Therapeutic vaccination based on side population cells transduced by the granulocyte–macrophage colony-stimulating factor gene elicits potent antitumor immunity

Abstract

Among cancer immunotherapies, granulocyte-macrophage colony-stimulating factor (GM-CSF) gene-transduced tumor cell vaccine (GVAX) therapies appear promising and have been shown to be safe and effective in multiple clinical trials. However, the antitumor efficacies of GVAX therapy alone are in some cases limited. Here we showed that GVAX therapy targeting cancer stem cells (CSCs) substantially suppressed tumor development in syngeneic immunocompetent mice recapitulating normal immune systems. CSCs were isolated as side population (SP) cells from 4T1 murine breast carcinoma cell line and transduced with GM-CSF gene delivered by non-transmissible Sendai virus (4T1-SP/GM). Impaired tumorigenicity of subcutaneously injected 4T1-SP/GM depended on CD8 T cells in concert with CD4 T cells and natural killer cells. Mice therapeutically vaccinated with irradiated 4T1-SP/GM cells had markedly suppressed tumor development of subcutaneously transplanted 4T1-SP cells compared with those treated with irradiated cells of non-transduced 4T1-SP cells or non-SP (4T1-NSP/GM) cells. Tumor suppression was accompanied by the robust accumulation of mature dendritic cells at vaccination sites and T-helper type 1-skewed systemic cellular immunity. Our results suggested that CSC cell-based GVAX immunotherapy might be clinically useful for inducing potent tumor-specific antitumor immunity.

Human Dendritic Cells: Their Heterogeneity and Clinical Application Potential in Cancer Immunotherapy

“…Another approach is based on the use of adjuvants to boost the immune response. Among these, GM-CSF used in vaccines as GVAX (253) and STINGVAX (254) and, even TLR agonists (255), may be more effective for cell maturation. Other adjuvants could be listed, as for example, aluminum salts (256) (an inflammasome activator), and montanide (257) (an equivalent to incomplete Freund's adjuvant).…”

Turbocharging vaccines: emerging adjuvants for dendritic cell based therapeutic cancer vaccines

“…GVAX is a vaccine platform comprising of irradiated allogeneic or autologous tumor cells engineered to secrete GM-CSF which can illicit T cell immunity against TAAs to improve median survival in patients [49]. The concept of leveraging cancer stem cells for the formulation of GVAX platform has been validated in murine models of breast cancer [50]. GM-CSF secreting, STINGVAX, has proven to be a promising anti-tumorigenic vaccine in murine studies [40].…”

Complexity in cancer stem cells and tumor evolution: Toward precision medicine

“…In fact, if the phenotypic switching mechanisms will be fully understood, it might be possible to target with a vaccine all the tumor cells in a way that does not allow them to switch. In a recent interesting paper, the authors showed that using a gene-transduced tumor cell vaccine therapy targeting CSCs they found a substantially suppression in syngenic immunocompetent mice recapitulating normal immune systems [72]. This system seems very interesting to induce potent tumor-specific antitumor immunity [72].…”

“…In a recent interesting paper, the authors showed that using a gene-transduced tumor cell vaccine therapy targeting CSCs they found a substantially suppression in syngenic immunocompetent mice recapitulating normal immune systems [72]. This system seems very interesting to induce potent tumor-specific antitumor immunity [72]. Moreover, considering the plasticity of both the tumor cells and the plasticity of immune system, the interaction between the two compartment might be protumorigenic or antitumorigenic.…”