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*
Department of Pathology, Stanford University School of Medicine, Palo Alto, CA 94304; and
Dendreon, Seattle, WA 98121
Many tumor-associated Ags represent tissue differentiation Ags that
are poorly immunogenic. Their weak immunogenicity may be due to immune
tolerance to self-Ags. Prostatic acid phosphatase (PAP) is just such an
Ag that is expressed by both normal and malignant prostate tissue. We
have previously demonstrated that PAP can be immunogenic in a rodent
model. However, generation of prostate-specific autoimmunity was seen
only when a xenogeneic homolog of PAP was used as the immunogen. To
explore the potential role of xenoantigen immunization in cancer
patients, we performed a phase I clinical trial using dendritic cells
pulsed with recombinant mouse PAP as a tumor vaccine. Twenty-one
patients with metastatic prostate cancer received two monthly
vaccinations of xenoantigen-loaded dendritic cells with minimal
treatment-associated side effects. All patients developed T cell
immunity to mouse PAP following immunization. Eleven of the 21 patients
also developed T cell proliferative responses to the homologous
self-Ag. These responses were associated with Ag-specific IFN-
and/or TNF-
secretion, but not IL-4, consistent with induction of
Th1 immunity. Finally, 6 of 21 patients had clinical stabilization of
their previously progressing prostate cancer. All six of these patients
developed T cell immunity to human PAP following vaccination. These
results demonstrate that xenoantigen immunization can break tolerance
to a self-Ag in humans, resulting in a clinically significant antitumor
effect.
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