Induction of human cytotoxic T lymphocytes specific for prostate-specific antigen

Xue, Bao Hua; Zhang, Yong; Sosman, Jeffrey A.; Peace, David

doi:10.1002/(sici)1097-0045(19970201)30:2<73::aid-pros1>3.0.co;2-l

Cited by 84 publications

(26 citation statements)

References 27 publications

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“…Several PSA-derived peptides have been shown to be able to induce specific cytotoxic T lymphocytes (CTL) in vitro. 9,10 However, PSA is a secreted protein and thus an antigen that is not exclusively present on neoplastic cells. Recently, a novel prostate-specific protein, prostate stem cell antigen (PSCA), has been identified.…”

mentioning

confidence: 99%

Vaccination of advanced prostate cancer patients with PSCA and PSA peptide‐loaded dendritic cells induces DTH responses that correlate with superior overall survival

Thomas-Kaskel

Zeiser

Jochim

et al. 2006

Intl Journal of Cancer

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Prostate stem cell antigen (PSCA) and prostate‐specific antigen (PSA) are overexpressed in most prostate cancers. PSCA‐ and PSA‐derived, HLA‐A2 binding peptides are specific targets for T‐cell responses in vitro. A phase I/II trial was performed to demonstrate feasibility, safety and induction of antigen‐specific immunity by vaccination with dendritic cells (DC) presenting PSCA and PSA peptides in patients with hormone‐ and chemotherapy‐refractory prostate cancer. Patients received 4 vaccinations with a median of 2.7 × 107 peptide‐loaded mature DC s.c. in biweekly intervals. Clinical responses were assessed 2 weeks after the 4th vaccination. Immune monitoring was performed by DTH and HLA multimer analysis. Twelve patients completed vaccination without relevant toxicities. Six patients had stable disease after 4 vaccinations. One patient had a complete disappearance of lymphadenopathy despite rising PSA. Four patients with SD and 1 progressor developed a positive DTH after the 4th vaccination. With a median survival of all patients of 13.4 months, DTH‐positivity was associated with significantly superior survival (p = 0.003). HLA tetramer analysis detected high frequencies of peptide‐specific T cells after 2 vaccinations in 1 patient who was also the sole responder to concomitant hepatitis B vaccination as an indicator of immune competence and survived 27 months after start of vaccination. Vaccination with PSA/PSCA peptide‐loaded, autologous DCs may induce cellular responses primarily in immunocompetent patients, which appear to be associated with clinical benefit. Testing of DC‐based vaccination is warranted for patients at earlier stages of prostate cancer. © 2006 Wiley‐Liss, Inc.

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confidence: 99%

Vaccination of advanced prostate cancer patients with PSCA and PSA peptide‐loaded dendritic cells induces DTH responses that correlate with superior overall survival

Thomas-Kaskel

Zeiser

Jochim

et al. 2006

Intl Journal of Cancer

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“…The most widely and consistently expressed tumor-associated Ag in prostate cancers is prostate-specific Ag (PSA 3 ). Because PSA expression is almost exclusively restricted to benign or malignant prostatic epithelium, much research has focused on investigations as to whether or not PSA could represent a relevant rejection Ag recognized by CTL (2)(3)(4)(5). The immunogenicity of PSA as a self Ag has been questioned because small amounts of this protein are continuously secreted into the bloodstream, which may lead to tolerance.…”

mentioning

confidence: 99%

Human Dendritic Cells Transfected with RNA Encoding Prostate-Specific Antigen Stimulate Prostate-Specific CTL Responses In Vitro

Heiser¹,

Dahm²,

Yancey³

et al. 2000

The Journal of Immunology

174

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Although immunological tolerance to self Ags represents an important mechanism to prevent normal tissue injury, there is growing evidence that tolerance to tumor Ags, which often represent normal peripherally expressed proteins, is not absolute and can be effectively reverted. Prostate-specific Ag (PSA) is a self Ag expressed by both normal and malignant prostatic epithelium, and therefore offers a unique opportunity to examine the ability of self Ags to serve as specific CTL targets. In this study, we investigated the efficacy of autologous dendritic cells (DC) transfected with mRNA encoding PSA to stimulate CTL against PSA Ags in vitro. Ag in form of RNA carries the advantage to encode multiple epitopes for many HLA alleles, thus permitting induction of CTL responses among many cancer patients independent of their HLA repertoire. In this study, we show that PSA mRNA-transfected DC were capable of stimulating primary CTL responses against PSA Ags in vitro. The PSA-specific CTL did not cross-react with kallikrein Ags, a protein, which shares significant homology with PSA, suggesting that harmful autoimmune toxicity may not represent a significant problem with this approach. PSA RNA-transfected DC generated from male or female healthy volunteers or from cancer patients were equally effective in stimulating PSA-specific CTL in vitro, implying that neither natural tolerance to PSA Ags nor tumor-mediated T cell anergy may represent major barriers for CTL generation against the self Ag PSA. This study provides a preclinical rationale for using PSA RNA-transfected DC in active or adoptive immunization protocols.

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“…[136][137] In some studies, CD8 þ T-cell responses were induced in vitro to specific peptides derived from PSA protein. Following repeated in vitro stimulation of peripheral blood lymphocytes from a normal HLA-A2 þ volunteer, Xue et al 138 generated CTL with specificity to one synthetic nonamer (9-mer) peptide corresponding to residues 146-154 of human PSA protein and containing a canonical HLA-A2-binding motif. In another study, two synthetic decamer (10-mer) peptides corresponding to residues 141-150 and 154-163 of PSA were able to elicit CTL responses in vitro from normal HLA-A2 þ volunteers.…”

Section: Prostate-associated Antigens Recognized By Cd8 þ T Lymphocytmentioning

confidence: 99%

Immunology and immunotherapy approaches for prostate cancer

Elkord

2007

Prostate Cancer Prostatic Dis

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Several mechanisms that impair the immune response to promote tumour progression are reported. These mechanisms aim to reduce the ability of antigen-presenting cells to present antigen and activate naïve T cells to support an active immune response or to create a suppressive environment that induce non-functional tumour-associated antigen-specific T cells. Prostate cancer (PC) alone accounts for 33% of incident cancer cases and about 9% of all cancer-related deaths among men in the USA during 2006. Whereas androgen deprivation has remained the first line of therapy for advanced PC, other therapies are still required due to progression to an androgen-resistant state and eventually loss of control in patients receiving hormonal therapy. Immunotherapy seems to be a promising approach to enhance tumour-specific T-cell responses in different cancers including prostate. More importantly, clinical trials in advanced PC patients have shown that immunotherapy may generate significant clinical responses. Immunology and immunotherapy aspects of PC with focus on prostate-specific antigen will be presented.

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Induction of human cytotoxic T lymphocytes specific for prostate-specific antigen

Cited by 84 publications

References 27 publications

Vaccination of advanced prostate cancer patients with PSCA and PSA peptide‐loaded dendritic cells induces DTH responses that correlate with superior overall survival

Vaccination of advanced prostate cancer patients with PSCA and PSA peptide‐loaded dendritic cells induces DTH responses that correlate with superior overall survival

Human Dendritic Cells Transfected with RNA Encoding Prostate-Specific Antigen Stimulate Prostate-Specific CTL Responses In Vitro

Immunology and immunotherapy approaches for prostate cancer

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