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

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

Author information

1
School of Biomedical Engineering, University of Oklahoma, 202 W. Boyd Street, Norman, OK, 73019, USA.
2
Section of Gynecologic Oncology, Stephenson Cancer Center, University of Oklahoma Health Sciences Centre, 825 NE 10th Street, Oklahoma City, OK, 73104, USA.
3
School of Biomedical Engineering, University of Oklahoma, 202 W. Boyd Street, Norman, OK, 73019, USA; School of Chemical, Biological and Materials Engineering, University of Oklahoma, 100 E. Boyd Street, Norman, OK, 73019, USA. Electronic address: rharrison@ou.edu.

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

PMID:
29574275
DOI:
10.1016/j.canlet.2018.03.027
[Indexed for MEDLINE]

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