Anti-CD73 and anti-OX40 immunotherapy coupled with a novel biocompatible enzyme prodrug system for the treatment of recurrent, metastatic ovarian cancer

Cancer Lett. 2018 Jul 1;425:174-182. doi: 10.1016/j.canlet.2018.03.027. Epub 2018 Mar 21.

Abstract

Approximately 75% of ovarian cancer is diagnosed once metastasis to the peritoneal cavity has occurred. A large proportion of patients eventually develop platinum-resistive tumors, which are considered terminal. In order to provide an alternative a novel fusion protein, mCTH-ANXA5, has been developed for the treatment of recurrent, metastatic ovarian cancer. The fusion protein combines annexin V (ANXA5), an ovarian tumor and tumor vasculature targeting protein, with mutated cystathionine gamma-lyase (mCTH), an enzyme that converts selenomethionine (SeMet) into toxic methylselenol, which generates reactive oxygen species and eventual tumor cell death. In order to further enhance the therapeutic efficacy, anti-CD73 and anti-OX40 immunostimulants were combined with mCTH-ANXA5, resulting in an increase of survival by 100% from 12 to 24 days post-therapy and decrease tumor burden in mice with orthotopic metastatic ovarian cancer. Further evaluation of the combination therapy revealed a strong antibody-mediated immune response, and an increased infiltration of cytotoxic T-cells along with a decrease in tumor promoting immune cells. This study demonstrates the efficacy of a synergistic, multi-drug system by attacking the tumor as well as enlisting the body's own defense system to treat the patient.

Keywords: Annexin V; Anti-CD73; Anti-OX40; Cancer; Enzyme prodrug; Phosphatidylserine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5'-Nucleotidase / antagonists & inhibitors
  • Animals
  • Annexin A5 / genetics
  • Annexin A5 / metabolism
  • Antibodies / administration & dosage*
  • Antibodies / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage*
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Cell Line, Tumor
  • Cystathionine gamma-Lyase / genetics
  • Cystathionine gamma-Lyase / metabolism
  • Drug Synergism
  • Female
  • Humans
  • Immunotherapy
  • Mice
  • Neoplasm Metastasis
  • Neoplasm Recurrence, Local / drug therapy*
  • Neoplasm Recurrence, Local / immunology
  • OX40 Ligand / antagonists & inhibitors
  • Ovarian Neoplasms / drug therapy*
  • Ovarian Neoplasms / immunology
  • Prodrugs / administration & dosage*
  • Prodrugs / pharmacology
  • Recombinant Fusion Proteins / administration & dosage*
  • Recombinant Fusion Proteins / pharmacology
  • T-Lymphocytes, Cytotoxic / immunology
  • Xenograft Model Antitumor Assays

Substances

  • Annexin A5
  • Antibodies
  • OX40 Ligand
  • Prodrugs
  • Recombinant Fusion Proteins
  • 5'-Nucleotidase
  • Cystathionine gamma-Lyase