Search

PDF file - 26KB

Purpose: We have previously reported that a DNA vaccine encoding prostatic acid phosphatase (PAP) could elicit PAP-specific T cells in patients with early recurrent prostate cancer. In the current pilot trial, we sought to evaluate whether prolonged immunization with regular booster immunizations, or “personalized” schedules of immunization determined using real-time immune monitoring, could elicit persistent, antigen-specific T cells, and whether treatment was associated with changes in PSA doubling time (PSA DT).Experimental Design: Sixteen patients with castration-resistant, nonmetastatic prostate cancer received six immunizations at 2-week intervals and then either quarterly (arm 1) or as determined by multiparameter immune monitoring (arm 2).Results: Patients were on study a median of 16 months; four received 24 vaccinations. Only one event associated with treatment >grade 2 was observed. Six of 16 (38%) remained metastasis-free at 2 years. PAP-specific T cells were elicited in 12 of 16 (75%), predominantly of a Th1 phenotype, which persisted in frequency and phenotype for at least 1 year. IFNγ-secreting T-cell responses measured by ELISPOT were detectable in 5 of 13 individuals at 1 year, and this was not statistically different between study arms. The overall median fold change in PSA DT from pretreatment to posttreatment was 1.6 (range, 0.6–7.0; P = 0.036).Conclusions: Repetitive immunization with a plasmid DNA vaccine was safe and elicited Th1-biased antigen-specific T cells that persisted over time. Modifications in the immunization schedule based on real-time immune monitoring did not increase the frequency of patients developing effector and memory T-cell responses with this DNA vaccine. Clin Cancer Res; 20(14); 3692–704. ©2014 AACR.

Background Prostatic acid phosphatase (PAP) is a prostate tumor antigen, and the target of the only FDA-approved anti-tumor vaccine, sipuleucel-T. We have previously reported in two clinical trials that a DNA vaccine encoding PAP (pTVG-HP) could elicit PAP-specific, Th1-biased T cells in patients with PSA-recurrent prostate cancer. In the current pilot trial we sought to evaluate whether this vaccine could augment PAP-specific immunity when used as a booster to immunization with sipuleucel-T in patients with metastatic, castration-resistant prostate cancer (mCRPC). Methods Eigthteen patients with mCRPC were randomized to receive sipuleucel-T alone or followed by intradermal immunization with pTVG-HP DNA vaccine. Patients were followed for time to progression, and immune monitoring was conducted at defined intervals. Results Overall, patients were followed for a median of 24 months. 11/18 patients completed treatments as per protocol. No treatment-associated events > grade 2 were observed. Th1-biased PAP-specific T-cell responses were detected in 11/18 individuals, and were not statistically different between study arms. Higher titer antibody responses to PAP were detectable in patients who received pTVG-HP booster immunizations. Median time to progression was less than 6 months and not statistically different between study arms. The median overall survival for all patients was 28 months. Conclusions These findings suggest that prime-boost vaccination can augment and diversify the type of immunity elicited with anti-tumor vaccination in terms of T-cell and humoral immunity. Future studies will explore DNA as priming immunization rather than a booster immunization. Trial registration NCT01706458.

Objective To assess the effects of timing and schedule of zoledronic acid (ZA) administration on bone mineral density (BMD) in patients beginning androgen deprivation therapy (ADT) for the treatment of recurrent prostate cancer. Patients and Methods In this randomized, 3-arm trial, we evaluated changes in BMD after 3 different ZA administration schedules in men with recurrent prostate cancer who were beginning ADT. Forty-four patients were enrolled and randomized to receive a single dose of ZA given 1 week before beginning ADT (arm 1), a single dose of ZA given 6 months after beginning ADT (arm 2), or monthly administration of ZA starting 6 months after beginning ADT, for a total of 6 doses (arm 3). Results Patients who received ZA before ADT had a significant improvement in BMD at the total proximal femur and trochanter after 6 months compared with the other groups. In addition, only patients in the arm that received multiple doses improved lumbar spine BMD while on ADT, with these findings persisting to 24 months. However, this group also experienced more grade 1 adverse events. Conclusions Analysis of these data suggests that ZA administration before initiation of ADT was superior to treatment 6 months after starting ADT in maintaining BMD. In addition, monthly ZA administration can increase BMD above baseline but is associated with more adverse events. Further study is needed to examine whether the timing and frequency of ZA therapy in patients on ADT can reduce fracture risk.

