Oncolytic HSV therapy increases trametinib access to brain tumors and sensitizes them in vivo

Abstract

Background Hyperactivation of the RAS-RAF-MEK-ERK signaling pathway is exploited by glioma cells to promote their growth and evade apoptosis. MEK activation in tumor cells can increase replication of ICP34.5-deleted herpes simplex virus type 1 (HSV-1), but paradoxically its activation in tumor-associated macrophages promotes a pro-inflammatory signaling that can inhibit virus replication and propagation. Here we investigated the effect of blocking MEK signaling in conjunction with oncolytic HSV-1 (oHSV) for brain tumors. Methods Infected glioma cells co-cultured with microglia or macrophages treated with or without trametinib were used to test trametinib effect on macrophages/microglia. Enzyme-linked immunosorbent assay, western blotting, and flow cytometry were utilized to evaluate the effect of the combination therapy. Pharmacokinetic (PK) analysis of mouse plasma and brain tissue was used to evaluate trametinib delivery to the CNS. Intracranial human and mouse glioma-bearing immune deficient and immune competent mice were used to evaluate the antitumor efficacy. Result Oncolytic HSV treatment rescued trametinib-mediated feedback reactivation of the mitogen-activated protein kinase signaling pathway in glioma. In vivo, PK analysis revealed enhanced blood–brain barrier penetration of trametinib after oHSV treatment. Treatment by trametinib, a MEK kinase inhibitor, led to a significant reduction in microglia- and macrophage-derived tumor necrosis factor alpha (TNFα) secretion in response to oHSV treatment and increased survival of glioma-bearing mice. Despite the reduced TNFα production observed in vivo, the combination treatment activated CD8+ T-cell mediated immunity and increased survival in a glioma-bearing immune-competent mouse model. Conclusion This study provides a rationale for combining oHSV with trametinib for the treatment of brain tumors.

MSCs Successfully Deliver Oncolytic Virotherapy to Diffuse Intrinsic Pontine Glioma

“…These findings are in line with prior studies of multiple tumors types treated with OV that demonstrate a modulated immune response to OV administration that contributes to control of tumor growth [47][48][49][50] . However, because this immune response is also responsible for the rapid clearance of viral particles, a delay in OV elimination could improve the therapeutic efficacy of this anti-cancer treatment strategy [51][52][53][54][55] .…”

Enhancing Antitumor Efficacy of Heavily Vascularized Tumors by RAMBO Virus through Decreased Tumor Endothelial Cell Activation

“…We have shown that RAMBO virus, an oHSV expressing an anti-angiogenic gene Vasculostatin, reduces endothelial cell migration and angiogenesis, thereby aiding in the reduction of tumor growth. In addition, we have shown that RAMBO virus also reduces an oHSV therapy-induced innate inflammatory response in part through the suppression of TNFα secretion from macrophage/microglia [31,32]. This allows for an enhancement in virus replication and longer viral presence in in vivo than control viruses (rHSVQ).…”

“…In addition to the direct killing of tumor and tumor endothelial cells, OV therapy activates innate and adaptive antitumor immunity, thereby inflaming the cold tumor into hot TME. Although oHSV replication and propagation can be limited by the antiviral innate immune response, the initial local tumor cell killing by virus infection can reverse the immunosuppressive TME, thereby resulting in tumor associated antigen (TAA) release, cross-presentation, and antitumoral T cell recruitment [31,32]. Therefore, fine-tuning of oHSV-triggered early innate immune responses by effectively increasing the virus propagation and antitumor immune response is important to maximize the therapeutic efficacy of oHSV.…”

“…Captured images were analyzed by BioTek Gen5 version 2.06 software program (BioTek Instruments, lnc., Winooski, VT, USA). GraphPad Prism version 7.03 (GraphPad Software, La Jolla, CA, USA) was used for curve fitting, LD50 calculations, and statistical analysis [31].…”

Herpes Simplex Virus Oncolytic Immunovirotherapy: The Blossoming Branch of Multimodal Therapy

“…In fact, some tumors may be, or may become, resistant to oHSV due to the pro-inflammatory response of tumor-associated macrophages (via a constitutively activated MEK or STAT signaling) in the tumor milieu, which blunts oHSV replication. The pharmacological blockade of these intracellular pathways in tumor-associated macrophages, and the overall modulation of the host inflammatory response to the virus, can restore oHSV replication in tumor cells and the consequent oHSV-related CD8+ T cell activation, responsible for the antitumor effect observed in animal models [155][156][157]. In turn, the alteration of the tumor microenvironment, following oHSV replication, can enhance the chemotherapeutic drug's diffusion to (and efficacy against) the tumor.…”