Thomas Frye

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.

Plasmid DNA vaccine encoding prostatic acid phosphatase is effective in eliciting autologous antigen-specific CD8+ T cells

Prostatic acid phosphatase (PAP) is a prostate cancer tumor antigen and a prostate-specific protein shared by rats and humans. Previous studies indicated that Copenhagen rats immunized with a recombinant vaccinia virus expressing human PAP (hPAP) developed PAP-specific cytotoxic T cells (CTL) with cross reactivity to rat PAP (rPAP) and evidence of prostate inflammation. Viral delivery of vaccine antigens is an active area of clinical investigation. However, a potential difficulty with viral-based immunizations is that immune responses elicited to the viral vector might limit the possibility of multiple immunizations. In this paper, we investigate the ability of another genetic immunization method, a DNA vaccine encoding PAP, to elicit antigen-specific CD8+ T cell immune responses. Specifically, Lewis rats were immunized with either a plasmid DNA-based (pTVG-HP) or vaccinia-based (VV-HP) vaccine each encoding hPAP. We determined that rats immunized with a DNA vaccine encoding hPAP developed a Th1-biased immune response as indicated by proliferating PAP-specific CD4+ and CD8+ cells and IFNγ production. Rats immunized with vaccinia virus encoding PAP did not develop a PAP-specific response unless boosted with a heterologous vaccination scheme. Most importantly, multiple immunizations with a DNA vaccine encoding the rat PAP homologue (pTVG-RP) could overcome peripheral self-tolerance against rPAP and generate a Th1-biased antigen-specific CD4+ and CD8+ T cell response. Overall, DNA vaccines provide a safe and effective method of generating prostate antigen-specific T cell responses. These findings support the investigation of PAP-specific DNA vaccines in human clinical trials.

HLA-A2-restricted T-cell epitopes specific for prostatic acid phosphatase

Prostatic acid phosphatase (PAP) has been investigated as the target of several antigen-specific anti-prostate tumor vaccines. The goal of antigen-specific active immunotherapies targeting PAP would ideally be to elicit PAP-specific CD8+ effector T cells. The identification of PAP-specific CD8+ T-cell epitopes should provide a means of monitoring the immunological efficacy of vaccines targeting PAP, and these epitopes might themselves be developed as vaccine antigens. In the current report, we hypothesized that PAP-specific epitopes might be identified by direct identification of pre-existing CD8+ T cells specific for HLA-A2-restricted peptides derived from PAP in the blood of HLA-A2-expressing individuals. 11 nonamer peptides derived from the amino acid sequence of PAP were used as stimulator antigens in functional ELISPOT assays with peripheral blood mononuclear cells from 20 HLA-A2+ patients with prostate cancer or ten healthy blood donors. Peptide-specific T cells were frequently identified in both groups for three of the peptides, p18–26, p112–120, and p135–143. CD8+ T-cell clones specific for three peptides, p18–26, p112–120, and p299–307, confirmed that these are HLA-A2-restricted T-cell epitopes. Moreover, HLA-A2 transgenic mice immunized with a DNA vaccine encoding PAP developed epitope-specific responses for one or more of these three peptide epitopes. We propose that this method to first identify epitopes for which there are pre-existing epitope-specific T cells could be used to prioritize MHC class I-specific epitopes for other antigens. In addition, we propose that the epitopes identified here could be used to monitor immune responses in HLA-A2+ patients receiving vaccines targeting PAP to identify potentially therapeutic immune responses.

Magnetic Resonance Imaging-Transrectal Ultrasound Guided Fusion Biopsy to Detect Progression in Patients with Existing Lesions on Active Surveillance for Low and Intermediate Risk Prostate Cancer

