Induction of PSA‐specific CTLs and anti‐tumor immunity by a genetic prostate cancer vaccine

Roos, Anna-Karin; Pavlenko, Maxim; Charo, Jehad; Egevad, Lars; Pisa, Pavel

doi:10.1002/pros.20135

Cited by 46 publications

(26 citation statements)

References 29 publications

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“…The potential of PSA as an antigen in immunotherapy is due to its overexpression in malignant prostate cells and low expression by normal prostate epithelial cells and other organs, such as the small intestine and testes (3). There is a great deal of information regarding the potential of this antigen for the treatment of prostate cancer (1,10,15,17,25). Previously, we showed that a recombinant L. monocytogenes vaccine expressing PSA (Lm-LLO-PSA) can cause the regression of solid tumors expressing PSA in a murine model for prostate cancer (27).…”

mentioning

confidence: 99%

Construction and Characterization of an Attenuated Listeria monocytogenes Strain for Clinical Use in Cancer Immunotherapy

Wallecha

Maciag

Rivera

et al. 2009

Clin Vaccine Immunol

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Listeria monocytogenes has been exploited previously as a vaccine vector for the delivery of heterologous proteins such as tumor-specific antigens for active cancer immunotherapy. However, for effective use of live vector in clinics, safety is a major concern. In the present study, we describe an irreversibly attenuated and highly immunogenic L. monocytogenes platform, the L. monocytogenes dal-, dat-, and actA-deleted strain that expresses the human prostate-specific antigen (PSA) using an antibiotic resistance marker-free plasmid (the dal dat ⌬actA 142 strain expressing PSA). Despite limited in vivo survival, the dal dat ⌬actA 142 strain was able to elicit efficient immune responses required for tumor clearance. Our results showed that immunization of mice with the dal dat ⌬actA 142 strain caused the regression of the tumors established by the prostate adenocarcinoma cell line expressing PSA. An evaluation of immunologic potency indicated that the dal dat ⌬actA 142 strain elicits a high frequency of PSA-specific immune responses. Interestingly, immunization with the dal dat ⌬actA 142 strain induced significant infiltration of PSA-specific T cells in the intratumoral milieu. Collectively, our data suggest that the dal dat ⌬actA 142 strain is a safe and potent vector for clinical use and that this platform may be further exploited as a potential candidate to express other single or multiple antigens for cancer immunotherapy.Biological and immunological characteristics of Listeria monocytogenes make this gram-positive bacterium an ideal vaccine vector. L. monocytogenes triggers potent cellular immune responses in an infected host due to its ability to survive in both phagocytic and cytosolic compartments. Several groups have shown recombinant L. monocytogenes to be an effective agent for immunotherapy against infection and cancer (2, 16, 19-21, 24, 27, 28). Currently, there are two methods to genetically modify L. monocytogenes to express heterologous antigens in vivo. These include the insertion of a heterologous gene in the bacterial chromosome either by homologous recombination (7,16) or by phage-specific insertion (13) and the transformation of L. monocytogenes with a plasmid carrying a foreign antigen (7, 26). The plasmid-based strategy has the advantage of multicopy expression but relies on complementation for the maintenance of the plasmid in vivo. To address this, two mechanisms have been described previously for L. monocytogenes. One is based on the complementation of a prfA-deficient L. monocytogenes strain (XFL7) with a copy of episomal prfA (a major gene transcription activator for several virulence genes in L. monocytogenes) (7). This complementation ensures the retention of the plasmid in vivo but requires the presence of antibiotic resistance genes for in vitro selection. The second approach uses complementation with alanine racemase (dal), an enzyme involved in the synthesis of the cell wall component D-alanine (35).In L. monocytogenes, the D-alanine metabolism is regulated by two genes, dal and d...

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confidence: 99%

Construction and Characterization of an Attenuated Listeria monocytogenes Strain for Clinical Use in Cancer Immunotherapy

Wallecha

Maciag

Rivera

et al. 2009

Clin Vaccine Immunol

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“…Other examples include treatment with defined peptide antigens like PSA (34), carbohydrate antigens (35), vaccinia vectors expressing PSA (36), and infusions of GM-CSF-activated autologous dendritic cells loaded ex vivo with defined prostate-specific peptides, such as prostate-specific membrane antigen and prostatic acid phosphatase (37,38), or even amplified prostate tumor RNA (39). New tumor-associated antigens and antibodies discovered in this and other immunotherapy trials could themselves become candidate therapeutic molecules using recombinant DNA technologies.…”

