Phase I clinical study of anti-apoptosis protein survivin-derived peptide vaccination for patients with advanced or recurrent urothelial cancer

Survivin, a member of the inhibitor of apoptosis protein family, is expressed in many malignant tumors including urothelial cancer but is hardly detectable in normal, differentiated adult tissues. Previously we reported CD8-positive cytotoxic T-lymphocytes (CTLs) were successfully induced by stimulation with survivin-2B80-88 peptide in vitro. We started a phase I clinical study of survivin-2B80-88 peptide vaccination for advanced urothelial cancer patients to assess the safety and efficacy of this vaccination. Nine patients were received vaccination and were evaluated for immunological evaluation, adverse events, and clinical responses. A total of 46 vaccinations were carried out. There was no severe adverse event. HLA-A24/survivin-2B80-88 peptide tetramer analysis revealed a significant increase in the peptide-specific CTL frequency after the vaccination in five patients. Slight reduction of the tumor volume was observed in one patient. Survivin-2B80-88 peptide-based vaccination is safe and should be further considered for potential immune and clinical efficacy in urothelial cancer patients.     

Initial experience with single-agent docetaxel as neoadjuvant therapy in men with locally advanced prostate cancer

Patients with locally advanced prostate cancer have worse outcomes after radical prostatectomy (RP) than patients with more favorable parameters. The findings of large, contemporary, RP series have led investigators at a number of centers to evaluate the potential role of neoadjuvant chemotherapy in patients with locally advanced disease. A currently ongoing study of 28 patients explores the antitumor response of a regimen of single-agent, docetaxel, 40 mg/m(2), administered intravenously on a weekly schedule for 6 weeks to patients with locally advanced prostate cancer before RP. Docetaxel has demonstrated significant antitumor activity in patients with advanced, androgen-independent disease. Study results showed that 75% of patients had reductions in prostate-specific antigen (PSA) levels ranging from 9%-79% at the completion of docetaxel therapy. In 25% of the patients, PSA levels increased by 2%-18% from baseline to completion of chemotherapy. In addition, noncastrate levels of testosterone were maintained in all patients. The docetaxel therapy has also been relatively well tolerated. Reporting of the primary endpoint of pathologic response is pending completion of accrual and surgery.     

Phase I study of a MUC1 vaccine composed of different doses of MUC1 peptide with SB-AS2 adjuvant in resected and locally advanced pancreatic cancer

MUC1 is a glycoprotein overexpressed in tumors as a hypoglycosylated form. A vaccine composed of a 100–amino acid peptide corresponding to five 20–amino acid long repeats, and SB-AS2 adjuvant, was tested in a phase I study for safety, toxicity, and ability to elicit or boost MUC1-specific immune responses. Patients with resected or locally advanced pancreatic cancer without prior chemotherapy or radiotherapy were eligible. Escalating doses of the peptide (100, 300, 1,000, and 3,000 g) were admixed with SB-AS2 and administered intramuscularly every 3 weeks for three doses, in cohorts of four patients. Sixteen patients were enrolled. Common adverse effects were grade 1 flu-like symptoms, tenderness, and erythema at the injection site. Delayed-type hypersensitivity (DTH) sites showed few or no T cells prevaccination (Pre V), but increased T-cell infiltration postvaccination (Post V). There was an increase in the percentage of CD8⁺ T cells in the peripheral blood Post V. An increase in total MUC1-specific antibody was seen in some patients, and several patients developed IgG antibody. Two of 15 resected pancreatic cancer patients are alive and disease free at follow-up of 32 and 61 months. MUC1 100mer peptide with SB-AS2 adjuvant is a safe vaccine that induces low but detectable mucin-specific humoral and T-cell responses in some patients. No difference was seen between different peptide doses. Further evaluation is warranted to examine the effect on disease-free survival and overall survival, especially in early disease and in the absence of immunosuppressive standard therapy.Work presented in part at the 36th Annual American Society of Clinical Oncology Meeting, New Orleans, LA, May 2000     

A genome-wide association study of prostate cancer in West African men

Age-adjusted mortality rates for prostate cancer are higher for African-American men compared with those of European ancestry. Recent data suggest that West African men also have elevated risk for prostate cancer relative to European men. Genetic susceptibility to prostate cancer could account for part of this difference. We conducted a genome-wide association study (GWAS) of prostate cancer in West African men in the Ghana Prostate Study. Association testing was performed using multivariable logistic regression adjusted for age and genetic ancestry for 474 prostate cancer cases and 458 population-based controls on the Illumina HumanOmni-5 Quad BeadChip. The most promising association was at 10p14 within an intron of a long non-coding RNA (lncRNA RP11-543F8.2) 360 kb centromeric of GATA3 (p = 1.29E?7). In sub-analyses, SNPs at 5q31.3 were associated with high Gleason score (≥7) cancers, the strongest of which was a missense SNP in PCDHA1 (rs34575154, p = 3.66E?8), and SNPs at Xq28 (rs985081, p = 8.66E?9) and 6q21 (rs2185710, p = 5.95E?8) were associated with low Gleason score (<7) cancers. We sought to validate our findings in silico in the African Ancestry Prostate Cancer GWAS Consortium, but only one SNP, at 10p14, replicated at p < 0.05. Of the 90 prostate cancer loci reported from studies of men of European, Asian or African-American ancestry, we were able to test 81 in the Ghana Prostate Study, and 10 of these replicated at p < 0.05. Further genetic studies of prostate cancer in West African men are needed to confirm our promising susceptibility loci.     

