Kowalsky et al. modified a clinically tested, tumor-selective oncolytic vaccinia virus to express a superagonist IL-15 (fusion protein of IL-15 and IL-15Rα). The virus (vvDD-IL15-Rα) increased the infiltration of CD8+ T and NK cells into the tumor, reduced tumor mass, increased survival of mice with colon or ovarian cancer, and led to formation of immunological memory. Although both CD8+ T and NK cells were increased in the tumor, depletion experiments showed that only CD8+ T cells, and not NK or CD4+ T cells, were required for efficacy. Combination of vvDD-IL15-Rα and anti-PD-1 dramatically increased survival compared with either monotherapy.
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-Ralpha, 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-Ralpha 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-Ralpha alone. These results demonstrate that the IL-15-IL-15Ralpha 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.
Author Info: (1) Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; UPMC Hillman Cancer Center, Pittsburgh, PA, USA. (2) Department of Surgery, University
Author Info: (1) Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; UPMC Hillman Cancer Center, Pittsburgh, PA, USA. (2) Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; UPMC Hillman Cancer Center, Pittsburgh, PA, USA. (3) Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; UPMC Hillman Cancer Center, Pittsburgh, PA, USA; Department of Surgery, CCM/CVK, Charite - Universitaetsmedizin Berlin, Berlin, Germany. (4) Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; UPMC Hillman Cancer Center, Pittsburgh, PA, USA. (5) Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; UPMC Hillman Cancer Center, Pittsburgh, PA, USA. (6) Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; UPMC Hillman Cancer Center, Pittsburgh, PA, USA. (7) Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; UPMC Hillman Cancer Center, Pittsburgh, PA, USA. (8) Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL, USA. (9) Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; UPMC Hillman Cancer Center, Pittsburgh, PA, USA. Electronic address: guozs@upmc.edu. (10) Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; UPMC Hillman Cancer Center, Pittsburgh, PA, USA. Electronic address: bartlettdl@upmc.edu.
