A plasmid DNA vaccine encoding prostatic acid phosphatase (PAP) elicits antigen-specific T cells in patients with stage D0 prostate cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 14570-14570
Author(s):  
D. G. McNeel ◽  
E. J. Dunphy ◽  
L. E. Johnson ◽  
T. P. Frye ◽  
M. J. Staab ◽  
...  

14570 Background: Prostatic acid phosphatase (PAP) is a tumor antigen in prostate cancer. Clinical trials conducted in patients with metastatic prostate cancer targeting PAP by means of antigen presenting-cell vaccines have suggested clinical benefit in terms of disease progression and overall survival. Ultimately, tumor vaccines may be most effective in the setting of minimal residual disease. We have been investigating plasmid DNA vaccines encoding PAP in rodent models. We found these to be safe and effective in eliciting PAP-specific CD8 T cells and saw evidence of anti-tumor efficacy. We report here the initial immunological results from a dose-escalation portion of a phase I trial testing a DNA vaccine encoding PAP in patients with minimal residual stage D0 prostate cancer. Methods: Patients with clinical stage D0 prostate cancer with rising PSA were vaccinated over a 12-week period, 6 times at 14-day intervals, with a plasmid DNA vaccine encoding PAP (pTVG-HP). Vaccinations were administered intradermally with 100 mcg, 500 mcg, or 1500 mcg doses, and with 200 mcg of GM-CSF co-administered as a vaccine adjuvant. Immunological responses were evaluated by antigen-specific T cell proliferation and IFNγ secretion, and by ELISA for PAP-specific IgG. Results: At present 9 patients have been enrolled in a dose-escalation portion of the trial, and 6 have completed all immunizations. No serious adverse events have been observed, and no patients have discontinued treatment. To date, immunological analysis has been performed for the first, lowest dose cohort. PAP-specific CD4 and CD8 T cell responses, measured by antigen-specific T cell proliferation, were elicited following immunization in 2 of 3 patients. PAP-specific IgG antibodies were not detectable in these patients following vaccination. Conclusions: Intradermal immunization of patients with stage D0 prostate cancer with pTVG-HP has been without evidence of adverse events in doses up to 500 mcg. CD4 and CD8 T cell responses have been observed, consistent with a predominantly cellular immune response, at even the lowest dose of vaccine. Immunological analysis will be performed for patients completing the other dose levels, and all patients will be followed for changes in serum PSA levels. No significant financial relationships to disclose.

Vaccine ◽  
2010 ◽  
Vol 28 (17) ◽  
pp. 3055-3065 ◽  
Author(s):  
Martha Sedegah ◽  
William O. Rogers ◽  
Maria Belmonte ◽  
Arnel Belmonte ◽  
Glenna Banania ◽  
...  

Vaccine ◽  
2006 ◽  
Vol 24 (3) ◽  
pp. 293-303 ◽  
Author(s):  
Laura E. Johnson ◽  
Thomas P. Frye ◽  
Alana R. Arnot ◽  
Carrie Marquette ◽  
Larry A. Couture ◽  
...  

2012 ◽  
Vol 86 (8) ◽  
pp. 4082-4090 ◽  
Author(s):  
Maria L. Knudsen ◽  
Alice Mbewe-Mvula ◽  
Maximillian Rosario ◽  
Daniel X. Johansson ◽  
Maria Kakoulidou ◽  
...  

2010 ◽  
Vol 33 (6) ◽  
pp. 639-647 ◽  
Author(s):  
Jordan T. Becker ◽  
Brian M. Olson ◽  
Laura E. Johnson ◽  
James G. Davies ◽  
Edward J. Dunphy ◽  
...  

2006 ◽  
Vol 56 (6) ◽  
pp. 885-895 ◽  
Author(s):  
Laura E. Johnson ◽  
Thomas P. Frye ◽  
Nachimuthu Chinnasamy ◽  
Dhanalakshmi Chinnasamy ◽  
Douglas G. McNeel

2011 ◽  
Vol 49 (1) ◽  
pp. 85 ◽  
Author(s):  
Hyo-Jin Kim ◽  
Bong-Kwang Jung ◽  
Jin-Joo Lee ◽  
Kyoung-Ho Pyo ◽  
Tae Yun Kim ◽  
...  

2009 ◽  
Vol 27 (25) ◽  
pp. 4047-4054 ◽  
Author(s):  
Douglas G. McNeel ◽  
Edward J. Dunphy ◽  
James G. Davies ◽  
Thomas P. Frye ◽  
Laura E. Johnson ◽  
...  

Purpose Prostatic acid phosphatase (PAP) is a prostate tumor antigen. We have previously demonstrated that a DNA vaccine encoding PAP can elicit antigen-specific CD8+ T cells in rodents. We report here the results of a phase I/IIa trial conducted with a DNA vaccine encoding human PAP in patients with stage D0 prostate cancer. Patients and Methods Twenty-two patients were treated in a dose-escalation trial with 100 μg, 500 μg, or 1,500 μg plasmid DNA, coadministered intradermally with 200 μg granulocyte-macrophage colony-stimulating factor as a vaccine adjuvant, six times at 14-day intervals. All patients were observed for 1 year after treatment. Results No significant adverse events were observed. Three (14%) of 22 patients developed PAP-specific IFNγ-secreting CD8+ T-cells immediately after the treatment course, as determined by enzyme-linked immunospot. Nine (41%) of 22 patients developed PAP-specific CD4+ and/or CD8+ T-cell proliferation. Antibody responses to PAP were not detected. Overall, the prostate-specific antigen (PSA) doubling time was observed to increase from a median 6.5 months pretreatment to 8.5 months on-treatment (P = .033), and 9.3 months in the 1-year post-treatment period (P = .054). Conclusion The demonstration that a DNA vaccine encoding PAP is safe, elicits an antigen-specific T-cell response, and may be associated with an increased PSA doubling time suggests that a multi-institutional phase II trial designed to evaluate clinical efficacy is warranted.


Blood ◽  
2008 ◽  
Vol 112 (12) ◽  
pp. 4585-4590 ◽  
Author(s):  
Ralf Geiben-Lynn ◽  
John R. Greenland ◽  
Kwesi Frimpong-Boateng ◽  
Nico van Rooijen ◽  
Avi-Hai Hovav ◽  
...  

Abstract There is evidence that the limited immunogenicity of plasmid DNA vaccines is the result, at least in part, of the rapid clearance of vaccine antigen expression by antigen-specific immune responses. However, the cell types responsible for the clearance of plasmid DNA vaccine antigens are not known. Here we demonstrate that macrophages, NK cells, and CD8+ T cells did not significantly contribute to the DNA antigen clearance but CD4+ T cells played the crucial role in attenuating plasmid DNA vaccine antigen expression. Adoptive transfer experiments demonstrate that CD4+ T cells facilitated DNA vaccine antigen clearance in a Fas/FasL-dependent manner. Furthermore, we show that depletion of CD4+ T cells prevented the clearance of vaccine antigen and the appearance of a CD8+ T-cell immune response. Inoculation of major histocompatibility complex class II KO mice with the plasmid DNA led to persistent antigen expression and abolition of a CD8+ T-cell immune response. Importantly, the prolongation of antigen expression by disrupting the CD4+ T-cell Fas/FasL myocytes signaling led to a 3- to 5-fold increase of antigen-specific CD8+ T-cell responses. These data demonstrate a dominant role of CD4+ T cell–mediated cytotoxicity in plasmid DNA vaccine antigen clearance.


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