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

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Stacy J Kowalsky1, Zuqiang Liu1, Mathilde Feist2

  • 1Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; UPMC Hillman Cancer Center, Pittsburgh, PA, USA.

Molecular Therapy : the Journal of the American Society of Gene Therapy
|August 2, 2018
PubMed

Insights

A novel oncolytic vaccinia virus (VV) engineered to express IL-15 and IL-15Rα demonstrated significant tumor regression and improved survival in preclinical cancer models. This enhanced immunotherapy shows potent CD8+ T cell-mediated antitumor immunity, especially when combined with anti-PD-1 therapy.

Area of Science:

  • Oncolytic immunotherapy
  • Cancer virotherapy
  • Immunology

Background:

  • Oncolytic immunotherapy offers a promising new approach to cancer treatment.
  • Optimizing oncolytic virus efficacy through preclinical studies is crucial.
  • Engineering viruses to express immune-stimulating factors can enhance antitumor responses.

Purpose of the Study:

  • To construct and evaluate a novel oncolytic vaccinia virus (VV) expressing a fusion protein of IL-15 and IL-15 receptor alpha (IL-15Rα).
  • To assess the therapeutic efficacy and immune-stimulating properties of the engineered virus, named vvDD-IL15-Rα.
  • To investigate the combination therapy of vvDD-IL15-Rα with anti-PD-1 antibodies for enhanced cancer treatment.

Main Methods:

  • Construction of a novel oncolytic vaccinia virus (vvDD-IL15-Rα) expressing IL-15-IL-15Rα fusion protein.
  • Evaluation of viral replication efficiency and tumor regression in mouse models (MC38 colon and ID8 ovarian cancer).
  • Assessment of adaptive antitumor immunity using ELISPOT assays and in vivo cell depletion studies; combination therapy with anti-PD-1 antibody.

Main Results:

  • vvDD-IL15-Rα exhibited similar replication efficiency to the parental virus but induced significantly greater tumor regression and prolonged survival.
  • The engineered virus elicited potent adaptive antitumor immunity, primarily mediated by CD8+ T cells.
  • Combination therapy with anti-PD-1 antibody dramatically improved therapeutic outcomes compared to monotherapies.

Conclusions:

  • The IL-15-IL-15Rα fusion protein-expressing oncolytic virus (OV) effectively stimulates potent antitumor immunity.
  • Rational combination of this OV with PD-1 blockade leads to significant tumor regression and survival benefits in preclinical cancer models.
  • This strategy holds promise for enhancing cancer immunotherapy efficacy.
Keywords:
IL-15antitumor immunityefficacyimmune checkpoint blockadeimmunotherapyoncolytic vicotherapyoncolytic virussuperagonistvaccinia virus

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