O1 IL-15 primes an mTOR-regulated gene-expression program to prolong anti-tumor capacity of human natural killer cells #### Andreas Lundqvist1, Vincent van Hoef1, Xiaonan Zhang1, Erik Wennerberg2, Julie Lorent1, Kristina Witt1, Laia Masvidal Sanz1, Shuo Liang1, Shannon Murray3, Ola Larsson1

CTLA-4 blockade has demonstrated antitumor efficacy in human clinical trials. The antitumor mechanism is presumably mediated in part by the expansion of tumor-specific T cells. Androgen deprivation, the cornerstone of treatment for patients with metastatic prostate cancer, has been shown to elicit prostate tissue apoptosis and lymphocytic inflammation. We hypothesized that treatment with androgen deprivation, followed by an anti-CTLA-4 antibody, could augment a tumor-specific immune response elicited by androgen deprivation. We report here the results of a phase I trial evaluating a humanized monoclonal antibody targeting CTLA-4, CP-675,206 (tremelimumab), in combination with androgen deprivation using an antiandrogen. Eligible patients were those with PSA-recurrent prostate cancer after primary surgery and/or radiation therapy, not previously treated with androgen deprivation, and without radiographic evidence of metastatic disease. Subjects were treated in two cycles, 3 months apart, in which they received bicalutamide 150 mg daily days 1–28 and tremelimumab on day 29. The primary endpoint of the trial was safety. Secondary endpoints included measures of PSA kinetics and identification of a maximum tolerated dose. Eleven patients were enrolled and completed at least 1 year of follow-up. Dose-limiting toxicities included grade 3 diarrhea and skin rash. No favorable changes in PSA doubling time were observed in a period shortly after completing treatment; however, three patients experienced a prolongation in PSA doubling time detectable several months after completing treatment. The identification of delayed, prolonged favorable changes in serum PSA suggests that future studies could explore this combination in studies evaluating time to disease progression.

Purpose: Docetaxel is standard of care for androgen-independent prostate cancer (AIPC). Doxercalciferol (1α-hydroxyvitamin D2) had modest activity in phase I/II trials. Preclinical data support combining vitamin D analogues with docetaxel to treat AIPC. Experimental Design: Chemotherapy-naive men with metastatic AIPC were randomized 1:1 to receive, on a 4-week cycle, docetaxel (35 mg/m2 i.v., days 1, 8, and 15) with or without doxercalciferol (10 μg orally, days 1-28). The primary end point was prostate-specific antigen (PSA) response. Secondary end points were progression-free survival, overall survival, objective response, and toxicity. Survival was analyzed as intent to treat. Results: Seventy patients were randomized. Median follow-up was 17.6 months (range, 3.3-45.2). PSA response rate was 46.7% [95% confidence interval (95% CI), 30-64] in the doxercalciferol arm and 39.4% (95% CI, 25-56) with placebo (P = 0.560). Median progression-free survival in the doxercalciferol arm was 6.17 months (95% CI, 4.20-10.7) versus 6.20 months (95% CI, 4.83-9.07) with placebo (P = 0.764). Median overall survival in the doxercalciferol arm was 17.8 months (95% CI, 14.9-23.6) versus 16.4 months (95% CI, 11.9-23.8) with placebo (P = 0.383). Twenty-four patients in the doxercalciferol arm and 23 in the placebo arm were evaluable for objective response. No complete responses were observed. Partial objective response rate was 12.5% with doxercalciferol versus 8.7% with placebo (P = 0.672). Rate of grade ≥3 toxicity was 46% with doxercalciferol versus 42% with placebo (P = 0.785). Conclusions: Daily doxercalciferol with weekly docetaxel did not enhance PSA response rate or survival. Toxicity was similar between arms. Despite the disappointing results of this study, other vitamin D analogues remain under active investigation.

