The chemokine receptor CXCR4 and its cognate ligand, CXCL12 form a pivotal axis for enabling metastasis by many solid tumor types, including head/neck, ovarian, and breast cancers. First, CXCR4 is essential for metastatic spread to organs where CXCL12 is expressed. Second, CXCL12 can stimulate survival and growth of neoplastic cells in a paracrine fashion and modulate the tumor microenvironment.
Novel advances in viral oncotherapy require effective direct oncolysis of stem cell-like cells or otherwise known as cancer initiating cells (CICs) and manipulation of the tumor microenvironment, which has proven to be an important target in cancer treatment. CICs contribute to tumor generation, metastasis, and chemotherapy resistance through hypoxia-resistance metabolism, have a reduced response to chemotherapeutic drugs in vitro, and plays an important role in metastatic disease.
The signals generated by the tumor microenvironment that regulate CICs are not fully understood, but recent studies provide strong evidence for the important role of the CXCL12 chemokine receptor CXCR4 for CIC maintenance, dissemination, and consequent metastatic colonization. In addition to a direct effect of CXCL12/CXCR4 axis on survival and growth of neoplastic cells, this signaling pathway plays a pivotal role in modulating the tumor microenvironment by inducing angiogenesis as well as recruiting pro-tumor myeloid cells and T regulatory cells, which impede innate and adaptive immune mechanisms of tumor destruction.
Engineering an oncolytic vaccinia virus (OVV) armed with a CXCR4 antagonist represents an innovative strategy that targets multiple elements within the tumor microenvironment while overcoming concerns related to the systemic delivery of soluble CXCR4 antagonists. Inhibition of this pathway by oncolytic viruses expressing the CXCR4 antagonist increases efficacy over that mediated by oncolysis alone. A systemic delivery of the armed virus after resection of the primary tumor was found to be efficacious in inhibiting the development of spontaneous metastasis and increased overall tumor-free survival. This inhibition was associated with destruction of tumor vasculature, reductions in expression of CXCL12 and VEGF, and decreased in intratumoral numbers of bone marrow-derived endothelial and myeloid cells.
Altogether, these findings demonstrate that oncolytic virotherapy with the CXCR4 antagonist represents a potent treatment for metastatic tumors with a broad antitumor repertoire including direct cytolysis of CICs, decreased angiogenesis, and reduced intratumoral infiltration of immunosuppressive elements which led to higher spontaneous antitumor immunity. OVV therapy with a CXCR4 antagonist may therefore be considered a method to achieve vaccination in situ, with the adaptive immune response being able to clear minimal residual disease and provide long term protection against tumor relapse.