We have demonstrated that vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor (GM-CSF) generates potent, specific, and long-lasting antitumor immunity in multiple murine tumor models. Vaccination requires the participation of both CD4 and CD8 positive lymphocytes, and likely involves augmenting the function of professional antigen-presenting cells, such as macrophages and dendritic cells. To test whether this approach will also augment antitumor immunity in cancer patients, we conducted a phase I clinical trial of vaccination with lethally irradiated, autologous melanoma cells engineered to secrete human GM-CSF. This study revealed the diffuse infiltration of pre-existing tumor masses with large numbers of CD4 and CD8 positive T lymphocytes and plasma cells following vaccination, but not before. We also observed the targeted destruction of tumor blood vessels by lymphocytes, eosinophils, and neutrophils.
Based on these promising results, we have expanded our trials to include patients with lung, ovarian, and breast carcinoma, myeloid leukemias, and pediatric solid tumors. To intensify the potency of immunity, we have also administered a blocking antibody to CTLA-4 (a negative immune regulator) to previously vaccinated subjects. Preliminary clinical results indicate that CTLA-4 blockade can accomplish significant additional tumor destruction, albeit with a risk of autoimmunity. Using clinical samples obtained from these studies, we are cloning the antigens that are the targets of T and B cell immune responses in vaccinated patients. These studies have yielded many interesting targets identified including MICA, ML-IAP, progranulin, and angiopoietins.
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