Testosterone administration can lead to increased antipyrine clearance in humans. Medical or surgical castration is a standard treatment of progressive prostate carcinoma, but the effect of the subsequent fall of testosterone concentrations upon drug metabolism has not been reported. Eleven men with a biopsy-proven diagnosis of progressive prostate cancer were enrolled after providing informed consent. CYP3A4 activity was determined using the erythromycin breath test (EBT) in each patient prior to their beginning with an LHRH-agonist (leuprolide or goserelin). No patients had elected to undergo orchiectomy during the period of subject accrual. Each subject underwent a second EBT 2 months after beginning LHRH suppression. Blood samples were collected at these time points to determine changes in testosterone and leutinizing hormone. All subjects had a predictable drop in serum testosterone concentrations over the 8-week course of the study, but concentrations in three did not fall below castrate levels (

Objective: To assess the efficacy and toxicity of the combination of interferon-alpha and doxycycline in patients with metastatic renal cell carcinoma and to assess the effect of this treatment on serum vascular endothelial growth factor (VEGF) levels. Patients and Methods: Seventeen patients with Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and life expectancy greater than 4 months with radiologically evident advanced renal cell carcinoma were enrolled. Eight patients had prior nephrectomy and 10 patients were treated within 4 months of their diagnosis. Treatment consisted of interferon-alpha up to 9 million units subcutaneously three times per week and doxycycline 300 mg orally twice per day for weeks one and three of each four-week cycle. Toxicity was evaluated on a biweekly basis and response on a bimonthly basis. VEGF plasma levels were assessed monthly as a measure of potential antiangiogenic effect. Results: No objective responses were seen. The mean duration of study was 2.6 cycles (range: 0.8–6.0 cycles). Three patients (17%) tolerated therapy and displayed stable disease for greater than four months. Five patients withdrew from study before the first response evaluation. Ten patients experienced grade 2 gastrointestinal toxicity requiring dose reduction of doxycycline. Eight patients experienced grade 2 fatigue requiring dose reduction of interferon. VEGF plasma levels were initially suppressed in patients who demonstrated progressive disease but not in patients with stable disease. Conclusion: This regimen of doxycycline and interferon-alpha was not efficacious as treatment for renal cell carcinoma. Plasma VEGF levels were significantly decreased during the first two cycles of treatment, but this does not correlate with clinical outcome.

168 Background: We have previously investigated a DNA vaccine encoding prostatic acid phosphatase (PAP, pTVG-HP) in patients with PSA-recurrent prostate cancer, and have demonstrated that this can be safely administered over many months and can elicit PAP-specific T cells. A phase 2 trial is currently underway. In preclinical models, we have found that blockade of regulatory receptors, including PD-1, at the time of T cell activation with vaccination produced anti-tumor responses in vivo. Similarly, we have recently found that patients with prostate cancer previously immunized with a DNA vaccine develop PD-1-regulated T cells. These findings suggested that combined PD-1 blockade with vaccination should elicit superior anti-tumor responses in patients with prostate cancer. Methods: A clinical trial was designed to evaluate the immunological and clinical efficacy of pTVG-HP when delivered in combination or in sequence with pembrolizumab, in patients with mCRPC. Serial biopsies, blood draws, and exploratory FLT PET/CT imaging are being conducted for correlative analyses. Results: While trial accrual continues, 1 of 14 subjects has experienced a grade 3 adverse event. There have been no grade 4 events. Several patients treated with the combination have experienced serum PSA declines, and several have experienced decreases in tumor volume by radiographic imaging at 12 weeks, including one partial response. Expansion of PAP-specific Th1-biased T cells has been detected in peripheral blood samples. Exploratory FLT PET/CT imaging has demonstrated proliferative responses in metastatic lesions and in vaccine-draining lymph nodes. Evaluation of biopsy specimens for recruitment of antigen-specific T cells is currently underway. Conclusions: PD-1 pathway inhibitors have demonstrated little clinical activity to date when used as single agents for treating prostate cancer. Our findings suggest that combining this blockade with tumor-targeted T-cell activation by a DNA vaccine is safe and can augment tumor-specific T cells, detectable within the peripheral blood and by imaging, and result in objective anti-tumor changes. Clinical trial information: NCT02499835.

