H A JHA Grönberg-Vähä-Koskela Susanna A M SAM Arias Victor V Pakola Santeri S Kudling Tatiana V TV Heiniö Camilla C Havunen Riikka R Cervera-Carrascon Victor V Sorsa Suvi S Anttila Marjukka M Kanerva Anna A Hemminki Akseli A

Molecular therapy oncolytics 20221228

Immunotherapy with bispecific T cell engagers has shown efficacy in patients with hematologic malignancies and uveal melanoma. Antitumor effects of bispecific T cell engagers in most solid tumors are limited due to their short serum half-life and insufficient tumor concentration. We designed a novel serotype 5/3 oncolytic adenovirus encoding a human mucin1 antibody and the human CD3 receptor, Ad5/3-E2F-d24-aMUC1aCD3 (TILT-321). TILT-321 is engineered to replicate only in cancer cells, leading to ...[more]

PMID: 36699617

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Project description:BackgroundOncolytic virus (OV)-based therapies have an emerging role in the treatment of solid tumors, involving both direct cell lysis and immunogenic cell death. Nonetheless, tumor-associated stroma limits the efficacy of oncolytic viruses by forming a barrier that blocks efficient viral penetration and spread. The stroma also plays a critical role in progression, immunosuppression and invasiveness of cancer. Fibroblast activation protein-α (FAP) is highly overexpressed in cancer-associated fibroblasts (CAFs), the main cellular component of tumor stroma, and in this study we assessed whether arming oncolytic adenovirus (OAd) with a FAP-targeting Bispecific T-cell Engager (FBiTE) could retarget infiltrated lymphocytes towards CAFs, enhancing viral spread and T cell-mediated cytotoxicity against the tumor stroma to improve therapeutic activity.MethodsThe bispecific T-cell Engager against FAP was constructed using an anti-human CD3 single-chain variable fragment (scFv) linked to an anti-murine and human FAP scFv. This FBiTE was inserted in the oncolytic adenovirus ICOVIR15K under the control of the major late promoter, generating the ICO15K-FBiTE. ICO15K-FBiTE replication and potency were assessed in HT1080 and A549 tumor cell lines. The expression of the FBiTE and the activation and proliferation of T cells that induced along with the T cell-mediated cytotoxicity of CAFs were evaluated by flow cytometry in vitro. In vivo, T-cell biodistribution and antitumor efficacy studies were conducted in NOD/scid/IL2rg-/- (NSG) mice.ResultsFBiTE expression did not decrease the infectivity and replication potency of the armed virus. FBiTE-mediated binding of CD3+ effector T cells and FAP+ target cells led to T-cell activation, proliferation, and cytotoxicity of FAP-positive cells in vitro. In vivo, FBiTE expression increased intratumoral accumulation of T cells and decreased the level of FAP, a marker of CAFs, in tumors. The antitumor activity of the FBiTE-armed adenovirus was superior to the parental virus.ConclusionsCombination of viral oncolysis of cancer cells and FBiTE-mediated cytotoxicity of FAP-expressing CAFs might be an effective strategy to overcome a key limitation of oncolytic virotherapy, encouraging its further clinical development.

Project description:Cancer immunotherapies strive to overcome tumor-induced immune suppression and activate antitumor immune responses. Although cytotoxic T lymphocytes (CTLs) play a pivotal role in this process, natural killer (NK) cells have also demonstrated remarkable tumor-killing abilities, given their ability to discriminate tumor cells from normal cells and mediate specific antitumoral cytotoxicity. NK cells activation depends on a balance between activation and inhibition signals from several ligands/receptors. Among them, MICA/NKG2D axis is a master regulator of NK activation. MHC class I chain-related polypeptide A (MICA) expression is upregulated by many tumor cell lines and primary tumors and serves as a ligand for the activating NK group 2D (NKG2D) receptor on NK cells and subpopulations of T cells. However, cancer cells can cleave MICA, making it soluble and de-targeting tumor cells from NK cells, leading to tumor immune escape.In this study, we present ICOVIR15KK-MICAMut, an oncolytic adenovirus (OAdv) armed with a transgene encoding a non-cleavable MICA to promote NK-mediated cell-killing capacity and activate the immune response against cancer cells. We first demonstrated the correct MICA overexpression from infected cells. Moreover, our MICA-expressing OAdv promotes higher NK activation and killing capacity than the non-armed virus in vitro. In addition, the armed virus also demonstrated significant antitumor activity in immunodeficient mice in the presence of human PBMCs, indicating the activation of human NK cells. Finally, OAdv-MICA overexpression in immunocompetent tumor-bearing mice elicits tumor-specific immune response resulting in a greater tumor growth control.In summary, this study highlights the significance of NK cells in cancer immunotherapy and presents an innovative approach using a modified oncolytic virus to enhance NK cell activation and antitumor immune response. These findings suggest promising potential for future research and clinical applications.

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Oncolytic adenovirus coding for bispecific T cell engager against human MUC-1 potentiates T cell response against solid tumors.

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Oncolytic adenovirus coding for bispecific T cell engager against human MUC-1 potentiates T cell response against solid tumors.

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