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. 2022 Jun 15:9:889395.
doi: 10.3389/fmolb.2022.889395. eCollection 2022.

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

Faith Howard  1 , Joe Conner  2 , Sarah Danson  3 , Munitta Muthana  1
Affiliations

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

Faith Howard et al. Front Mol Biosci. .

Abstract

Treatment with HSV1716 via intralesional administration has proven successful for melanoma patients with the hope that oncolytic virotherapy would become another weapon in the systemic anticancer therapy (SACT) arsenal. In addition to challenges surrounding the systemic delivery of oncolytic viruses (OVs), problems associated with its in vivo modeling have resulted in low predictive power, contributing to the observed disappointing clinical efficacy. As OV's efficacy is elicited through interaction with the immune system, syngeneic orthotopic mouse models offer the opportunity to study these with high reproducibility and at a lower cost; however, inbred animals display specific immune characteristics which may confound results. The systemic delivery of HSV1716 was, therefore, assessed in multiple murine models of breast cancer. Tolerability to the virus was strain-dependent with C57/Bl6, the most tolerant and Balb/c experiencing lethal side effects, when delivered intravenously. Maximum tolerated doses were not enough to demonstrate efficacy against tumor growth rates or survival of Balb/c and FVB mouse models; therefore; the most susceptible strain (Balb/c mice) was treated with immunomodulators prior to virus administration in an attempt to reduce side effects. These studies demonstrate the number of variables to consider when modeling the efficacy of OVs and the complexities involved in their interpretation for translational purposes. By reporting these observations, we have potentially revealed a role for T-cell helper polarization in viral tolerability. Importantly, these findings were translated to human studies, whereby a Th1 cytokine profile was expressed in pleural effusions of patients that responded to HSV1716 treatment for malignant pleural mesothelioma with minimal side effects, warranting further investigation as a biomarker for predictive response.

Keywords: T helper cells; biomarker; oncolytic virotherapy; preclinical modeling; tolerability.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Maximum tolerated dose of HSV1716 is mouse strain-dependent. C57/Bl6, FVB, and Balb/c mice were implanted with mLuc-E0771, PyMT-TS1, and mLuc-4T1-Br breast cancer cells, respectively [(A), created using BioRender], and received a range of OV treatment (1 × 104–1 × 106 pfu/mouse) once average tumor volume had reached 100 mm3 to determine the maximum tolerated dose (MTD) (B). Mice receiving their MTD were culled 30 min post-treatment at each timepoint for analysis (n = 3/group per timepoint). Health was monitored by measuring body weight (C), and a final health score was calculated (D) using severity and duration of adverse effects seen during 30 min observation window (E). Data are shown as mean ± SD. Statistical significance was determined by one-way ANOVA where ∗ = p< 0.05 versus PBS group.
FIGURE 2
FIGURE 2
Model dependent T-cell activation. Representative images of tumor sections examined by terminal immunofluorescence staining (A) and their quantification of signals for HSV1716 + cells (B), CD3+ T cells (C), CD8+ T cells (D), CD4+ T cells (E), and F4/80 + macrophages (F). Intratumoral concentrations of TNF-α (G), GM-CSF (H), and IFN-ϒ (I) were detectable using the CBA assay. Data are shown as mean ± SD. Statistical significance was determined by one-way ANOVA with a Tukey post hoc test.
FIGURE 3
FIGURE 3
Prophylactic immunomodulation to enhance OV efficacy. Tumor-bearing Balb/c mice (n = 4/group) were pre-treated intraperitoneally with different immunomodulators (vertical dotted lines) prior to intravenous OV administration (vertical dashed line) [(A), created using BioRender] in an effort to alter the immune microenvironment for enhanced efficacy and tolerability. Tumor volume (B) and body weight (C) were measured prior to killing 24 h post OV treatment. Dissociated cell populations from spleen (D) and tumor (E) samples were analyzed by flow cytometry for pro-inflammatory (CD14+/CD16+) or immunosuppressive markers (CD14+/CD163+). Lymphocytes harvested from blood samples were positively selected for CD4+ (F) and CD8+ (G) T-cell markers. T-cell analysis from cell populations within spleen and tumor samples was also quantified (H). Data are shown as mean ± SD. Statistical significance was determined by one-way ANOVA with a Tukey post hoc test where ∗ = p < 0.05, ∗∗ = p< 0.001, and ∗∗∗∗ = p< 0.0001 versus PBS no tumor.
FIGURE 4
FIGURE 4
Viral tolerability correlates with host Th bias in both mice and humans. Murine tolerability of HSV1716 correlated with T helper cell polarization associated with prototypical strains of inbred mice [(A), created using BioRender]. Pleural effusion samples taken from MPM patients (n = 2), having received four doses of HSV1716, revealed a Th1-dominant cytokine pattern (B) and T-cell activation (C), following the analysis of differentially expressed genes (DEG) by NanoString. Flow cytometry of cell populations demonstrated an overall balanced immune system in the weeks following treatment (D) with a significant CD8+ T-cell–mediated response which declined over time (E). Data are shown as mean ± SD. Statistical significance was determined by Students t-test where ∗ = p< 0.001.
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