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Blood, 15 April 2002, Vol. 99, No. 8, pp. 2845-2850
IMMUNOBIOLOGY
Flt3 ligand as a vaccine adjuvant in association
with HER-2/neu peptide-based vaccines in patients with
HER-2/neu-overexpressing cancers
Mary L. Disis,
Kristine Rinn,
Keith L. Knutson,
Donna Davis,
Dania Caron,
Corazon dela
Rosa, and
Kathy Schiffman
From the Division of Oncology, University of
Washington, and Immunex Corporation, Seattle, WA.
Dendritic cells (DCs) are potent antigen-presenting cells and have
shown promise to function as "natural" vaccine adjuvants. Currently, most cancer vaccine trials using DCs generate autologous DCs
ex vivo for each patient. Systemic treatment with Flt3 ligand (FL)
results in a marked increase of DCs in tissues such as spleen and lymph
nodes in mice and in the peripheral blood and skin of humans. In light
of these observations, we questioned whether FL could be used
systemically as a vaccine adjuvant to stimulate DC mobilization in
vivo, circumventing the need to generate DCs ex vivo. Ten patients with
HER-2/neu-overexpressing cancer were enrolled in a phase 1 study to
receive a HER-2/neu peptide-based vaccine targeting the intracellular
domain of the HER-2/neu protein. All patients received 20 µg/kg FL
per day subcutaneously for 14 days. Five patients received the
HER-2/neu peptide-based vaccine alone on day 7 of the 14-day cycle, and
5 patients received the vaccine admixed with 150 µg granulocyte
macrophage-colony-stimulating factor (GM-CSF) on day 7 of the FL
cycle. T-cell proliferative responses to HER-2/neu peptides and
intracellular domain protein suggest that vaccine regimens including FL
as an adjuvant were not effective in eliciting a significant HER-2/neu
protein-specific T-cell proliferative response. However, including FL
as a vaccine adjuvant was effective in boosting the precursor
frequency of interferon- -secreting HER-2/neu-specific T
cells. The small sample size of each group, however, did not
allow a statistically significant comparison of immune responses
between the FL alone and FL with GM-CSF arms. Finally, vaccine regimens
including FL as a vaccine adjuvant were associated with the development
of apparent autoimmune phenomena in some patients.
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