Phase I trial of tremelimumab in combination with short-term androgen deprivation in patients with PSA-recurrent prostate cancer

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.     

Results from a prostate cancer admixture mapping study in African-American men

There are considerable racial disparities in prostate cancer risk, with a 60% higher incidence rate among African-American (AA) men compared with European-American (EA) men, and a 2.4-fold higher mortality rate in AA men than in EA men. Recently, studies have implicated several African-ancestry associated prostate cancer susceptibility loci on chromosome 8q24. In the current study, we performed admixture mapping in AA men from two independent case–control studies of prostate cancer to confirm the 8q24 ancestry association and also identify other genomic regions that may harbor prostate cancer susceptibility genes. A total of 482 cases and 261 controls were genotyped for 1,509 ancestry informative markers across the genome. The mean estimated individual admixture proportions were 20% European and 80% African. The most significant observed increase in European ancestry occurred at rs2141360 on chromosome 7q31 in both the case-only (P = 0.0000035) and case–control analyses. The most significant observed increase in African ancestry across the genome occurred at a locus on chromosome 5q35 identified by SNPs rs7729084 (case-only analysis P = 0.002), and rs12474977 (case–control analysis P = 0.004), which are separated by 646 kb and were adjacent to one another on the panel. On chromosome 8, rs4367565 was associated with the greatest excess African ancestry in both the case-only and case–control analyses (case-only and case–control P = 0.02), confirming previously reported African-ancestry associations with chromosome 8q24. In conclusion, we confirmed ancestry associations on 8q24, and identified additional ancestry-associated regions potentially harboring prostate cancer susceptibility loci.     

Hospitalization for osteoarthritis and prostate cancer specific mortality among Swedish men with prostate cancer

Purpose: To examine the potential role of nonsteroidal anti-inflammatory drugs (NSAIDs) use on prostate cancer (PCa) specific mortality. Methods: We studied the association between hospitalization for osteoarthritis prior to PCa diagnosis, as a surrogate for heavy use of NSAIDs, and PCa specific mortality in a large population of PCa patients in Sweden in 1980–2004. Results: Hospitalization for osteoarthritis before PCa diagnosis was associated to a lower PCa specific mortality (hazard ratio [HR], 0.92; 95% confidence interval [CI], 0.88–0.96), but not to the risk of death from other causes (HR, 1.03; 95% CI, 0.99–1.08). The association was stronger among younger patients and patients diagnosed in earlier calendar years. Conclusions: Our data demonstrate a modestly decreased PCa specific mortality among PCa patients with hospitalization for osteoarthritis prior to PCa diagnosis, compared to those without such experience. This finding lends support to the hypothesis that NSAIDs use may influence PCa progression.     

Adiponectin as a potential marker of prostate cancer progression: studies in organ-confined and locally advanced prostate cancer

Serum levels of adiponectin were measured in patients with benign prostatic hyperplasia and prostate cancer of pT2 and pT3 stage. Adiponectin ELISA assay, immunohistochemistry, and selected metabolic and biochemical parameters measurement was performed in 25 patients with benign prostatic hyperplasia and 43 with prostate cancer (17 patients with organ-confined and 26 patients with locally advanced disease). Serum adiponectin levels did not differ between prostate benign hyperplasia and cancer clinical stage T2, but was significantly higher in pT3 relative to pT2 group (14.51+/-4.92 vs. 21.41+/-8.12, P = 0.003). Tissue immunohistochemistry showed enhanced staining in neoplastic prostate glands and intraepithelial neoplasia relative to benign prostatic hyperplasia without distinction between disease grade and stage. Serum adiponectin levels are higher in locally advanced relative to organ-confined prostate cancer and may thus serve as an auxiliary marker providing further improvement for discrimination between pT2 and pT3 stages.     

Mortality and incidence of new primary cancers in men with prostate cancer: A Danish population-based cohort study

Background: Prostate cancer (PC) survivors may have an increased risk of new primary cancers (NPCs) due to shared risk factors or PC-directed treatments. Methods: Using Danish registries, we conducted a cohort study of men with (n = 30,220) and without PC (n = 151,100) (comparators), matched 1:5 on age and PC diagnosis/index date. We computed incidence rates of NPCs per 10,000 person years (PY) and associated 95% confidence intervals (CI), and used Cox proportional hazards regression to compute hazard ratios (HRs) and 95%CI, adjusting for comorbidities. In order to obviate any impact of shorter survival among prostate cancer patients, we censored comparator patients when the matched prostate cancer patient died or was censored. Results: Follow-up spanned 113,487 PY and 462,982 PY in the PC and comparison cohorts, respectively. 65% of the cohorts were aged >70 years at diagnosis. Among PC patients, 51% had distant/unspecified stage, and 63% had surgery as primary treatment. The PC cohort had lower incidence of NPCs than their comparators. The adjusted HR of NPC among men with PC versus the comparators was 0.84 (95%CI = 0.80, 0.88). Lowest HRs were among older men, those with distant stage, and were particularly evident for cancers of the brain, liver, pancreas, respiratory, upper gastrointestinal, and urinary systems. Conclusions: We find no evidence of an increased risk of NPCs among men with PC. The deficit of NPCs among men with PC may be a true effect but is more likely due to lower levels of risk factors (e.g., smoking) in PC patients versus comparators, clinical consideration of cancers at new organs as metastases rather than new primaries, or under-recording/under-reporting of NPCs among PC patients.     