Assessment of skeletal metastases' response to therapy is a highly relevant but unresolved clinical problem. The main goal of this work was to compare pharmacodynamic responses to therapy assessed with positron emission tomography-computed tomography (PET/CT) using fluorine-18 sodium fluoride (NaF) and fluorine-18 fluorodeoxyglucose (FDG) as the tracers.Patients with prostate cancer with known osseous metastases were treated with zibotentan (ZD4054) and imaged with combined dynamic NaF/FDG PET/CT before therapy (baseline), after 4 weeks of therapy (week 4), and after 2 weeks of treatment break (week 6). Kinetic analysis allowed comparison of the voxel-based tracer uptake rate parameter Ki, the vasculature parameters K1 (measuring perfusion/permeability) and Vb (measuring vasculature fraction in the tissue), and the standardized uptake values (SUVs).Correlations were high for the NaF and FDG peak uptake parameters (Ki and SUV correlations ranged from 0.57 to 0.88) and for vasculature parameters (K1 and Vb correlations ranged from 0.61 to 0.81). Correlation was low between the NaF and FDG week 4 Ki responses (ρ = 0.35; P = .084) but was higher for NaF and FDG week 6 Ki responses (ρ = 0.72; P.0001). Correlations for vasculature responses were always low (ρ0.35). NaF and FDG uptakes in the osseous metastases were spatially dislocated, with overlap in the range from 0% to 80%.This study found that late NaF and FDG uptake responses are consistently correlated but that earlier uptake responses and all vasculature responses can be unrelated. This study also confirmed that FDG and NaF uptakes are spatially dislocated. Although treatment responses assessed with NaF and FDG may be correlated, using both tracers provides additional information.

Purpose: We have previously reported that a DNA vaccine encoding prostatic acid phosphatase (PAP) could elicit PAP-specific T cells in patients with early recurrent prostate cancer. In the current pilot trial, we sought to evaluate whether prolonged immunization with regular booster immunizations, or “personalized” schedules of immunization determined using real-time immune monitoring, could elicit persistent, antigen-specific T cells, and whether treatment was associated with changes in PSA doubling time (PSA DT). Experimental Design: Sixteen patients with castration-resistant, nonmetastatic prostate cancer received six immunizations at 2-week intervals and then either quarterly (arm 1) or as determined by multiparameter immune monitoring (arm 2). Results: Patients were on study a median of 16 months; four received 24 vaccinations. Only one event associated with treatment >grade 2 was observed. Six of 16 (38%) remained metastasis-free at 2 years. PAP-specific T cells were elicited in 12 of 16 (75%), predominantly of a Th1 phenotype, which persisted in frequency and phenotype for at least 1 year. IFNγ-secreting T-cell responses measured by ELISPOT were detectable in 5 of 13 individuals at 1 year, and this was not statistically different between study arms. The overall median fold change in PSA DT from pretreatment to posttreatment was 1.6 (range, 0.6–7.0; P = 0.036). Conclusions: Repetitive immunization with a plasmid DNA vaccine was safe and elicited Th1-biased antigen-specific T cells that persisted over time. Modifications in the immunization schedule based on real-time immune monitoring did not increase the frequency of patients developing effector and memory T-cell responses with this DNA vaccine. Clin Cancer Res; 20(14); 3692–704. ©2014 AACR.

