Abstract
Oncolytic viruses can target neoplasms, triggering oncolytic and immune effects. Their delivery to melanoma lesions remains challenging. Bone-marrow-derived mesenchymal stem cells (MSCs) were shown to be permissive for oncolytic myxoma virus (MYXV), allowing its transfer to melanoma cells, leading to their killing. Involvement of progeny virus was demonstrated in the transfer from MSCs to co-cultured melanoma cells. The inhibitory effect of virus on melanoma foci formation in murine lungs was revealed using melanoma cells previously co-cultured with MYXV-infected MSCs. Virus accumulation and persistence in lungs of lesion-bearing mice were shown following intravenous administration of MSC-shielded MYXV construct encoding luciferase. Therapy of experimentally induced lung melanoma in mice with interleukin (IL)-15-carrying MYXV construct delivered by MSCs led to marked regression of lesions and could increase survival. Elevated natural killer (NK) cell percentages in blood indicated robust innate responses against unshielded virus only. Lung infiltration by NK cells was followed by inflow of CD8+ T lymphocytes into melanoma lesions. Elevated expression of genes involved in adaptive immune response following oncolytic treatment was confirmed using RT-qPCR. No adverse pathological effects related to MSC-mediated oncolytic therapy with MYXV were observed. MSCs allow for safe and efficient ferrying of therapeutic MYXV to pulmonary melanoma foci triggering immune effects.
Highlights
The attractiveness of anti-cancer strategy using replication-competent oncolytic viruses relies on their ability to infect, replicate in, and destroy neoplastic cells and to induce antitumor immunity.[1,2] Native oncolytic viral platforms can be engineered to reprogram expression of immunomodulatory, apoptotic, or tumor-vasculaturetargeting proteins or interactions with receptors and viral gene expression cofactors.[3,4] Oncolytic virotherapy has been gaining importance since the clinical success of talimogene laherparepvec, approved for patients with advanced melanoma in 2015
myxoma virus (MYXV) infection induces no significant changes in major histocompatibility complex (MHC) class I expression on mesenchymal stem cells (MSCs) between constitutive expression of the b-2 microglobulin (B2M) gene in MYXV Is Cytotoxic to Melanoma Cells MSCs remained viable (Figure 2E) after infection, and their proliferation was not remarkably reduced
Ara-C added to the co-culture of infected MSCs and B16-F10 cells (Figure 3E) led to strongly inhibited late MYXV gene expression after 24 h
Summary
The attractiveness of anti-cancer strategy using replication-competent oncolytic viruses relies on their ability to infect, replicate in, and destroy neoplastic cells and to induce antitumor immunity.[1,2] Native oncolytic viral platforms can be engineered to reprogram expression of immunomodulatory, apoptotic, or tumor-vasculaturetargeting proteins or interactions with receptors and viral gene expression cofactors.[3,4] Oncolytic virotherapy has been gaining importance since the clinical success of talimogene laherparepvec (trade name, T-VEC or Imlygic), approved for patients with advanced melanoma in 2015. The attractiveness of anti-cancer strategy using replication-competent oncolytic viruses relies on their ability to infect, replicate in, and destroy neoplastic cells and to induce antitumor immunity.[1,2]. Native oncolytic viral platforms can be engineered to reprogram expression of immunomodulatory, apoptotic, or tumor-vasculaturetargeting proteins or interactions with receptors and viral gene expression cofactors.[3,4]. Oncolytic virotherapy has been gaining importance since the clinical success of talimogene laherparepvec (trade name, T-VEC or Imlygic), approved for patients with advanced melanoma in 2015. Clinical trials have investigated T-VEC as neoadjuvant monotherapy and in combination with checkpoint inhibitors in other malignancies.[5]. Stand-alone T-VEC is only injected into accessible melanoma lesions or lymph nodes, and the distant tumor eradication rate needs to be improved. The challenge posed by poorly accessible/disseminated lesions encourages systemic delivery of oncolytic virotherapeutics
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