Purpose: Active surveillance is an established option for men with low risk prostate cancer. Multiparametric magnetic resonance imaging with magnetic resonance imaging‐transrectal ultrasound fusion guided biopsy may better identify patients for active surveillance compared to systematic 12‐core biopsy due to improved risk stratification. To our knowledge the performance of multiparametric magnetic resonance imaging in following men on active surveillance with visible lesions is unknown. We evaluated multiparametric magnetic resonance imaging and magnetic resonance imaging‐transrectal ultrasound fusion guided biopsy to monitor men on active surveillance. Materials and Methods: This retrospective review included men from 2007 to 2015 with prostate cancer on active surveillance in whom magnetic resonance imaging visible lesions were monitored by multiparametric magnetic resonance imaging and fusion guided biopsy. Progression was defined by ISUP (International Society of Urological Pathology) grade group 1 to 2 and ISUP grade group 2 to 3. Significance was considered at p ≤0.05. Results: A total of 166 patients on active surveillance with 2 or more fusion guided biopsies were included in analysis. Mean followup was 25.5 months. Of the patients 29.5% had pathological progression. Targeted biopsy alone identified 44.9% of patients who progressed compared to 30.6% identified by systematic 12‐core biopsy alone (p = 0.03). Fusion guided biopsy detected 26% more cases of pathological progression on surveillance biopsy compared to systematic 12‐core biopsy. Progression on multiparametric magnetic resonance imaging was the sole predictor of pathological progression at surveillance biopsy (p = 0.013). Multiparametric magnetic resonance imaging progression in the entire cohort had 81% negative predictive value, 35% positive predictive value, 77.6% sensitivity and 40.5% specificity in detecting pathological progression. Conclusions: Multiparametric magnetic resonance imaging progression predicts the risk of pathological progression. Patients with stable multiparametric magnetic resonance imaging findings have a low rate of progression. Incorporating fusion guided biopsy in active surveillance nearly doubled our detection of pathological progression compared to systematic 12‐core biopsy.

Combined Biparametric Prostate Magnetic Resonance Imaging and Prostate-specific Antigen in the Detection of Prostate Cancer: A Validation Study in a Biopsy-naive Patient Population

OBJECTIVE To validate the use of biparametric (T2- and diffusion-weighted) magnetic resonance imaging (B-MRI) and prostate-specific antigen (PSA) or PSA density (PSAD) in a biopsy-naive cohort at risk for prostate cancer (PCa). METHODS All patients (n = 59) underwent PSA screening and digital rectal exam prior to a B-MRI followed by MRI or transrectal ultrasound fusion-guided targeted biopsy. Previously reported composite formulas incorporating screen positive lesions (SPL) on B-MRI and PSA or PSAD were developed to maximize PCa detection. For PSA, a patient was considered screen positive if PSA level + 6 × (the number of SPL) >14. For PSAD, screening was positive if PSAD × 14 + (the number of SPL) >4.25. These schemes were employed in this new test set to validate the initial formulas. Performance assessment of these formulas was determined for all cancer detection and for tumors with Gleason ≥3 + 4. RESULTS Screen positive lesions on B-MRI had the highest sensitivity (95.5%) and negative predictive value of 71.4% compared with PSA and PSAD. B-MRI significantly improved sensitivity (43.2-72.7%, P = .0002) when combined with PSAD. The negative predictive value of PSA increased with B-MRI, achieving 91.7% for B-MRI and PSA for Gleason ≥3 + 4. Overall accuracies of the composite equations were 81.4% (B-MRI and PSA) and 78.0% (B-MRI and PSAD). CONCLUSION Validation with a biopsy-naive cohort demonstrates the parameter SPL performed better than PSA or PSAD alone in accurately detecting PCa. The combined use of B-MRI, PSA, and PSAD resulted in improved accuracy for detecting clinically significant PCa.

Tumor contact with prostate capsule on magnetic resonance imaging: A potential biomarker for staging and prognosis.