TPS11616Background: Quantitative Total Bone Imaging (QTBI) is novel methodology utilizing 18F-Sodium Fluoride (NaF) PET/CT that allows automatic identification, segmentation, and subsequent co-regi...

277 Background: 18F-Sodium Fluoride (NaF) PET/CT has been shown to be superior to 99mTc-MDP SPECT in detection of bone metastases and shows great promise to reliably measure functional changes in bone. This study assesses the relationship of Progression Free Survival (PFS) with NaF PET/CT measures in patients with metastatic Castration-Resistant Prostate Cancer (CRPC). Methods: 55 CRPC patients had NaF PET/CT scans performed at baseline, which was repeated at week 9 if receiving taxane-based therapy (N = 16) or week 12 if receiving androgen-signaling pathway (AR) inhibitors (N = 39). Bone lesions were identified using a novel technique allowing for extraction and tracking of PET metrics from individual lesions at every timepoint. Cox proportional hazard regression analyses were conducted to evaluate associations between imaging metrics and PFS. Results: Median PFS was 8.3 months (range 1.0-30.3+). The strongest predictor of PFS in univariate analysis was total functional burden (SUVtotal) (P < 0.0001) during treatment for all patients. Predictors of PFS differed between both treatment cohorts of patients (Table 1), including number of lesions, fraction of skeletal involvement, and average lesion activity (SUVmean). Maximum PSA benefit (percent decrease) during the first 12 weeks of therapy was highly predictive of PFS in the AR-directed cohort of patients (HR = 1.012 , P = 0.0005), as was change in the number of lesions (HR = 1.01, P = 0.03). Conclusions: There is indication thattotal functional burden of disease during treatment with taxane or AR-directed therapy is a strong predictor of PFS. In addition, change in number of lesions was predictive of treatment efficacy. This supports ongoing development of NaF PET/CT based imaging biomarkers in mCRPC. Clinical trial information: NCT01516866. [Table: see text]

Prior to the advent of VEGF-targeted therapies, renal cell carcinoma (RCC) was among the few solid tumors shown to respond to cytokine-based therapies such as interleukin-2 (IL-2) and interferon alpha. Previous work has shown that aminobisphosphonates, including zoledronic acid (ZA), are capable of activating human Vγ9 Vδ2 T cells in vitro, and these cells can be further expanded with IL-2. Moreover, these Vγ9 Vδ2 T cells have cytolytic activity in vitro to multiple human tumor cell lines. In the current report, we have conducted a pilot trial in patients with metastatic RCC, evaluating different doses of ZA in combination with low-dose IL-2 to determine whether combining these agents can promote in vivo proliferation of Vγ9 Vδ2 T cells and elicit an antitumor response. In 12 patients evaluated, no objective clinical responses were observed by RECIST criteria; however, two patients experienced prolonged stable disease. A modest increase in Vγ9 Vδ2 T-cell frequency could be detected by Day 8 of therapy in four of the nine patients who received at least one cycle of therapy, but not to the magnitude anticipated from preclinical models. Repeated administration of IL-2 and ZA resulted in both a diminished in vivo percentage of Vγ9 Vδ2 T cells as well as impaired expansion in vitro after the first cycle of therapy. These results suggest that repeated administration of IL-2 and ZA, at the doses and schedules used in this trial, may actually inhibit the proliferative capacity of Vγ9 Vδ2 T cell in patients with metastatic RCC.

PurposeProstatic 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 MethodsTwenty-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.ResultsNo 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).ConclusionThe 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.

