A tumor‐targeting nanomedicine carrying the p53 gene crosses the blood–brain barrier and enhances anti‐PD‐1 immunotherapy in mouse models of glioblastoma

Abstract

Despite its anticipated clinical potential, anti‐PD‐1 immunotherapy has only yielded poor outcomes in recent clinical trials for glioblastoma patients. Strategies combining anti‐PD‐1 antibody with other treatment modalities are being explored to alter the immunosuppressive microenvironment that appears to characterize these anti‐PD‐1‐insensitive tumors. Here, we evaluated whether introducing wild‐type p53 gene via a tumor‐targeting nanomedicine (termed SGT‐53) could provide immune stimulation and augment anti‐PD‐1 therapy in mouse syngeneic GL261 tumor models (either subcutaneous or intracranial). In both models, anti‐PD‐1 monotherapy had no demonstrable therapeutic effect. However, combining anti‐PD‐1 with our investigational nanomedicine SGT‐53 was very effective in inhibiting tumor growth, inducing tumor cell apoptosis and increasing intratumoral T‐cell infiltration. A significant survival benefit was observed in mice bearing intracranial glioblastoma receiving combination treatment. Importantly, SGT‐53 upregulated PD‐L1 expression both in vitro and in vivo. Transcriptome analysis revealed modulation of genes linked to either cancer progression or immune activation after combination treatment. Our data suggest that SGT‐53 can boost antitumor immunity and sensitize glioblastoma to anti‐PD‐1 therapy by converting immunologically “cold” tumors into “hot” tumors. Combining SGT‐53 with anti‐PD‐1 might benefit more patients from anti‐PD‐1 immunotherapy and our data support evaluation of this combination in patients with glioblastoma.

Mouse Tumor Models for Advanced Cancer Immunotherapy

“…Usually, tumor cells are injected subcutaneously, as it is easier to track tumor development [25]. In order to make TME closer to that of people, the tumor cells can be orthotopically transplanted into the corresponding organs [26], such as intravenous administration of leukemia and lymphoma cells [27], injection of breast tumor cell lines into mammary adipose tissue [28], intrapancreatic injection of pancreatic duct adenocarcinoma [29], and intracranial injection for glioblastoma cell lines [30,31]. These administration routes more accurately reflect TME, but require more complicated manipulations and special equipment for both the transplantation and monitoring of the further tumor development [32].…”

“…Syngeneic tumor models are also used to investigate the antitumor activity of ICIs, including anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) [39] and anti-programmed death (PD)-1 anti-PD-L1 antibodies [31,40]. For example, using the syngeneic model of immunocompetent B6 mice transplanted with E.G7 hematopoietic cell line or its analogue with PD-L1 deficiency it has been shown that the PD-L1 pathway blockade contributed to the rejection of tumor cells in mice transplanted with both wild-type (WT) E.G7 cells or PD-L1 deficient E.G7 cells in the same degree.…”

“…Thus, the expression of PD-L1 on the cells of TME (either tumor infiltrating leukocytes or stromal cells) may contribute more significantly than the expression of PD-L1 on tumor cells [41]. One of the significant drawbacks of using syngeneic models to evaluate the effectiveness of ICIs is that the rapid Syngeneic tumor models are also used to investigate the antitumor activity of ICIs, including anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) [39] and anti-programmed death (PD)-1 anti-PD-L1 antibodies [31,40]. For example, using the syngeneic model of immunocompetent B6 mice transplanted with E.G7 hematopoietic cell line or its analogue with PD-L1 deficiency it has been shown that the PD-L1 pathway blockade contributed to the rejection of tumor cells in mice transplanted with both wild-type (WT) E.G7 cells or PD-L1 deficient E.G7 cells in the same degree.…”

Nanomedicine-based immunotherapy for central nervous system disorders

“…In patients with newly diagnosed resectable glioblastoma, administration of adenovirus-mediated gene therapy containing the prodrug converting enzyme sitimagene ceradenovec followed by intravenous administration of the antiviral drug ganciclovir increases the mortality rate in patients, but does not increase overall survival [ 148 ]. Interestingly, gene therapy is being proposed as a valuable adjuvant for current glioblastoma treatment [ 149 – 151 ]. Supporting this approach, Speranza et al utilized a nonreplicating adenovirus containing the HSV TK gene (AdV-tk) to enhance anti-PD-1 efficacy in syngeneic glioblastoma-bearing mouse models [ 152 ].…”

A doxycycline-inducible C17.2 neural stem cell-based combination of differentiation and suicide gene therapy for an in vitro tumorigenic C6 glioma model

“…Multiple kinds of gene therapies have been developed to cure brain cancers, including suicide gene therapy, cytokine-mediated gene therapy, tumor suppressor gene therapy and oncolytic gene therapy [7][8][9][10]. Among them, suicide gene therapy is the most frequently used approach to cure glioma both in preclinical studies and in clinical trials [11].…”