A phase I study of telomerase-specific replication competent oncolytic adenovirus (telomelysin) for various solid tumors.

A phase I clinical trial was conducted to determine the clinical safety of Telomelysin, a human telomerase reverse transcriptase (hTERT) promoter driven modified oncolytic adenovirus, in patients with advanced solid tumors. A single intratumoral injection (IT) of Telomelysin was administered to three cohorts of patients (1 x 10(10), 1 x 10(11), 1 x 10(12) viral particles). Safety, response and pharmacodynamics were evaluated. Sixteen patients with a variety of solid tumors were enrolled. IT of Telomelysin was well tolerated at all dose levels. Common grade 1 and 2 toxicities included injection site reactions (pain, induration) and systemic reactions (fever, chills). hTERT expression was demonstrated at biopsy in 9 of 12 patients. Viral DNA was transiently detected in plasma in 13 of 16 patients. Viral DNA was detectable in four patients in plasma or sputum at day 7 and 14 post-treatment despite below detectable levels at 24 h, suggesting viral replication. One patient had a partial response of the injected malignant lesion. Seven patients fulfilled Response Evaluation Criteria in Solid Tumors (RECIST) definition for stable disease at day 56 after treatment. Telomelysin was well tolerated. Evidence of antitumor activity was suggested.

Procoagulant inhibitory properties of paclitaxel poliglumex.

BACKGROUND: In Phase I evaluation of CT-2103 (paclitaxel poliglumex), prolongation of prothrombin time (PT) and activated thromboplastin time (aPTT) was observed, without clinical consequence, with doses 1.3-1.5 times higher than the current clinical dose of 175 mg/m(2). This Phase I, open-label, nonrandomized pilot study was performed to study the effect of the standard dose regimen on blood coagulation. METHODS: Seven previously treated solid tumor patients received CT-2103 175 mg/m(2) intravenously on day 1 of 21-day cycles for a mean of 5.4 cycles (median 4, range 2-14). Plasma samples were collected for cycle 1 predose and at hours 1, 24, 48, and 72 after the end of administration for drug levels, and for PT and aPTT assays. RESULTS: No coagulopathy-related adverse events were documented. Bleeding time remained normal in the six patients tested, with transient increases in PT and aPTT noted but resolving within 72 hours. Titration studies at 100 µg/mL of CT-2103 (corresponding to the standard clinical dose) prolonged PT and aPTT clotting times, produced a modest dose-dependent reduction of thrombin and factor Xa, and no significant changes in factors IXa, XIa, or XIIa. Two patients achieved stable disease for ≥10 cycles. CONCLUSION: CT-2103 is associated with transient prolongation of PT and aPTT without clinical sequelae.

Primary effusion lymphoma diagnosed by pericardiocentesis.

Primary effusion lymphoma (PEL), formerly known as body cavity-based lymphoma, is a high-grade B-cell non-Hodgkin's lymphoma associated with Kaposi's sarcoma and human herpesvirus 8 infection. It usually affects serous body cavities and results in recurrent lymphomatous effusions. PEL is often diagnosed in patients with HIV infection and carries a poor prognosis, with median survival near 6 months. We describe a patient who presented with symptomatic pericardial effusion, secondary to newly diagnosed PEL, and no prior history of HIV infection.

Induction of immune responses and clinical efficacy in a phase II trial of IDM-2101, a 10-epitope cytotoxic T-lymphocyte vaccine, in metastatic non-small-cell lung cancer.

PURPOSE: Generation of broad cytotoxic T-lymphocyte responses against multiple epitopes and tumor-associated antigens (TAAs) may provide effective immunotherapy in patients with cancer. We evaluated a single-vial peptide vaccine consisting of nine HLA-A2 supertype-binding epitopes (two native and seven analog epitopes modified for optimal HLA binding or T-cell receptor stimulation) covering five TAAs and the universal helper pan-DR epitope, formulated as a stable emulsion with incomplete Freund's adjuvant (Montanide ISA 51; Seppic SA, Paris, France). The clinical efficacy, safety, and multiepitope immunogenicity of IDM-2101 was evaluated in patients with stage IIIB or IV non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: A total of 63 patients were enrolled who were positive for HLA-A2. End points included survival, safety, and immune response. IDM-2101 (previously EP-2101) was administered every 3 weeks for the first 15 weeks, then every 2 months through year 1, then quarterly through year 2, for a total of 13 doses. Epitope-specific cytotoxic and helper T-lymphocyte immunogenic responses were measured by the interferon gamma enzyme-linked immunosorbent spot assay. RESULTS: No significant adverse events were noted. Low-grade erythema and pain at the injection site were the most common adverse effects. One-year survival in the treated patients was 60%, and median survival was 17.3 months. One complete and one partial response were identified. Survival was longer in patients demonstrating an immune response to epitope peptides (P < .001). CONCLUSION: IDM-2101 was well tolerated, and evidence of efficacy was suggested.

p53 therapy in a patient with Li-Fraumeni syndrome.

Li-Fraumeni syndrome is an autosomal dominant disorder that greatly increases the risk of developing multiple types of cancer. The majority of Li-Fraumeni syndrome families contain germ-line mutations in the p53 tumor suppressor gene. We describe treatment of a refractory, progressive Li-Fraumeni syndrome embryonal carcinoma with a p53 therapy (Advexin) targeted to the underlying molecular defect of this syndrome. p53 treatment resulted in complete and durable remission of the injected lesion by fluorodeoxyglucose-positron emission tomography scans with improvement of tumor-related symptoms. With respect to molecular markers, the patient's tumor had abnormal p53 and expressed coxsackie adenovirus receptors with a low HDM2 and bcl-2 profile conducive for adenoviral p53 activity. p53 treatment resulted in the induction of cell cycle arrest and apoptosis documented by p21 and cleaved caspase-3 detection. Increased adenoviral antibody titers after repeated therapy did not inhibit adenoviral p53 activity or result in pathologic sequelae. Relationships between these clinical, radiographic, and molecular markers may prove useful in guiding future application of p53 tumor suppressor therapy.