Background Virotherapeutics leverage oncolytic and pro-inflammatory properties to ultimately engage multiple mechanisms of action that lead to holistic modulation of the tumor microenvironment (TME) and induction of anti-tumor immunity. As such, they serve as off-the-shelf in situ cancer vaccines to generate a personalized immune response. We have previously introduced CodaLytic, a codon-modified influenza virus, as an efficient kick-starter of the cancer immunity cycle in several murine models with different baseline immune contexture and in human tumor explant cultures. Here, we are presenting a deeper dive into the immune cell composition infiltrating syngeneic mouse tumors after treatment with CodaLytic.
Methods Effects on the TME were measured after intratumoral administration of 108 PFU CodaLytic as monotherapy and in combination with immune checkpoint blockade (ICB) and/or chemotherapy in orthotopic EMT6 and 4T1 triple-negative breast cancer, subcutaneous B16-F10 melanoma and MC38 colon cancer mouse models. Tumors were harvested and dissociated for characterization of immune infiltrate by flow cytometry after ≥2 doses of virus and after onset of efficacy based on tumor volume in at least one experimental group.
Results Across all models, virus treatment increased tumor infiltration with T and antigen-presenting cells, which could be further boosted by addition of ICB. Both total CD3+ T and importantly CD8+ T cells were recruited to tumors in response to treatment and their frequency within the immune infiltrate correlated directly with tumor volumes (CD3+: MC38 R2=0.58, p<0.02; EMT6 R2=0.31, p<0.02; 4T1 R2=0.50, p<0.0001. CD8+: MC38 R2=0.60, p<0.02; EMT6 R2=0.20, p<0.05; 4T1 R2=0.15, p<0.05). Interestingly, addition of ICB further supported the increase of T cell infiltration in alignment with improved efficacy, while Granzyme B expression was primarily driven by CodaLytic, in particular in B16 and MC38 models, independently of combination with PD-1 blockade. Importantly, these increases were not offset by parallel recruitment of regulatory T cells in B16 and EMT6 models. Furthermore, the frequency of the cross-presenting subset of dendritic cells increased after CodaLytic treatment and directly associated with tumor volume (4T1: R2=0.30, p<0.01). A TME conducive to anti-tumor immunity was further supported by recruitment of B, NK and CD4+ T cells.
Conclusions CodaLytic treatment induced changes in the murine tumor immune infiltrate suggesting anti-tumor immune activity independently of the baseline immune contexture associated with the tumor model. This supports the utility of CodaLytic, a codon-modified virus being developed for breast cancer immunovirotherapy, as a valuable component of novel therapeutic regimens.
Ethics Approval The animal work in this study was approved after MisPro Biotech Services IACUC review, protocols 2019–01-17-COD-1, 2022-COD-02 and LC 2022-COD-03. MC38 data was generated according to the IACUC guidelines of Champions Oncology.
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