Section: Discussionmentioning

confidence: 99%

Phase I/II Trial of an Allogeneic Cellular Immunotherapy in Hormone-Naïve Prostate Cancer

Simons

Carducci

Mikhak

et al. 2006

Clinical Cancer Research

113

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Purpose: To determine the toxicity, immunologic, and clinical activity of immunotherapy with irradiated, allogeneic, prostate cancer cells expressing granulocyte macrophage colony-stimulating factor (GM-CSF) in patients with recurrent prostate cancer. Patients and Methods: A single-institution phase I/II trial was done in hormone therapy^naI« ve patients with prostate-specific antigen (PSA) relapse following radical prostatectomy and absence of radiologic metastases.Treatments were administered weekly via intradermal injections of1.2 Â 10 8 GM-CSF gene^transduced, irradiated, cancer cells (6 Â 10 7 LNCaP cells and 6 Â 10 7 PC-3 cells) for 8 weeks.Results: Twenty-one patients were enrolled and treated. Toxicities included local injection-site reactions, pruritus, and flu-like symptoms. One patient had a partial PSA response of 7-month duration. At 20 weeks post first treatment, 16 of 21 (76%) patients showed a statistically significant decrease in PSA velocity (slope) compared with prevaccination (P < 0.001). Injection site biopsies showed intradermal infiltrates consisting of CD1a + dendritic cells and CD68 + macrophages, similar to previous clinical trials using autologous GM-CSF-transduced cancer cells. Posttreatment, patients developed new oligoclonal antibodies reactive against at least five identified antigens present in LNCaP or PC-3 cells. A high-titer antibody response against a 250-kDa antigen expressed on normal prostate epithelial cells was induced in a patient with partial PSA remission; titers of this antibody decreased when treatment ended, and subsequent PSA relapse occurred. Conclusions: This non-patient-specific prostate cancer immunotherapy has a favorable safety profile and is immunologically active. Continued clinical investigation at higher doses and with longer boosting schedules is warranted.

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“…It was previously reported that a DNA vaccine encoding PSA induces Ag-specific Ab and cellular immunity, in particular CTL in mice (Kim et al, 1998b). Further co-injection of PSA DNA vaccines with DNA expressing IL-2 and GM-CSF induced a significant level of Ag-specific CTL and antitumor responses to PSA-expressing tumors (Roos et al, 2005). More recently, ID-EP has been demonstrated to be a more effective way to induce PSA-specific immune responses (Roos et al, 2006).…”

Section: Prostate Cancermentioning

confidence: 99%

DNA Vaccines against Infectious Diseases and Cancer

Han¹,

Weiner²,

Sin³

2010

Biomolecules and Therapeutics

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-Progress in the development of DNA vaccines and their delivery strategies has been made since their initial concept as a next generation vaccine. Since DNA vaccine includes non-infectious DNA parts of pathogens, it can't cause disease yet it closely mimic the natural process of infection and immune responses. Despite their early promising results of controlling infectious diseases and cancer in small animal models, DNA vaccines failed to display a level of immunogenicity required for combating these diseases in humans, possibly due to their lower protein expression levels. However, increasing evidence has shown that DNA vaccines are clinically well-tolerated and safe. Furthermore, one notable advantage of DNA vaccines includes convenient utilities of plasmid DNAs coding for antigens. For instance, any emerging pathogens could be prevented easily and timely by allowing the simple exchange of antigen-encoding genes. In this review, newly developed DNA vaccine strategies, including electroporation, which has emerged as a potent method for DNA delivery, targeting infectious diseases and cancer will be discussed with a focus on any on-going DNA vaccine trials or progress made pre-clinically and in clinics.

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Induction of PSA‐specific CTLs and anti‐tumor immunity by a genetic prostate cancer vaccine

Abstract: We demonstrate that immunization with a PSA DNA vaccine can evoke PSA-specific cellular immune responses. We also show, for the first time, that a PSA DNA vaccine can induce anti-tumor immunity in vivo.

Cited by 46 publications

References 29 publications

Construction and Characterization of an Attenuated Listeria monocytogenes Strain for Clinical Use in Cancer Immunotherapy

Construction and Characterization of an Attenuated Listeria monocytogenes Strain for Clinical Use in Cancer Immunotherapy

Phase I/II Trial of an Allogeneic Cellular Immunotherapy in Hormone-Naïve Prostate Cancer

DNA Vaccines against Infectious Diseases and Cancer

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