Local secretion of anti-CTLA-4 enhances the therapeutic efficacy of a cancer immunotherapy with reduced evidence of systemic autoimmunity.

Promising anti-tumor responses have been observed in the clinic using monoclonal antibodies (mAbs) that block immune checkpoints. One concern with these therapeutic agents remains the potential induction of immune breakthrough events (IBEs) resulting from the disruption of T cell homeostasis or the breaking of tolerance to self antigens. As an approach to maintaining anti-tumor responses but decreasing the likelihood of these events, the local expression of a mAb in combination with a GM-CSF-secreting cancer immunotherapy was evaluated.

GM-CSF-secreting cancer immunotherapies: preclinical analysis of the mechanism of action.

Granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting tumor cell immunotherapies have demonstrated long-lasting, and specific anti-tumor immune responses in animal models. The studies reported here specifically evaluate two aspects of the immune response generated by such immunotherapies: the persistence of irradiated tumor cells at the immunization site, and the breadth of the immune response elicited to tumor associated antigens (TAA) derived from the immunotherapy. To further define the mechanism of GM-CSF-secreting cancer immunotherapies, immunohistochemistry studies were performed using the B16F10 melanoma tumor model.

Recombinant IL-7 enhances the potency of GM-CSF-secreting tumor cell immunotherapy.

IL-7 is known for its role in lymphopoiesis and T-cell homeostasis. In addition, its capacity to augment the immune response to weak or low affinity antigens makes it an ideal candidate to evaluate in combination with a GM-CSF-secreting tumor cell immunotherapy, which has been shown to elicit broad humoral and cellular immune responses. The studies reported here show that IL-7, when combined with a GM-CSF-secreting tumor cell immunotherapy, significantly prolonged the survival of tumor-bearing mice.

Vascular endothelial growth factor blockade reduces intratumoral regulatory T cells and enhances the efficacy of a GM-CSF-secreting cancer immunotherapy.

Purpose: The purpose of the present study was to evaluate granulocyte macrophage colony-stimulating factor (GM-CSF)-secreting tumor cell immunotherapy in combination with vascular endothelial growth factor (VEGF) blockage in preclinical models.

Experimental Design: Survival and immune response were monitored in the B16 melanoma and the CT26 colon carcinoma models. VEGF blockade was achieved by using a recombinant adeno-associated virus vector expressing a soluble VEGF receptor consisting of selected domains of the VEGF receptors 1 and 2 (termed sVEGFR1/R2).

AAV serotype 8-mediated gene delivery of a soluble VEGF receptor to the CNS for the treatment of glioblastoma.

The presence of the blood-brain barrier complicates drug delivery in the development of therapeutic agents for the treatment of glioblastoma multiforme (GBM). The use of local gene transfer in the brain has the potential to overcome this delivery barrier by allowing the expression of therapeutic agents directly at the tumor site. In this study, we describe the development of a recombinant adeno-associated (rAAV) serotype 8 vector that encodes an optimized soluble inhibitor, termed sVEGFR1/R2, of vascular endothelial growth factor (VEGF).

Inhibition of lymphogenous metastasis using adeno-associated virus-mediated gene transfer of a soluble VEGFR-3 decoy receptor.

The presence of metastases in regional lymph nodes is a strong indicator of poor patient survival in many types of cancer. It has recently been shown that the lymphangiogenic growth factor, vascular endothelial growth factor-C (VEGF-C), and its receptor, VEGF receptor-3 (VEGFR3), may play a pivotal role in the promotion of metastasis to regional lymph nodes. In this study, human prostate and melanoma tumor models that preferentially metastasize to the lymph nodes following s.