American Association for Cancer Research
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Supplementary Figures S1-5, Tables S1-3, Captions for Movies S1-3 from An Oncolytic Virus Expressing a T-cell Engager Simultaneously Targets Cancer and Immunosuppressive Stromal Cells

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posted on 2023-03-31, 02:02 authored by Joshua D. Freedman, Margaret R. Duffy, Janet Lei-Rossmann, Alice Muntzer, Eleanor M. Scott, Joachim Hagel, Leticia Campo, Richard J. Bryant, Clare Verrill, Adam Lambert, Paul Miller, Brian R. Champion, Leonard W. Seymour, Kerry D. Fisher

Supplementary Files detailing additional experiments supporting the conclusions of the manuscript, including additional activation, cytotoxicity, and cytokine analyses. Supplementary tables contain more details on characterisation of patient biopsies and virus stocks used in the study.

Funding

Medical Research Council

Cancer Research UK

Kay Kendall Leukaemia Fund

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ARTICLE ABSTRACT

Effective immunotherapy of stromal-rich tumors requires simultaneous targeting of cancer cells and immunosuppressive elements of the microenvironment. Here, we modified the oncolytic group B adenovirus enadenotucirev to express a stroma-targeted bispecific T-cell engager (BiTE). This BiTE bound fibroblast activation protein on cancer-associated fibroblasts (CAF) and CD3ϵ on T cells, leading to potent T-cell activation and fibroblast death. Treatment of fresh clinical biopsies, including malignant ascites and solid prostate cancer tissue, with FAP-BiTE–encoding virus induced activation of tumor-infiltrating PD1+ T cells to kill CAFs. In ascites, this led to depletion of CAF-associated immunosuppressive factors, upregulation of proinflammatory cytokines, and increased gene expression of markers of antigen presentation, T-cell function, and trafficking. M2-like ascites macrophages exhibited a proinflammatory repolarization, indicating spectrum-wide alteration of the tumor microenvironment. With this approach, we have actively killed both cancer cells and tumor fibroblasts, reversing CAF-mediated immunosuppression and yielding a potent single-agent therapeutic that is ready for clinical assessment. An engineered oncolytic adenovirus that encodes a bispecific antibody combines direct virolysis with endogenous T-cell activation to attack stromal fibroblasts, providing a multimodal treatment strategy within a single therapeutic agent.

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