A Cetuximab–CCL5 Fusion Protein–Expressing Oncolytic Virus Has Efficacy in GBM

Glioblastoma (GBM) is an immunologically “cold” tumor, and considerable interest exists in making these “cold” tumors “hot” by targeting chemokines, which attract both innate and adaptive immune cells to the tumor. However, the short half-lives and toxic off-target effects observed when targeting these chemokines have impacted their clinical use. To overcome these issues, Tian, Xu, and colleagues generated OV-Cmab-CCL5, an oncolytic herpes simplex virus type I (HSV1) that expresses a bispecific fusion protein containing the EGFR-targeting antibody cetuximab linked to CCL5. OV-Cmab-CCL5 allows for continuous CCL5 production within the tumor microenvironment, as well as binding to both wild-type EGFR and the mutant EGFRvIII. Treatment with OV-Cmab-CCL5 was found to promote natural killer (NK) cell, macrophage, and both CD4⁺ and CD8⁺ T-cell migration; to induce NK-cell antibody-dependent cellular cytotoxicity targeting both wild-type and EGFRvIII GBM cells; and to enhance macrophage antibody-dependent cellular phagocytosis against GBM cells. Investigation into the efficacy of OV-Cmab-CCL5 in a xenograft murine model of GBM revealed prolonged median survival as compared to both saline and OV-Q1 (the same oncolytic HSV1 backbone but lacking the Cmab-CCL5 insert) controls, with similar results being observed in immunocompetent murine GBM models. Further studies indicated that OV-Cmab-CCL5 treatment increases the infiltration and activation of both innate and adaptive cytolytic immune cells, with the observed antitumor effects of OV-Cmab-CCL5 being more dependent on T cells as compared to NK cells and macrophages. Moreover, OV-Cmab-CCL5 enriched the abscopal effect, referring to the shrinking of untreated tumors after the local treatment of a separate tumor, as treatment on one side of the brain also had effects on tumors on the other side of the brain. This feature was not observed in OV-Q1 controls and was correlated with the improved immune cell infiltration seen after OV-Cmab-CCL5 treatment. In summary, this study shows that treatment of GBM with the developed oncolytic virus OV-Cmab-CCL5 induces innate and adaptive immune cell infiltration leading to tumor reduction, suggesting its use in this disease as well as other EGFR⁺ tumors.

Tian L, Xu B, Chen Y, Li Z, Wang J, Zhang J, et al. Specific targeting of glioblastoma with an oncolytic virus expressing a cetuximab-CCL5 fusion protein via innate and adaptive immunity. Nat Cancer 2022 Nov 10 [Epub ahead of print].

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