Preclinical investigation of combined gene-mediated cytotoxic immunotherapy and immune checkpoint blockade in glioblastoma

Abstract

Our data show that the GMCI/anti-PD-1 combination is well tolerated and effective in glioblastoma mouse models. These results support evaluation of this combination in glioblastoma patients.

Modeling Oncolytic Viral Therapy, Immune Checkpoint Inhibition, and the Complex Dynamics of Innate and Adaptive Immunity in Glioblastoma Treatment

“…When PD-1 on the surface of a T cell is engaged by PD-L1 on neighboring tumor or innate immune cells, the T cell becomes dysfunctional or "exhausted" and loses the ability to kill its target cells. In recent years, monoclonal antibody therapies against PD-1 and PD-L1, known as immune checkpoint inhibitors, have been developed to target the PD-1/PD-L1 pathway (Barber et al, 2006;He et al, 2015;Speranza et al, 2018). Our initial model investigations suggest the necessity of increased T cell activity in response to OVT, so we also present a second model that combines OVT and an anti-PD-1 immunotherapy, known as nivolumab.…”

Immune checkpoint inhibitors for the treatment of glioblastoma: Where we are

“…Gene-mediated cytotoxic immunotherapy has been proposed as another potential paired therapy, yielding significantly elevated (88%) long-term survival in animal models when combined with PD-1 treatment relative to non-combined controls (0%). [13] Clinical studies involving PD-1 therapy for GBM are relatively limited, with most clinical data involving Pembrolizumab indicating no signal of efficacy for treatment with anti-PD-1 antibodies, despite safety and general patient tolerability. [14] However, a recent clinical study found that compared to adjuvant therapy with PD-1 blockade, neoadjuvant administration of PD-1 blockade before surgery for the treatment of recurrent GBM increased the overall survival (7.5 in control vs 13.7 months in neoadjuvant therapy group, p = .04) and progression free survival (2.4 in control vs 3.3 months in neoadjuvant, p = .03).…”

Oncolytic virus and PD-1/PD-L1 blockade combination therapy

“…One recent example is a study published by Speranza et al, who investigated the use of a recombinant oncolytic adeno-virus expressing herpes simplex virus thymidine kinase to treat syngeneic models of glioblastoma. 53 Thymidine kinase metabolizes the prodrug ganciclovir to its bioactive form, which creates double-stranded DNA breaks leading to cell death and the production of type I immune responses. 53 , 54 While this therapy was effective, analysis of treated animals revealed that it also upregulated intratumoral expression of PD-L1.…”

“… 53 Thymidine kinase metabolizes the prodrug ganciclovir to its bioactive form, which creates double-stranded DNA breaks leading to cell death and the production of type I immune responses. 53 , 54 While this therapy was effective, analysis of treated animals revealed that it also upregulated intratumoral expression of PD-L1. Combining these therapies with anti-PD-1 antibody increased tumor infiltration of CD8 + T cells and increased production of IFNγ, dramatically improving overall survival.…”