An Oncolytic Virus Expressing a T-cell Engager Simultaneously Targets Cancer and Immunosuppressive Stromal Cells

Cancer Res. 2018 Dec 15;78(24):6852-6865. doi: 10.1158/0008-5472.CAN-18-1750. Epub 2018 Nov 18.

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. SIGNIFICANCE: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / immunology*
  • Biopsy
  • CD3 Complex / metabolism
  • Coculture Techniques
  • Combined Modality Therapy
  • Cytokines / metabolism
  • Fibroblasts / metabolism
  • HEK293 Cells
  • Humans
  • Immunosuppression
  • Inflammation
  • Leukocytes, Mononuclear / cytology
  • Lymphocyte Activation
  • Neoplasms / immunology*
  • Neoplasms / metabolism*
  • Neoplasms / therapy
  • Oncolytic Viruses / immunology*
  • T-Lymphocytes / immunology*

Substances

  • CD3 Complex
  • Cytokines
  • enadenotucirev