Antitumor virotherapy using syngeneic or allogeneic mesenchymal stem cell carriers induces systemic immune response and intratumoral leukocyte infiltration in mice

Abstract

Oncolytic virotherapy uses oncolytic viruses that selectively replicate in cancer cells. The use of cellular vehicles with migration ability to tumors has been considered to increase their delivery to target sites. Following this approach, the antitumor efficacy of the treatment Celyvir (mesenchymal stem cells infected with the oncolytic adenovirus ICOVIR-5) has been demonstrated in patients with neuroblastoma. However, the better efficacy of syngeneic or allogeneic mesenchymal stem cells as cell carriers and the specific role of the immune system in this therapy are still unknown. In this study we use our virotherapy Celyvir with syngeneic and allogeneic mouse mesenchymal stem cells to determine their antitumor efficacy in a C57BL/6 murine adenocarcinoma model. Adoptive transfer of splenocytes from treated mice to new tumor-bearing mice followed by a secondary adoptive transfer to a third group was performed. Similar reduction of tumor growth and systemic activation of the innate and adaptive immune system was observed in groups treated with syngeneic or allogeneic mesenchymal stem cells loaded with ICOVIR-5. Moreover, a different pattern of infiltration was observed by immunofluorescence in Celyvir-treated groups. While non-treated tumors presented higher density of infiltrating immune cells in the periphery of the tumor, both syngeneic and allogeneic Celyvir-treated groups presented higher infiltration of CD45+ cells in the core of the tumor. Therefore, these results suggest that syngeneic and allogeneic Celyvir induce systemic activation of the immune system, similar antitumor effect and a higher intratumoral infiltration of leukocytes.

Cellular Virotherapy Increases Tumor-Infiltrating Lymphocytes (TIL) and Decreases their PD-1+ Subsets in Mouse Immunocompetent Models

“…Results from previous preclinical models and veterinary and human clinical trials using this therapy have also shown an increase or activation of TILs in the tumor biopsies of treated patients [12,16,19,20], as observed in our results. This increase of TILs and the CD8 + T cell subset in the tumor microenvironment is largely associated with a favorable prognosis and survival in melanoma, renal cancer, and other solid tumors [17,18].…”

“…This obtained antitumor effect remarkably improves the results observed in previous immunocompetent mouse models using mouse MSCs and the human OAd ICOVIR-5, in which tumor growth was only reduced by 35% [19,20]. Similarly, while no differences in tumor angiogenesis were observed in the previous models [19], a significantly reduced angiogenesis area was observed in renal cancer and melanoma tumors treated with our mouse version of Celyvir, which correlates with better clinical outcome in a wide variety of cancers [35,36].…”

“…These and other studies have demonstrated that adaptive immune subsets like CD8 + T cells are crucial mediators of the induced antitumor immunity in patients treated with oncolytic virotherapies [ 17 , 18 ]. Nevertheless, although some immunocompetent mouse models have been developed [ 5 , 19 , 20 ], most commonly used preclinical models for studying oncolytic viruses are immunodeficient, which might not represent the real mechanism of action of these viroimmunotherapies, as they present later clearance, higher viral replication, and increased antitumor effects compared to immunocompetent hosts [ 21 ]. In addition, most mouse cells are refractory to the replication of human adenovirus, and as a result, the study of human OAd has been almost restricted to xenograft mouse models, which need to be performed in immunodeficient mice.…”

Myxoma Virus-Loaded Mesenchymal Stem Cells in Experimental Oncolytic Therapy of Murine Pulmonary Melanoma

“… 10 Syngeneic and allogeneic MSCs were reported to induce in mice systemic immune response and intratumoral leukocyte infiltration. 35 Efficacy of MSCs was demonstrated in a phase I ovarian cancer clinical trial. 14 We show human bone-marrow-derived MSCs to be suitable for i.v.…”

Mesenchymal stem cell carriers enhance anti‑tumor efficacy of oncolytic virotherapy (Review)

“…Although there is some controversy over whether MSCs inhibit or promote tumor growth, emerging evidence indicates that oncolytic adenovirus (OAD)-infected MSCs induce anti-tumor immune responses and increase leukocyte infiltration into tumor lesions (89). Similarly, Mahasa et al (10) predicted the therapeutic efficacy of MSCs loaded with OAD in a Hep3B cell tumor model using an integrated mathematical-experimental model, and demonstrated that MSCs loaded with OAD can promote tumor therapeutic efficacy.…”