BACKGROUND The high-spatial resolution of multiparametric magnetic resonance imaging (mpMRI) has improved the detection of clinically significant prostate cancer. mpMRI characteristics (extraprostatic extension [EPE], number of lesions, etc.) may predict final pathological findings (positive lymph node [pLN] and pathological ECE [pECE]) and biochemical recurrence (BCR). Tumor contact length (TCL) on MRI, defined as the length of a lesion in contact with the prostatic capsule, is a novel marker with promising early results. We aimed to evaluate TCL as a predictor of +pathological EPE (+pEPE),+pathological LN (+pLN), and BCR in patients undergoing robotic-assisted laparoscopic radical prostatectomy. MATERIALS AND METHODS A review was performed of a prospectively maintained single-institution database of men with prostate cancer who underwent prostate mpMRI followed by robotic-assisted laparoscopic radical prostatectomy without prior therapy from 2007 to 2015. TCL was measured using T2-weighted magnetic resonance images. Logistic and Cox regression analysis were used to assess associations of clinical, imaging, and histopathological variables with pEPE, pLN, and BCR. Receiver operating characteristic curves were used to characterize and compare TCL performance with Partin tables. RESULTS There were 87/379 (23.0%)+pEPE, 18/384 (4.7%)+pLN, and 33/371 (8.9%) BCR patients. Patients with adverse pathology/oncologic outcomes had longer TCL compared to those without adverse outcomes (+pEPE: 19.8 vs. 10.1mm, P<0.0001,+pLN: 38.0 vs. 11.7mm, P<0.0001, and BCR: 19.2 vs. 11.2mm, P = 0.001). On multivariate analysis, TCL remained a predictor of+pEPE (odds ratio: 1.04, P = 0.001),+pLN (odds ratio: 1.07, P<0.0001), and BCR (hazard ratio: 1.03, P = 0.02). TCL thresholds for predicting+pEPE and+pLN were 12.5 and 19.7mm, respectively. TCL alone was found to have good predictive ability for+pEPE and+PLN (pEPE:TCLAUC: 0.71 vs. PartinAUC: 0.66, P = 0.21; pLN:TCLAUC: 0.77 vs. PartinAUC: 0.88, P = 0.04). CONCLUSION We demonstrate that TCL is an independent predictor of+pEPE, +pLN, and BCR. If validated, this imaging biomarker may facilitate and inform patient counseling and decision-making.

Impact of County Rurality and Urologist Density on Urological Cancer Mortality in Illinois

PURPOSE The urology work force is contracting at a time when service demand is increasing due to demographic changes, especially in rural areas. We investigated the impact of rural status and urologist density on kidney and renal pelvis, bladder and prostate cancer mortality at the county level in Illinois. MATERIALS AND METHODS We stratified the 102 Illinois counties by 2003 RUCCs as urban (36, RUCCs 1 to 3) and rural (66, RUCCs 4 to 9). Area Health Resource Files were used for county demographic data and urologist density. County level age adjusted mortality rates from 1990 to 2010 were derived from National Center for Health Statistics data using SEER*Stat. We examined the associations of urological cancer mortality rates with rural status and urologist density. RESULTS Average urologist density significantly differed between rural and urban counties (1.9 vs 3.4/100,000 population, p < 0.01). The kidney and renal pelvis cancer mortality rate in rural counties was higher than in urban counties while that of prostate cancer was lower (4.9 vs 4.3 and 28.7 vs 32.2/100,000 population, respectively, each p < 0.01). Urologist density correlated with the mortality rate of kidney and renal pelvis cancer (Pearson coefficient -0.33, p < 0.01) but not with the bladder or prostate cancer mortality rate. Multiple regression analysis revealed that rurality and lower urologist density (p = 0.01 and < 0.05) were significantly associated with higher kidney and renal pelvis cancer mortality. CONCLUSIONS Rural residence and low urologist density were associated with increased kidney and renal pelvis cancer mortality on the county level in Illinois. Further expansion and testing of evidence-based telemedicine is warranted because remote technical consultation is now technologically feasible, effective, inexpensive and satisfactory to patients.

The significance of anterior prostate lesions on multiparametric magnetic resonance imaging in African-American men