180 Background: CRPC is frequently associated with the development of osseous metastases. While imaging allows treatment response determination in soft tissue metastasis, its application in bony metastasis is limited to staging. Methods: QTBI is an innovative tool that allows extraction of comprehensive functional information in all osseous metastases, as well as treatment response in individual lesions, using 18F-Sodium Fluoride (NaF) PET/CT. We completed a multi-center trial assessing the performance characteristics (test-retest) and responsiveness of QTBI as an imaging biomarker of treatment response in men with metastatic CRPC to bone treated with either a taxane-based or androgen-signaling pathway directed therapy. Results: 54 patients have been enrolled from three academic centers. Potential imaging biomarkers of treatment response have been identified. Here we present initial data regarding the inter-lesional response heterogeneity and implications. Conclusions: Changes in SUVmax, SUVtotal, and SUVmean reflect quantifiable PET measurements that are complementary, but may have different meaning depending on the treatment administered (cytotoxic vs cytostatic). Relying on one measure alone can be misleading, particularly when assessing treatment response. For example, some lesions may experience a decrease in SUVmax, while simultaneously having an increase in SUVtotal. This implies that the therapy decreased the max functional activity of the lesion, but the overall functional burden of the lesion increased analogous to “slowing down” progression. This is in contrast with lesions that decrease (increase) in both SUVmax and SUVtotal, which would imply decreased activity and burden (increased activity and burden). We will show data representative of the above along with clinical outcomes in support of this conclusion, as well as the implications of treatment response heterogeneity in the clinical outcome. In summary, QTBI provides a unique tool in understanding the dynamics of treatment response, allowing newer trial designs that can explore combination, sequence, and the issue of continuing treatment beyond progression with existing therapies. Clinical trial information: NCT01516866.

Purpose: To determine whether the preclinical antitumor and antiangiogenic activity of 2-methoxyestradiol can be translated to the clinic. Experimental Design: Men with hormone-refractory prostate cancer were enrolled into this phase II randomized, double-blind trial of two doses of oral 2-methoxyestradiol capsules (400 and 1,200 mg/d) given in 4-week cycles. Pharmacokinetic sampling was done on day 1 of cycles 1 and 2 and trough samples were obtained weekly. Results: Thirty-three men were accrued between February and September 2001. The notable toxicity related to therapy was one grade 2 and two grade 3 episodes of liver transaminase elevation, which resolved with continued treatment in two patients. There were two cases of deep venous thromboses. The drug had nonlinear pharmacokinetic, rapid conversion to 2-methoxyestrone and ∼85% conjugation. Trough plasma levels of unconjugated 2-methoxyestradiol and 2-methoxyestrone were ∼4 and 40 ng/mL, respectively. Prostate-specific antigen declines between 21% and 40% were seen in seven patients in the 1,200 mg group and in one patient in the 400 mg group. The higher-dose group showed significantly decreased prostate-specific antigen velocity (P = 0.037) and compared with the 400 mg dose had a longer median time to prostate-specific antigen progression (109 versus 67 days; P = 0.094) and time on study (126 versus 61 days; P = 0.024). There was a 2.5- and 4-fold increase in sex hormone-binding globulin for the 400 and 1,200 mg dose levels, respectively, at days 28 and 56. Conclusion: 2-Methoxyestradiol is well tolerated and, despite suboptimal plasma levels and limited oral bioavailability with this capsule formulation, still showed some anticancer activity at 1,200 mg/d.

Objective. We conducted a phase II multicenter trial of perillyl alcohol in patients with advanced hormone refractory prostate cancer (HRPC). The primary endpoint was to evaluate the 6-month progression-free survival given the potential cytostatic nature of the drug. Secondary objectives included assessing acute and chronic toxicities, as well as measuring objective response rates. Methods. Patients with metastatic androgen-independent prostate cancer that failed at least one prior chemotherapeutic or experimental regimen were eligible. Perillyl alcohol was administered orally at 1200 mg/m2/dose four times daily and continued until disease progression or development of unacceptable toxicity. Results. Fifteen patients were eligible. Six patients received less than one cycle (4 weeks) of drug, four of which stopped because of drug intolerance. Only six patients received more than two cycles of therapy and were considered evaluable for response. Main toxicity included grade 1–2 gastrointestinal intolerance (nausea/vomiting in 60% of the patients) and fatigue (47%). One patient developed a grade 4 hypokalemia that was felt likely attributable to the drug. No objective responses were seen. All patients either progressed or withdrew from the study secondary to drug intolerance before the 6-month time period. Conclusion. Perillyl alcohol administered at this dose and formulation did not have any objective clinical activity in this patient population.

