Dendritic Cell-Based Xenoantigen Vaccination for Prostate Cancer Immunotherapy

Abstract

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.

Immunotherapy with allotumour mRNA-transfected dendritic cells in androgen-resistant prostate cancer patients

“…In prostate cancer patients, DCs loaded with different types of antigens have been used as vaccines. These antigens include recombinant mouse prostate-acid phosphatase (PAP) (Fong et al, 2001), human PAP (Small et al, 2000), PSA proteins or RNA (Heiser et al, 2002;Barrou et al, 2004), PSMA peptides (Tjoa et al, 1996), allogeneic tumour lysate (Pandha et al, 2004) and RNA amplified from autotumour cells (Heiser et al, 2001). In general, DC vaccination turns out to be safe to patients and evidence for clinical benefit is accumulating.…”

Immune responses against PSMA after gene-based vaccination for immunotherapy – A: results from immunizations in animals

“…proteins. 21,22,24 Similarly to the in vitro experiments, performed by us, 9 in vivo administration of tVacs or sVacs stimulates cytotoxic T-cell responses (Figure 3). The stronger cytotoxicity seen after immunization with hPSMAt may reflect stimulation of T-cell clones that have high-affinity receptors for the antigen.…”

“…9,20 Additionally, gene-based vaccines encoding for a xenogeneic rather than autologous protein have been shown to more likely break existing immunological tolerance. 3,[21][22][23][24] We tested this approach and compared immunizations in rats with tVacs encoding the human PSMA or its rat equivalent. Additionally, since transfection with hPSMAt does not result in the expression of a full-length glycosylated and folded protein, 9 it is of academic interest whether immunization with hPSMAs will lead to formation of antibody against the native antigen, against carbohydrate residues or against linear epitopes.…”

Targeting TARP, a novel breast and prostate tumor‐associated antigen, with T cell receptor‐like human recombinant antibodies

“…Several tumor antigens and HLA allele-specific peptides from prostate cancer-associated antigens have been identified as CD8 + T cell epitopes, including HLA-A2-binding peptides derived from prostate-specific antigen (PSA) [1,2], prostate-specific membrane antigen (PSMA) [3], prostate stem cell antigen (PSCA) [4,5], and prostate acid phosphatase 6, which are all now components of current vaccine trials [5][6][7][8][9][10][11].…”