Edward J. Dunphy

Safety and Immunological Efficacy of a DNA Vaccine Encoding Prostatic Acid Phosphatase in Patients With Stage D0 Prostate Cancer

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 microg, 500 microg, or 1,500 microg plasmid DNA, coadministered intradermally with 200 microg 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 IFN gamma-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.

DNA Vaccine Encoding Prostatic Acid Phosphatase (PAP) Elicits Long-term T-cell Responses in Patients With Recurrent Prostate Cancer

Prostatic acid phosphatase (PAP) is a tumor antigen in prostate cancer and the target of several anti-tumor vaccines in earlier clinical trials. Ultimately, the goal of anti-tumor vaccines is to elicit a sustainable immune response, able to eradicate a tumor, or at least restrain its growth. We have investigated plasmid DNA vaccines and have previously conducted a phase 1 trial in which patients with recurrent prostate cancer were vaccinated with a DNA vaccine encoding PAP. In this study, we investigated the immunologic efficacy of subsequent booster immunizations, and conducted more detailed longitudinal immune analysis, to answer several questions aimed at guiding optimal schedules of vaccine administration for future clinical trials. We report that antigen-specific cytolytic T-cell responses were amplified after immunization in 7 of 12 human leukocyte antigen-A2-expressing individuals, and that multiple immunizations seemed necessary to elicit PAP-specific interferon-γ-secreting immune responses detectable by enzyme-linked immunosorbent spot assay. Moreover, among individuals who experienced a ≥200% increase in prostate-specific antigen doubling time, long-term PAP-specific interferon-γ-secreting T-cell responses were detectable in 6 of 8, but in only 1 of 14 individuals without an observed change in prostate-specific antigen doubling time (P=0.001). Finally, we identified that immune responses elicited could be further amplified by subsequent booster immunizations. These results suggest that future trials using this DNA vaccine, and potentially other anti-tumor DNA vaccines, could investigate ongoing schedules of administration with periodic booster immunizations. Moreover, these results suggest that DNA vaccines targeting PAP could potentially be combined in heterologous immunization strategies with other vaccines to further augment PAP-specific T-cell immunity.

Identification of Antigen-Specific IgG in Sera from Patients with Chronic Prostatitis

Antigen-specific vaccines are one of several molecularly targeted approaches under investigation as possible treatments for prostate cancer. Important to the development of vaccines is the identification of appropriate target antigens. We hypothesized that antigens of the prostate might be identified in patients with the chronic prostatitis/pelvic pain syndrome, a syndrome for which an autoimmune pathology has been proposed. Such antigens might represent naturally recognized target antigens of the prostate that could be investigated in the future as prostate tumor antigens. In this report, we used SEREX to identify proteins expressed in a prostate cDNA expression library recognized by IgG from the sera of patients with chronic prostatitis. Candidate proteins were evaluated using a panel of sera from 62 subjects with symptomatic prostatitis and 71 control male blood donors. We identified one protein that was recognized primarily in sera from subjects with prostatitis compared with controls. MAD-PRO-34, a nucleolar autoantigen, was recognized in 6/62 subjects and 0/71 controls (p = 0.00897). This protein had previously been identified as an autoantigen in patients with prostate cancer. In addition, the NY-CO-7 protein was recognized in 9/62 subjects and 3/71 controls (p = 0.0654). Two subjects had IgG specific for both the MAD-PRO-34 and NY-CO-7 gene products. Our results demonstrate that some patients with the chronic prostatitis/pelvic pain syndrome have autoantibodies to specific proteins. Proteins identified, and MAD-PRO-34 in particular, could be further investigated as potential prostate tumor antigens.

Identification of autoantibodies elicited in a patient with prostate cancer presenting as dermatomyositis

Objectives:  Dermatomyositis is an uncommon autoimmune disease distinguished by proximal muscle weakness and a characteristic skin rash. Dermatomyositis has also frequently been associated with malignancy, typically heralding the diagnosis of ovarian, lung, gastric, or colorectal cancer. We report an unusual case of prostate adenocarcinoma preceded by a diagnosis of dermatomyositis. We hypothesized that in this particular patient, proteins produced by the neoplastic prostatic tissue, which might be normally expressed in muscle tissue, were immunologically recognized as autoantigens.