Nanobugs as Drugs: Bacterial Derived Nanomagnets Enhance Tumor Targeting and Oncolytic Activity of HSV‐1 Virus

Abstract

The survival strategies of infectious organisms have inspired many therapeutics over the years. Indeed the advent of oncolytic viruses (OVs) exploits the uncontrolled replication of cancer cells for production of their progeny resulting in a cancer‐targeting treatment that leaves healthy cells unharmed. Their success against inaccessible tumors however, is highly variable due to inadequate tumor targeting following systemic administration. Coassembling herpes simplex virus (HSV1716) with biocompatible magnetic nanoparticles derived from magnetotactic bacteria enables tumor targeting from circulation with magnetic guidance, protects the virus against neutralizing antibodies and thereby enhances viral replication within tumors. This approach additionally enhances the intratumoral recruitment of activated immune cells, promotes antitumor immunity and immune cell death, thereby inducing tumor shrinkage and increasing survival in a syngeneic mouse model of breast cancer by 50%. Exploiting the properties of such a nanocarrier, rather than tropism of the virus, for active tumor targeting offers an exciting, novel approach for enhancing the bioavailability and treatment efficacy of tumor immunotherapies for disseminated neoplasms.

Inconsistencies in Modeling the Efficacy of the Oncolytic Virus HSV1716 Reveal Potential Predictive Biomarkers for Tolerability

“…E0771-bearing C57/Bl6 mice were unaffected by the highest concentration of virus used in this study (1 × 10 6 PFU/mouse). This is congruent with our previously published studies ( Howard et al, 2022 ); therefore, lower doses in this mouse strain were not tested. The spleens of all tumor-bearing mice were noticeably larger than those of normal mice, regardless of the strain.…”

“…We have recently demonstrated that magnetization of the oncolytic virus HSV1716 enhances tumor targeting resulting in increased tumor elimination and a 50% survival advantage in a C57/Bl6 model of E0771 TNBC ( Howard et al, 2022 ), as well as the ability to steer magnetic macrophages via magnetic resonance imaging ( Muthana et al, 2015 ). Whilst these studies overcome some of the limitations associated with systemic delivery of OVs, we have uncovered some interesting differences in response when repeated in other syngeneic, orthotopic models of triple-negative breast cancer (TNBC).…”

“…Whilst these studies overcome some of the limitations associated with systemic delivery of OVs, we have uncovered some interesting differences in response when repeated in other syngeneic, orthotopic models of triple-negative breast cancer (TNBC). The treatment protocol from Howard et al (2022 ) was replicated in a Balb/c mouse model using 4T1-Luc-BR cells ( Supplementary Figure S1A ). Tumor growth was rapid as detected by IVIS imaging of luciferase-expressing 4T1 cells ( Supplementary Figure S1B ) and caliper measurements ( Supplementary Figure S1C ).…”

“…OVs were tolerated at a concentration of 1 × 10 5 pfu/mouse by all groups, and mice were culled 24 h later in order to evaluate T helper cell activation following treatment. Our previous studies have shown that the cessation of treatment results in tumor regrowth ( Howard et al, 2022 ); therefore, the timepoint was selected to ensure immunological changes following a single virus dose were detected. No adverse effects as a result of treatment with immunomodulators were observed, and body weights remained stable throughout the study ( Figure 3C ).…”

“…Here, we present a series of conflicting interventional efficacy studies using HSV1716 for the treatment of breast cancer in syngeneic orthotopic mouse models. These immunocompetent models are required to understand the mechanistic biology of OVs, but in an attempt to recapitulate our previous success ( Howard et al, 2022 ), we have uncovered valuable determinants of viral toxicity, and the heterogenic immune responses seen.…”