Depletion of Peripheral Macrophages and Brain Microglia Increases Brain Tumor Titers of Oncolytic Viruses

Abstract

Clinical trials have proven oncolytic virotherapy to be safe but not effective. We have shown that oncolytic viruses (OV) injected into intracranial gliomas established in rodents are rapidly cleared, and this is associated with up-regulation of markers (CD68 and CD163) of cells of monocytic lineage (monocytes/microglia/macrophages). However, it is unclear whether these cells directly impede intratumoral persistence of OV through phagocytosis and whether they infiltrate the tumor from the blood or the brain parenchyma. To investigate this, we depleted phagocytes with clodronate liposomes (CL) in vivo through systemic delivery and ex vivo in brain slice models with gliomas. Interestingly, systemic CL depleted over 80% of peripheral CD163 + macrophages in animal spleen and peripheral blood, thereby decreasing intratumoral infiltration of these cells, but CD68 + cells were unchanged. Intratumoral viral titers increased 5-fold. In contrast, ex vivo CL depleted only CD68 + cells from brain slices, and intratumoral viral titers increased 10-fold. These data indicate that phagocytosis by both peripheral CD163 + and brain-resident CD68 + cells infiltrating tumor directly affects viral clearance from tumor. Thus, improved therapeutic efficacy may require modulation of these innate immune cells. In support of this new therapeutic paradigm, we observed intratumoral up-regulation of CD68 + and CD163 + cells following treatment with OV in a patient with glioblastoma. [Cancer Res 2007;67(19):9398-406]

Cellular effects of oncolytic viral therapy on the glioblastoma microenvironment

“…48 In contrast, accumulation of CD68-positive cells within the tumor bed was only observed around viral plaques. Whether the inflammatory cells were present due to natural killer cell-induced interferon-g or were they recruited by other means to phagocytose virus-lysed cells is not clear.…”

Gene therapy progress and prospects cancer: oncolytic viruses

“…These studies demonstrated that cyclophosphamide is able to inhibit neutralizing antibody induction, macrophages, regulatory T cells (Tregs) induction and intratumoral interferon (IFN)-g production. [2][3][4][5][6][7][8] It remains to be determined, however, how much this approach will benefit cancer patients who often have already various degrees of 'pre-existing' immunosuppression due to disease and chemotherapy.…”

The oncolytic adenovirus AdΔΔ enhances selective cancer cell killing in combination with DNA-damaging drugs in pancreatic cancer models

“…10,18 In vivo, the absence of the E3B immuno-modulatory genes has also been suggested to prevent efficient spread of this mutant. 19,20 More recently, improved oncolytic viruses have been engineered with smaller specific gene deletions to retain viral potency. Several of these mutants target the pRb/p16 pathway by deletion of the small E1ACR2 domain, essential for pRb binding and inactivation, and S-phase entry to support viral replication and propagation.…”