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Biomedical subjects

Philip M Arlen

Publications and source records attributed to Philip M Arlen.

29 records · Page 2Linked to original sources
PubMed2005

Therapeutic vaccines for prostate cancer: a review of clinical data.

Prostate cancer is the most common, non-cutaneous cancer and the second leading cause of cancer death among men in the US. A greater understanding of basic immunological principles has led to the development of a variety of new techniques, which in turn has led to advances in the field of prostate cancer vaccines. This review will discuss the rationale for the development of vaccines involving whole tumor cells and dendritic cells, as well as pox viral vectors, and will summarize selected clinical studies that have incorporated these strategies.

Cancer Vaccines↗
PubMed2004

Phase I study of sequential vaccinations with fowlpox-CEA(6D)-TRICOM alone and sequentially with vaccinia-CEA(6D)-TRICOM, with and without granulocyte-macrophage colony-stimulating factor, in patients with carcinoembryonic antigen-expressing carcinomas.

PURPOSE: Our previous clinical experience with vaccinia and replication-defective avipox recombinant carcinoembryonic antigen (CEA) vaccines has demonstrated safety and clinical activity with a correlation between CEA-specific immune response and survival. Preclinical evidence demonstrated that the addition of the transgenes for three T-cell costimulatory molecules (B7-1, ICAM-1, LFA-3, designated TRICOM) results in a significant improvement in antigen-specific T-cell responses and antitumor activity. We describe here the first trial in humans of the CEA-TRICOM vaccines (also including an enhancer agonist epitope within the CEA gene). PATIENTS AND METHODS: Fifty-eight patients with advanced CEA-expressing cancers were accrued to eight cohorts that involved vaccinations with the following: replication-defective fowlpox recombinant (rF)-CEA(6D)-TRICOM; primary vaccination with recombinant vaccinia (rV)-CEA(6D)-TRICOM plus rF-CEA(6D)-TRICOM booster vaccinations; and rV-CEA(6D)-TRICOM and then rF-CEA(6D)-TRICOM, plus granulocyte-macrophage colony-stimulating factor (GM-CSF) with vaccines, or with divided doses of vaccine with GM-CSF. Vaccines were administered every 28 days for six doses and then once every 3 months. Reverting to treatments every 28 days was allowed if patients progressed on the 3-month schedule. RESULTS: In this phase I study, no significant toxicity was observed. Twenty-three patients (40%) had stable disease for at least 4 months, with 14 of these patients having prolonged stable disease (> 6 months). Eleven patients had decreasing or stable serum CEA, and one patient had a pathologic complete response. Enhanced CEA-specific T-cell responses were observed in the majority of patients tested. CONCLUSION: We demonstrated that the CEA-TRICOM vaccines are safe and can generate significant CEA-specific immune responses, and they seem to have clinical benefit in some patients with advanced cancer.

Adult↗
PubMed2004

Randomized phase II trial of docetaxel plus thalidomide in androgen-independent prostate cancer.

PURPOSE: Both docetaxel and thalidomide have demonstrated activity in androgen-independent prostate cancer (AIPC). We compared the efficacy of docetaxel to docetaxel plus thalidomide in patients with AIPC. METHODS: Seventy-five patients with chemotherapy-naïve metastatic AIPC were randomly assigned to receive either docetaxel 30 mg/m(2) intravenously every week for 3 consecutive weeks, followed by a 1-week rest period (n = 25); or docetaxel at the same dose and schedule, plus thalidomide 200 mg orally each day (n = 50). Prostate-specific antigen (PSA) consensus criteria and radiographic scans were used to determine the proportion of patients with a PSA decline, and time to progression. RESULTS: After a median potential follow-up time of 26.4 months, the proportion of patients with a greater than 50% decline in PSA was higher in the docetaxel/thalidomide group (53% in the combined group, 37% in docetaxel-alone arm). The median progression-free survival in the docetaxel group was 3.7 months and 5.9 months in the combined group (P =.32). At 18 months, overall survival in the docetaxel group was 42.9% and 68.2% in the combined group. Toxicities in both groups were manageable after administration of prophylactic low-molecular-weight heparin in the combination group. CONCLUSION: In this randomized phase II trial, the addition of thalidomide to docetaxel resulted in an encouraging PSA decline rate and overall median survival rate in patients with metastatic AIPC. After the prophylactic low-molecular-weight heparin was instituted to prevent venous thromboses, the combination regimen was well tolerated. Larger randomized trials are warranted to assess the impact of this combination.

