Superagonist IL-15-Armed Oncolytic Virus Elicits Potent Antitumor Immunity and Therapy That Are Enhanced with PD-1 Blockade

Stacy J. Kowalsky, Zuqiang Liu, Mathilde Feist, Sara E. Berkey, Congrong Ma, Roshni Ravindranathan, Enyong Dai, Edward J Roy, Zong Sheng Guo, David L. Bartlett

Research output: Contribution to journalArticle

Abstract

Oncolytic immunotherapy is a promising novel therapeutic for cancer, and further preclinical studies may maximize its therapeutic efficacy. In this study, we construct a novel oncolytic vaccinia virus (VV) expressing a superagoinst IL-15, a fusion protein of IL-15 and IL-15Ralpha. This virus, named vvDD-IL15-Rα possesses similar replication efficiency as the parental virus vvDD yet leads to significantly more regression of the disease and extends the survival of mice bearing MC38 colon or ID8 ovarian cancer. This novel virus elicits potent adaptive antitumor immunity as shown by ELISPOT assays for interferon-gamma-secreting CD8+ T cells and by the rejection of tumor implants upon re-challenge in the mice, which were previously cured by vvDD-IL15-Rα treatment. In vivo cell depletion assays with antibodies showed that this antitumor activity is highly dependent on CD8+ T cells but much less so on CD4+ T cells and NK cells. Finally, the combination of the oncolytic immunotherapy with anti-PD-1 antibody dramatically improves the therapeutic outcome compared to either anti-PD-1 alone or vvDD-IL15-Rα alone. These results demonstrate that the IL-15-IL-15Rα fusion protein-expressing OV elicits potent antitumor immunity, and rational combination with PD-1 blockade leads to dramatic tumor regression and prolongs the survival of mice bearing colon or ovarian cancers.

Original languageEnglish (US)
Pages (from-to)2476-2486
Number of pages11
JournalMolecular Therapy
Volume26
Issue number10
DOIs
StatePublished - Oct 3 2018

Fingerprint

Oncolytic Viruses
Interleukin-15
Immunity
Viruses
T-Lymphocytes
Ovarian Neoplasms
Immunotherapy
Therapeutics
Enzyme-Linked Immunospot Assay
Neoplasms
Antibodies
Vaccinia virus
Adaptive Immunity
Natural Killer Cells
Colonic Neoplasms
Interferon-gamma
Colon
Proteins

Keywords

  • IL-15
  • antitumor immunity
  • efficacy
  • immune checkpoint blockade
  • immunotherapy
  • oncolytic vicotherapy
  • oncolytic virus
  • superagonist
  • vaccinia virus

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

Cite this

Kowalsky, S. J., Liu, Z., Feist, M., Berkey, S. E., Ma, C., Ravindranathan, R., ... Bartlett, D. L. (2018). Superagonist IL-15-Armed Oncolytic Virus Elicits Potent Antitumor Immunity and Therapy That Are Enhanced with PD-1 Blockade. Molecular Therapy, 26(10), 2476-2486. https://doi.org/10.1016/j.ymthe.2018.07.013

Superagonist IL-15-Armed Oncolytic Virus Elicits Potent Antitumor Immunity and Therapy That Are Enhanced with PD-1 Blockade. / Kowalsky, Stacy J.; Liu, Zuqiang; Feist, Mathilde; Berkey, Sara E.; Ma, Congrong; Ravindranathan, Roshni; Dai, Enyong; Roy, Edward J; Guo, Zong Sheng; Bartlett, David L.

In: Molecular Therapy, Vol. 26, No. 10, 03.10.2018, p. 2476-2486.

Research output: Contribution to journalArticle

Kowalsky, SJ, Liu, Z, Feist, M, Berkey, SE, Ma, C, Ravindranathan, R, Dai, E, Roy, EJ, Guo, ZS & Bartlett, DL 2018, 'Superagonist IL-15-Armed Oncolytic Virus Elicits Potent Antitumor Immunity and Therapy That Are Enhanced with PD-1 Blockade', Molecular Therapy, vol. 26, no. 10, pp. 2476-2486. https://doi.org/10.1016/j.ymthe.2018.07.013
Kowalsky, Stacy J. ; Liu, Zuqiang ; Feist, Mathilde ; Berkey, Sara E. ; Ma, Congrong ; Ravindranathan, Roshni ; Dai, Enyong ; Roy, Edward J ; Guo, Zong Sheng ; Bartlett, David L. / Superagonist IL-15-Armed Oncolytic Virus Elicits Potent Antitumor Immunity and Therapy That Are Enhanced with PD-1 Blockade. In: Molecular Therapy. 2018 ; Vol. 26, No. 10. pp. 2476-2486.
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