Dendritic cell-based xenoantigen vaccination for prostate cancer immunotherapy.
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-gamma and/or TNF-alpha 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.
Fong
L
L
Department of Pathology, Stanford University School of Medicine, Palo Alto, CA 94304, USA. lfong@stanford.edu
Brockstedt
D
D
Benike
C
C
Breen
J K
JK
Strang
G
G
Ruegg
C L
CL
Engleman
E G
EG
D000135:Acid Phosphatase; D000818:Animals; D015478:Antigens, Heterophile / Q000276:immunology*; D019496:Cancer Vaccines / Q000627:therapeutic use*; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000637:transplantation*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D016219:Immunotherapy, Adoptive; D007700:Kinetics; D008297:Male; D051379:Mice; D008875:Middle Aged; D011471:Prostatic Neoplasms / Q000175:diagnosis / Q000276:immunology / Q000628:therapy*; D017027:Protein Tyrosine Phosphatases / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D016896:Treatment Outcome
D015478:Antigens, Heterophile; D019496:Cancer Vaccines; D016207:Cytokines; D000135:Acid Phosphatase; C428439:prostatic acid phosphatase; D017027:Protein Tyrosine Phosphatases