In this single institution Phase II trial, we evaluated the efficacy of the vitamin D analogue, 1alpha-OH-D(2), in patients with advanced hormone-refractory prostate cancer.The patients initially received 1alpha-OH-D(2) at 12.5 micro g p.o. every day, which was dose adjusted for hypercalcemia. Given the cytostatic nature of the drug, the primary study end point was progression-free survival for a minimum of 6 months. The secondary end point was further characterization of drug toxicity.A total of 26 patients was enrolled. Using the intent-to-treat population, stable disease was seen for an average of 19.2 weeks (median 12 weeks, range 3-108 weeks). Twenty patients were evaluable for response. The one patient that achieved disease stabilization for2 years elected to come off-study because of patient preference. His last disease evaluation showed no evidence of progression. No objective responses were seen. Previous and ongoing clinical observations strongly imply that PSA could be a misleading surrogate marker for clinical effect with this type of drug. Therefore, prostate-specific antigen was not used as a marker for disease response. Toxicity was as expected with mild hypercalcemia and associated symptoms like constipation and prerenal azotemia seen in some patients. Six (30%) evaluable patients experienced stable disease for6 months, suggesting possible cytostatic activity.The results of this and other trials suggest further clinical investigation in this disease with vitamin D analogues alone or in combination with other agents, such as chemotherapy, should be pursued.

In a prior study, high resolution ultrasound (US) was shown to be accurate for evaluating rib metastasis detected on bone scan. However, that study did not address the specific US appearance typical of osteoblastic rib metastasis. Our objective was to determine the specific US imaging appearance of osteoblastic prostate carcinoma rib metastasis using osteolytic renal cell carcinoma rib metastasis as a comparison group.The Institutional Review Board approval and informed consent were obtained for this prospective feasibility study. We performed high resolution US of 16 rib metastases in 4 patients with prostate carcinoma metastases and compared them to 8 rib metastases in 3 male patients with renal cell carcinoma. All patients had rib metastases proven by radiographs and computed tomography (CT). High resolution US scanning was performed by a musculoskeletal radiologist using a 12-5 MHz linear-array transducer. Transverse and longitudinal scans were obtained of each rib metastasis.All 16 prostate carcinoma metastases demonstrated mild cortical irregularity of the superficial surface of the rib without associated soft tissue mass, cortical disruption, or bone destruction. 7 of 8 (88%) renal cell carcinoma rib metastases demonstrated cortical disruption or extensive bone destruction without soft tissue mass. One of 8 (12%) renal cell carcinoma rib metastases demonstrated only minimal superficial cortical irregularity at the site of a healed metastasis.Osteoblastic prostate carcinoma rib metastases have a distinctive appearance on US. Our success in visualizing these lesions suggests that US may be a useful tool to characterize isolated rib abnormalities seen on a bone scan in high-risk prostate cancer patients who are being evaluated for curative surgery or radiation treatment.

4643 Background: Androgen deprivation therapy (ADT), the primary treatment for patients (pts) with metastatic prostate cancer (PC), causes bone loss. Zoledronic acid (ZA) is FDA approved for the tr...

