MIP-1  Antagonizes the Effect of a GM-CSF-Enhanced Subcutaneous Vaccine in a Mouse Glioma Model

Abstract

Subcutaneous vaccination using granulocyte-macrophage colony-stimulating factor (GM-CSF)-transduced glioma cells substantially prolongs survival in the mouse GL261 glioma model. To potentiate the efficacy of GM-CSF-based vaccination, syngeneic C57BL/6 mice bearing pre-implanted intracerebral GL261 gliomas were vaccinated twice subcutaneously with various combinations of glioma cells retrovirally engineered to release GM-CSF, interleukin (IL)-4 or macrophage inflammatory protein (MIP)-1alpha. More than 80% of the animals vaccinated with GM-CSF-secreting or GM-CSF- and IL-4-secreting cells were long-term survivors (> 120 days). Their survival was significantly prolonged compared with animals vaccinated with wild-type cells, which died after a median survival time of 30 days. The combination of IL-4 with GM-CSF did not provide a survival advantage over GM-CSF alone, regardless of whether the animals carried a small or large intracranial tumor load. Further, when the animals were vaccinated with a mixture of GM-CSF-, IL-4- and MIP-1alpha-secreting cells, the median survival was 37 days, and only 22% of the animals in this group were long-term survivors, similar to the vaccination effect of non-modified glioma cells. Thus, unexpectedly, the co-expression of MIP-1alpha, which was meant to attract T cells for stimulation by GM-CSF- and IL-4-stimulated dendritic cells, nullified the induction of an immune response against the GL261 glioma by a GM-CSF- and IL-4-expressing subcutaneous vaccine.

Dendritic Cell-Based Vaccine Efficacy: Aiming for Hot Spots

“…Conditioning the injection site with macrophage inflammatory protein (MIP)-3α-expressing irradiated cells prior to DC vaccination effectively suppresses B16F1 melanoma growth in animals (50). However, co-expression of MIP-1α nullified the GM-CSF-induced immune response against the GL261 glioma, rather than attracting T cells to GM-CSF-stimulated DC (51). TLR-ligands are added to vaccine formulations to avoid Ag-specific tolerance, i.e., when targeting DEC205 (35), and to further stimulate cells of the innate immune system, thereby increasing the potency of the elicited immune response (52).…”

Overview of Cellular Immunotherapy for Patients with Glioblastoma

“…The way all these potential adjuvants act is poorly understood and their real impact is debate. For example, the use of combined GM-CSF is supported by numerous preclinical studies, in gliomas and in other cancers [90–92]. However, two recent randomized trials in melanoma patients showed that GM-CSF could be harmful as immune adjuvant.…”

Anticancer Dendritic Cell Vaccines Producing effective Antitumor T Cell Responses

“…Conditioning vaccination site with irradiated MIP-3α-transfected tumor cells prior to injection of DCs enhanced antitumor efficacy of DC vaccine in a melanoma tumor model [54]. However, co-expression of MIP-1α antagonized the GM-CSFinduced antitumor immune responses of subcutaneous GM-CSFstimulated DCs in a mouse glioma model [55]. Thus, it should be considered to avoid toxicity or opposite effects in combinational therapies.…”