Administration, Oral↗
PubMed2003

A novel ELISPOT assay to enhance detection of antigen-specific T cells employing antigen-presenting cells expressing vector-driven human B7-1.

The ELISPOT assay is used to detect T-cell responses in patients enrolled in vaccine clinical trials; it is a relatively sensitive assay that can be performed without in vitro stimulation (IVS) of PBMC. However, this assay may be limited in some cases because of a weak signal 1 (as is the case for tumor-associated antigens [TAA]), or by a limited number of PBMC available from patients. The objective of this study is to enhance the sensitivity of the ELISPOT by increasing the level of signal 2, in this case, B7-1 expression on antigen-presenting cells (APC), allowing for a more sensitive detection of antigen-specific T-cell precursors. C1RA2 cells were used as APC and were uninfected, or infected with either recombinant avipox (fowlpox)-B7-1 (rF-B7-1) or control fowlpox wild-type (FP-WT) vector. The expressions of B7-1, MHC Class II, as well as HLA-A2 on the infected cells were analyzed by flow cytometry. A nearly threefold increase in B7-1 mean fluorescence intensity (MFI) occurred in the rF-B7-1-infected C1RA2 cells with no changes in MHC Class II or HLA-A2 expression. Various PBMC/APC ratios were used to further analyze the use of rF-B7-1-infected C1RA2 cells as APC in the ELISPOT assay. Fewer APC were required to activate PBMC when C1RA2 infected with rF-B7-1 were used as APC. Furthermore, using a PBMC/APC ratio of 1:1, similar detection was achieved using fewer PBMC. In addition, we demonstrated that the reactivity can be blocked by adding anti-B7-1 antibody. We performed the assay using APC on five normal healthy donors. All five donors showed substantial increases in PF to the Flu matrix peptide (Flu peptide) using the rF-B7-1-infected C1RA2 cells. Finally, we evaluated five cancer patients who received a carcinoembryonic antigen (CEA) vaccine-based therapy. Increases in CEA peptide precursors were noted in all five patients using the B7-1-infected APC. In conclusion, we have demonstrated the ability to enhance the sensitivity of the ELISPOT assay through infection of C1RA2 with rF-B7-1.

Antigen-Presenting Cells↗
PubMed2003

Strategies for the development of PSA-based vaccines for the treatment of advanced prostate cancer.

Prostate cancer is the second leading cause of cancer death in males in the USA. Vaccine strategies represent a novel therapeutic approach. One potential target for a prostate cancer vaccine is prostate-specific antigen (PSA), due to its restricted expression in prostate cancer and normal prostatic epithelial cells. A number of PSAspecific epitopes have been identified that can activate cytotoxic T-lymphocytes (CTLs) and in turn lead to the killing of tumor targets by the peptide-specific CTLs. Strategies have now been employed in clinical trials using RNA-pulsed dendritic cell vaccines, recombinant protein vaccines, and recombinant viral vector delivery of vaccines. Newer approaches incorporating costimulatory molecules that enhance Tcell activation are also being investigated.

Cancer Vaccines↗
PubMed2003

Docetaxel and thalidomide as a treatment option for androgen- independent, nonmetastatic prostate cancer.

Prostate cancer usually presents with early-stage disease, yet a significant proportion of patients present or will progress to androgen-independent, nonmetastatic prostate cancer (AIPC). Chemotherapy has demonstrated statistically significant improvements in palliation of AIPC. Docetaxel in particular has demonstrated high response rates as a single agent. Thalidomide is effective in treating many malignancies, including prostate cancer. Thalidomide may act synergistically with docetaxel through their antiangiogenic effects. We performed a phase II trial of docetaxel with or without thalidomide in patients with AIPC and demonstrated encouraging response rates with combination therapy. We advocate further investigation of this promising combination regimen.

Journal Article↗
PubMed2002

Phase I study of a vaccine using recombinant vaccinia virus expressing PSA (rV-PSA) in patients with metastatic androgen-independent prostate cancer.