INTRODUCTION African-American (AA) men tend to harbor high-risk prostate cancer (PCa) and exhibit worse outcomes when compared to other groups. It has been postulated that AA men may harbor more anterior prostate lesions (APLs) that are undersampled by the standard transrectal ultrasound guided-biopsy (SBx), potentially resulting in greater degree of Gleason score (GS) upgrading at radical prostatectomy. We aimed to evaluate the detection rate of anterior PCa significance of APLs in AA men on multiparametric magnetic resonance imaging (mpMRI) and compare it to a matched cohort of White/Other (W/O) men. MATERIALS AND METHODS A review of 1,267 men who had an mpMRI with suspicious prostate lesions and who underwent magnetic resonance transrectal ultrasound fusion-guided biopsy (FBx) with concurrent SBx in the same biopsy session was performed. All AA men were matched to a control group of W/O using a 1:1 propensity score-matching algorithm with age, prostate-specific antigen, and prostate volume as matching variables. Logistic regression analysis was used to determine predictors of APLs in AA men. RESULTS Of the 195 AA men who underwent mpMRI, 93 (47.7%) men had a total of 109 APLs. Prior negative SBx was associated with the presence of APLs in AA men (Odds ratio = 1.81; 95% CI: 1.03-3.20; P = 0.04). On multivariate logistic regression analysis, smaller prostate (P = 0.001) and rising prostate-specific antigen (P = 0.007) were independent predictors of cancer-positive APLs in AA men. Comparative analysis of AA (93/195, 47.7%) vs. W/O (100/194, 52%) showed no difference in the rates of APLs (P = 0.44) or in cancer detection rate within those lesions or the distribution of GS within those cancers (P = 0.63) despite an overall higher cancer detection rate in AA men (AA: 124/195 [63.6%] vs. W/O: 97/194 [50.0%], P = 0.007). In cases where APLs were positive for PCa on FBx, the GS of APL was equal to the highest GS of the entire gland in 82.9% (29/35) and 90.9% (30/33) of the time in AA and W/O men, respectively. CONCLUSION Cancer-positive APLs represented the highest risk GS in most cases. AA men with prior negative SBx are twice as likely to harbor a concerning APL. In our cohort, AA and W/O men had comparable rates of APLs on mpMRI. Thus, differences in APLs do not explain the higher risk of AA men for deahth due to PCa. However, targeting of APLs via FBx can clinically improve PCa risk stratification and guide appropriate treatment options.

Reproducibility of Multiparametric Magnetic Resonance Imaging and Fusion Guided Prostate Biopsy: Multi-Institutional External Validation by a Propensity Score Matched Cohort

PURPOSE As the adoption of magnetic resonance imaging/ultrasound fusion guided biopsy expands, the reproducibility of outcomes at expert centers becomes essential. We sought to validate the comprehensive NCI (National Cancer Institute) experience with multiparametric magnetic resonance imaging and fusion guided biopsy in an external, independent, matched cohort of patients. MATERIALS AND METHODS We compared 620 patients enrolled in a prospective trial comparing systematic biopsy to fusion guided biopsy at NCI to 310 who underwent a similar procedure at Long Island Jewish Medical Center. The propensity score, defined as the probability of being treated outside NCI, was calculated using the estimated logistic regression model. Patients from the hospital were matched 1:1 for age, prostate specific antigen, magnetic resonance imaging suspicion score and prior negative biopsies. Clinically significant disease was defined as Gleason 3 + 4 or greater. RESULTS Before matching we found differences between the cohorts in age, magnetic resonance imaging suspicion score (each p <0.001), the number of patients with prior negative biopsies (p = 0.01), and the overall cancer detection rate and the cancer detection rate by fusion guided biopsy (each p <0.001). No difference was found in the rates of upgrading by fusion guided biopsy (p = 0.28) or upgrading to clinically significant disease (p = 0.95). A statistically significant difference remained in the overall cancer detection rate and the rate by fusion guided biopsy after matching. On subgroup analysis we found a difference in the overall cancer detection rate and the rate by fusion guided biopsy (p <0.001 and 0.003) in patients with prior negative systematic biopsy but no difference in the 2 rates (p = 0.39 and 0.51, respectively) in biopsy naïve patients. CONCLUSIONS Improved detection of clinically significant cancer by magnetic resonance imaging and fusion guided biopsy is reproducible by an experienced multidisciplinary team consisting of dedicated radiologists and urologists.

Optimizing Patient Population for MP-MRI and Fusion Biopsy for Prostate Cancer Detection

The diagnosis and treatment of prostate cancer continue to evolve with advances in science and technology. The utilization of multiparametric MRI (mp-MRI) to identify lesions in the prostate has given clinicians the ability to visualize malignancy in the prostate with greater confidence. With this new ability came the advancement of fusion biopsy platforms, which allow for direct targeting of these lesions. As with any new technology in medicine, the proper use of these modalities and how they fit into current clinical practice need to be addressed. This review summarizes the current knowledge on how to best optimize which men undergo mp-MRI and fusion biopsies both in the screening and treatment settings.