Metabolic effects of single-dose pamidronate administration in prostate cancer patients with bone metastases

BACKGROUND: Increased osteolysis usually accompanies sclerotic bone metastases from prostate cancer. This provides a rationale for the use of bisphosphonates to treat bone pain and prevent skeletal complications. METHODS: The fasting urinary levels of calcium, hydroxyproline (OHPRO), pyridinolines (PYD), deoxypyridinolines (DPYD), collagen cross-linked N-telopeptide (NTX) and the serum values of calcium, total alkaline phosphatase and relevant bone isoenzyme, bone gla protein (BGP), carboxy-telopeptide of type I collagen (ICTP) and parathyroid hormone (PTH) were determined at baseline and on the 15th, 30th, 60th and 90th days after single-dose (90 mg) pamidronate administration in 35 consecutive prostate cancer patients with bone metastases. These biochemical indices and serum interleukin 6 (IL-6) were also measured after four days in the last consecutive 17 cases. RESULTS: PYD, DPYD and NTX showed a significant decrease lasting four weeks (p<0.01, <0.01 and <0.001, respectively). OHPRO and ICTP did not change significantly. The NTX decline was greater than that of PYD and DPYD (maximum percent decrease: -71.3, -23.1 and -28.2, respectively). Bone formation markers and serum calcium did not change significantly. Serum PTH showed a rapid initial increase followed by a slow decrease (p<0.001). DPYD and NTX patterns did not correlate with changes in bone pain. As observed in the last 17 cases, the maximum osteolysis inhibition after pamidronate occurred on the fourth day after drug infusion. Serum IL-6 levels showed a short-lived decrease preceded by a transient rise on the fourth day. CONCLUSIONS: Pamidronate is able to induce a decrease in bone resorption without significantly influencing bone formation. The maximum decrease in bone resorption occurs very early. NTX is the most sensitive bone resorption marker in bisphosphonate therapy monitoring. Changes in IL-6 but not bone resorption markers may be useful in the prediction of symptomatic response.     

Phase I study of cancer therapy with recombinant interleukin-2 administered by intravenous bolus injection

Sixty-six patients with disseminated malignancy were treated with recombinant interleukin-2 (IL-2) on a three times a week (M, W, F) IV-bolus injection schedule. Doses ranged from 0.001 to 14.0 × 10⁶ units/M² body surface area. Consecutive groups of 3-5 patients were placed on each dose level and were maintained on that level except for dosage de-escalation for toxicity. Toxicity to all major organ systems were noted with major toxicity including fever and chills, anorexia, fatigue and malaise, arthralgias and arthritis as well as hepatic and renal toxicity. All toxicity reversed within one week of drug cessation. Renal toxicity manifested by azotemia, arthritis and fatigue were the common dose limiting toxicities and the maximally tolerated dose was 12 × 10⁶ units/M². Pharmacokinetic studies indicated a short half-life (T 1/2 = 7–23 minutes). At doses over 0.5 × 10⁶ units/M² increases in absolute lymphocytes and eosinophil counts were noted. All T lymphocyte subsets increased. Maximal increases were seen at 4–8 × 10⁶ units/M² with a lesser increase at 10–14 × 10⁶ units/M² dosage level. Circulating NK cells also increased while circulating LAK cells were detected during therapy. Partial responses were noted in 3 patients with melanoma. These lasted 4, 6 and 16 months and involved pulmonary, pulmonary plus mesenteric and retro-orbital plus hepatic metastases respectively in these patients.     

The importance of pelvic lymph node dissection in men with clinically localized prostate cancer

Despite advances in noninvasive staging, pelvic lymph node dissection (PLND) remains the most accurate means of detecting lymph node metastases in men with clinically localized prostate cancer. Nomograms exist that can identify patients at low risk for lymphatic metastases according to preoperative information. In general, it seems reasonable to omit PLND in men with a biopsy Gleason sum of 6 or less and a prostate-specific antigen level of 10 ng/mL or less. Ultimately, however, this decision should be made according to physician and patient preference, considering the low contemporary morbidity associated with PLND. When PLND is performed, studies suggest that an extended dissection maximizes the detection rate of nodal involvement. Retrospective data indicate that an extended dissection might play a therapeutic role in a subset of patients with a limited lymph node burden. However, this might be an artifact of stage migration, and prospective studies are needed to evaluate this further.