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Priming Tissue-specific Cellular Immunity in a Phase I Trial of Autologous Dendritic Cells for Prostate Cancer¹

Patrick A. Burch, Jami K. Breen, Jan C. Buckner, Dennis A. Gastineau, Judith A. Kaur, Reiner L. Laus, Douglas J. Padley, Madhusudan V. Peshwa, Henry C. Pitot, Ronald L. Richardson, Bouwien J. Smits, Pitsata Sopapan, George Strang, Frank H. Valone and Stanimir Vuk-Pavlovi²

Divisions of Medical Oncology [P. A. B., J. C. B., J. A. K., H. C. P., R. L. R.], Transfusion Medicine [D. A. G., D. J. P.], and Stem Cell Laboratory [S. V-P.], Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905, and Dendreon Corporation, Seattle, Washington 98121 [R. L. L., M. V. P., B. J. S., P. S., G. S., F. H. V.]

We attempted to induce therapeutic immunity against prostate-derived tissues in patients suffering from progressive hormone-refractory metastatic prostate carcinoma. Thirteen patients were treated with two infusions, 1 month apart, of autologous dendritic cells (APC8015) preexposed ex vivo to PA2024, a fusion protein consisting of human granulocyte/macrophage-colony stimulating factor (GM-CSF) and human prostatic acid phosphatase (PAP). The infusions were followed by three s.c. monthly doses of PA2024 without cells. Three groups of patients each received PA2024 at 0.3, 0.6, or 1.0 mg/injection. All Ps were two-sided. Treatment was well tolerated. After infusions of APC8015, patients experienced only mild (grade 1–2) short-lived fever and/or chills, myalgia, pain, and fatigue. One patient developed grade 3 fatigue. Four patients developed mild local reactions to s.c. PA2024. Twelve patients were evaluable for response to treatment. Circulating prostate-specific antigen levels dropped in three patients. T cells, drawn from patients after infusions of APC8015, but not before, could be stimulated in vitro by GM-CSF (P = 0.0004) and PAP (P = 0.0001), demonstrating broken immune tolerance against these two normal proteins. Injections of PA2024 did not influence the reactivity of T cells against PAP and GM-CSF. However, antibodies to GM-CSF and, to a much lesser extent, to PAP reached maximum titers only after two or even three injections of PA2024, showing that directly injected PA2024 was involved in stimulation of humoral immunity. Dendritic cells exposed to antigen ex vivo can induce antigen-specific cellular immunity in prostate cancer patients, warranting further studies of this mode of immunotherapy.

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