174 Background: Antibodies targeting CTLA-4 have demonstrated anti-tumor efficacy in human clinical trials. The mechanism of this effect is presumably in part mediated by the expansion of tumor-specific T cells. Androgen deprivation (AD), the cornerstone of treatment for patients with metastatic prostate cancer, has been demonstrated to cause prostate tissue apoptosis and lymphocytic inflammation. We hypothesized that treatment with AD, followed by an anti-CTLA-4 antibody, could have benefit by augmenting a tumor-specific immune response elicited with AD. We report the initial results from the dose-escalation portion of a phase I trial evaluating tremelimumab in combination with high-dose bicalutamide. Methods: Eligible patients were those with clinical stage D0 prostate cancer (rising serum PSA but no evidence of metastatic disease). Subjects were treated in two courses, 3 months apart, in which they received bicalutamide 150 mg daily for 28 days and tremelimumab on day 29. Patients were treated in cohorts of six, defined by tremelimumab dose (3 mg/kg, 6 mg/kg, 10 mg/kg, 15 mg/kg). The primary endpoint of the trial was safety. Secondary endpoints included measures of PSA kinetics and identification of a maximum tolerated dose (MTD). Results: Eleven patients were enrolled and completed the dose-escalation portion of the trial and at least one year of follow up. Dose-limiting toxicities (DLTs) were observed in 2/5 subjects treated at 6 mg/kg, and included grade 3 diarrhea and a grade 3 skin rash. One of six subjects treated at 3 mg/kg tremelimumab required hospitalization for colitis. No other grade 3 or grade 4 events were observed. Common grade 1/2 events included fatigue, hot flashes, diarrhea, abdominal discomfort, rash, pruritis, and gynecomastia. Two patients experienced a prolongation in PSA doubling time detectable months after completing treatment. Conclusions: Tremelimumab, administered at 3 mg/kg every 3 months in combination with AD, was found to be the MTD and with reasonable safety in this population. The identification of patients with prolonged stable disease following treatment suggests that future studies could explore repetitive administration of this combination. [Table: see text]

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.

14607 Background: Approximately 3–6% of human peripheral blood lymphocytes express the γδ T cell receptor (TCR). The majority of these cells express the Vδ2 TCR variable segment associated with the Vγ9 segment. Vγ9Vδ2 T cells can recognize phosphorylated nonpeptidic microbial metabolites and alkylamines. This recognition of phosphorylated molecules requires neither antigen uptake/processing, nor MHC class I/II expression, allowing for a rapid response to immune challenge. Aminobisphosphonates are a class of agents capable of activating human Vγ9Vδ2 T cells. Here we conduct a study using ZA with low-dose IL-2 in order to augment Vγ9Vδ2 T cells for therapeutic use in mRCC. Methods: Patients with immunotherapy naïve mRCC were treated with ZA (4 mg IV d1) with IL-2 (ranging from 1–7 MU/m2 SQ days 1–5, repeated weekly × 3, in 4 week cycles). Blood was collected at various timepoints between day 1 and 15 of the first cycle of therapy to assess the relative frequency, proliferative capacity, and cytolytic activity of each subjects’ Vg9Vd2 T cells. Clinical responses were assessed using RECIST criteria. Results: To date, 7 patients have received treatment on protocol. No objective clinical responses were observed by RECIST criteria but prolonged stable disease (with one minor response) was observed in 2 patients (on study for 280 and 224 days respectively) on this trial. A relative increase in Vγ9Vδ2 T cell frequency could be detected by day 8 of therapy including one patient with an increase in Vγ9/Vδ2 positive T cells from 9.6 to 19.4%. Results of the change in Vγ9Vδ2 T cell frequency, proliferative capacity, and cytolytic activity against RCC cell lines will be presented in detail. Conclusions: Modest amplification of Vγ9Vδ2 T cell frequency was seen; however, not to the degree appreciated in preclinical models. At present, we are planning a dose-titration of ZA with fixed dosed IL-2 in order to optimize this therapeutic strategy. The exploitation of Vγ9Vδ2 T cells as a therapy for mRCC is novel, and the current study suggests this approach deserves further evaluation. No significant financial relationships to disclose.

e16016 Background: Advanced prostate cancer is associated with the development of osseous metastases. There are no current tools that allow assessment of treatment response in bone. Methods: Quanti...