BACKGROUND: A Phase I trial of recombinant vaccinia prostate specific antigen (rV-PSA) in patients with advanced metastatic prostate cancer was conducted. This report describes 42 patients who were treated with up to three monthly vaccinations. METHODS: All patients were entered on a dose-escalation phase I study of recombinant vaccinia containing the gene for PSA (rV-PSA). The primary objective of this study was to determine the safety of this vaccine in metastatic androgen-independent prostate cancer patients. A secondary objective was to assess evidence of anti-tumor activity by PSA measurements, radiologic findings, and immunologic methods. RESULTS: There was no significant treatment-related toxicity apart from erythema, tenderness, and vesicle formation that lasted several days at the site of injection in some patients. There were immunologic responses, in selected patients, as evidenced by an increase in the proportion of PSA-specific T cells after vaccination. Furthermore, we show that these patients' T cells can lyse PSA-expressing tumor cells in vitro. CONCLUSION: Given the low toxicity profile and the evidence of immunologic activity, we believe future study is warranted with PSA-based vaccines in prostate cancer. New PSA-based vaccines and vaccine strategies are currently being evaluated.

Adenocarcinoma↗
PubMed2002

National Cancer Institute intramural approach to advanced prostate cancer.

Adenocarcinoma of the prostate is the most common cancer diagnosed in men in the United States, with approximately 189,000 new cases estimated to be diagnosed in 2002. It is believed that men with this disease pass through a series of clinical states. In the intramural program of the National Cancer Institute, we have designed clinical trials that have addressed each disease state. In addition to clinical endpoints, each trial also encompasses molecular or immunologic endpoints in an attempt to determine if our therapy is acting on its presumed target. In patients with localized disease, we are evaluating cancer vaccines in combination with radiation therapy as well as comparing this vaccine against second-line hormonal therapy in patients with rising serum prostate-specific antigen (PSA) but no radiographically measurable disease. We are also evaluating the ability of the antiangiogenesis agent thalidomide to prolong the rest period in patients with a biochemical recurrence (stage D0) that are receiving intermittent hormonal therapy. In patients with metastatic prostate cancer, we are evaluating the addition of the bisphosphonate alendronate when added to ketoconazole for impact on matrix metalloproteinase (MMP)-2 and MMP-9 as well as traditional clinical endpoints. In addition, we have 3 ongoing trials involving the chemotherapeutic agent docetaxel. One trial is examining the combination of thalidomide with docetaxel. The other 2 trials are exploring the PSA vaccine with docetaxel and the combination of docetaxel with ketoconazole. As we obtain information from these ongoing studies, we will be able to take this information and integrate it in the development of newer and more successful treatment regimens as well as look for novel agents that may help in the fight against this disease.

Adenocarcinoma↗
PubMedDate not supplied

Vaccine therapy for a patient with androgen-insensitive prostate cancer without evidence of measurable disease on scans.

Androgen ablation therapy is the mainstay treatment of patients who have failed local therapy for prostate cancer. PSA is a serum marker commonly used to monitor patients who have undergone primary therapy for evidence of disease progression. However, there currently is no standard therapy for patients once they have demonstrated disease progression. We report a case of a 65-year-old man with castrate testosterone levels but a rising serum PSA level without radiographic evidence of metastasis. After failing prior antiandrogen therapy, he enrolled on a clinical trial comparing a PSA-based vaccine with nilutamide. When his PSA level rose on nilutamide, he commenced treatment with the vaccine therapy. He has continued to have a PSA response with the vaccine treatments with no radiographic evidence disease for >20 months.

Adenocarcinoma↗
PubMedDate not supplied

Prolonged response to nilutamide in a patient with stage D0.5 prostate cancer who previously failed androgen deprivation therapy.

There is currently no standard therapy for patients with prostate cancer who have progressive rise in PSA levels despite treatment with hormonal ablation and antiandrogen withdrawal (stage D0.5). One potential treatment option is the use of a different androgen receptor antagonist (ARA), such as nilutamide. We report a case of a 66-year-old gentleman with greater than a 46 month sustained response to nilutamide therapy after failing bicalutamide therapy and its subsequent withdrawal. The patient continues to have undetectable PSA levels and an excellent performance status. This case demonstrates the prolonged response to a second-line ARA in patients deemed to have androgen insensitive prostate cancer. Further investigation of the potential role of nilutamide therapy as second-line antiandrogen therapy is warranted as monotherapy and/or in combination with other promising novel approaches including PSA-based vaccines.

Aged↗