Belagenpumatucel-L is well tolerated, and the survival advantage justifies further phase III evaluation.

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.

Although genetically engineered adenoviruses hold promise for the treatment of cancer, clinical trial reports have utilized intratumoral injection to date. To determine the feasibility of intravenous delivery of ONYX-015, an E1B-55kD genedeleted replication selective adenovirus with demonstrated clinical safety and antitumoral activity following intratumoral injection, we performed a clinical trial in patients with metastatic solid tumors. ONYX-015 was infused intravenously at escalating doses of 2 × 10 10 to 2 × 10 13 particles via weekly infusion within 21-day cycles in 10 patients with advanced carcinoma metastatic to the lung. No dose-limiting toxicity was identified. Mild to moderate fever, rigors and a dosedependent transient transaminitis were the most common

Little is known about the potential for engraftment of autologous hematopoietic stem cells in human adults not subjected to myeloablative conditioning regimens. Five adult patients with the p47 phox deficiency form of chronic granulomatous disease received intravenous infusions of autologous CD34 ؉ peripheral blood stem cells (PBSCs) that had been transduced ex vivo with a recombinant retrovirus encoding normal p47 phox . Although marrow conditioning was not given, functionally corrected granulocytes were detectable in peripheral blood of all five patients. Peak correction occurred 3-6 weeks after infusion and ranged from 0.004 to 0.05% of total peripheral blood granulocytes. Corrected cells were detectable for as long as 6 months after infusion in some individuals. Thus, prolonged engraftment of autologous PBSCs and continued expression of the transduced gene can occur in adults without conditioning. This trial also piloted the use of animal protein-free medium and a blood-bankcompatible closed system of gas-permeable plastic containers for culture and transduction of the PBSCs. These features enhance the safety of PBSCs directed gene therapy.

We performed a phase I trial of FANG vaccine, an autologous tumor-based product incorporating a plasmid encoding granulocyte-macrophage colony-stimulating factor (GMCSF) and a novel bifunctional short hairpin RNAi (bi-shRNAi) targeting furin convertase, thereby downregulating endogenous immunosuppressive transforming growth factors (TGF) β1 and β2. Patients with advanced cancer received up to 12 monthly intradermal injections of FANG vaccine (1 × 10(7) or 2.5 × 10(7) cells/ml injection). GMCSF, TGFβ1, TGFβ2, and furin proteins were quantified by enzyme-linked immunosorbent assay (ELISA). Safety and response were monitored. Vaccine manufacturing was successful in 42 of 46 patients of whom 27 received ≥1 vaccine. There were no treatment-related serious adverse events. Most common grade 1, 2 adverse events included local induration (n = 14) and local erythema (n = 11) at injection site. Post-transfection mean product expression GMCSF increased from 7.3 to 1,108 pg/10(6) cells/ml. Mean TGFβ1 and β2 effective target knockdown was 93.5 and 92.5% from baseline, respectively. Positive enzyme-linked immunospot (ELISPOT) response at month 4 was demonstrated in 9 of 18 patients serially assessed and correlated with survival duration from time of treatment (P = 0.025). Neither dose-adverse event nor dose-response relationship was noted. In conclusion, FANG vaccine was safe and elicited an immune response correlating with prolonged survival. Phase II assessment is justified.

To evaluate the feasibility, safety, and efficacy of vaccination with autologous tumor cells genetically modified with an adenoviral vector (Ad-GM) to secrete human granulocyte-macrophage colony-stimulating factor (GM-CSF), we conducted a phase I/II multicenter trial in patients with early and advanced stage non-small-cell lung cancer (NSCLC). Vaccines were generated from autologous tumor harvests. Intradermal injections were given every 2 weeks for a total of three to six vaccinations. Tumors were harvested from 83 patients, 20 with early-stage NSCLC and 63 with advanced- stage NSCLC; vaccines were successfully manufactured for 67 patients, and 43 patients were vaccinated. The most common toxicity was a local injection-site reaction (93%). Three of 33 advanced-stage patients, two with bronchioloalveolar carcinoma, had durable complete tumor responses (lasting 6, 18, and >or=22 months). Longer survival was observed in patients receiving vaccines secreting GM-CSF at more than 40 ng/24 h per 10(6) cells (median survival = 17 months, 95% confidence interval [CI] = 6 to 23 months) than in patients receiving vaccines secreting less GM-CSF (median survival = 7 months, 95% CI = 4 to 10 months) (P =.028), suggesting a vaccine dose-related survival advantage.

Stathmin 1 (STMN1), also known as p17, p18, p19, 19K, metablastin, oncoprotein 18, LAP 18 and Op18, is a 19 kDa cytosolic protein. It was the first discovered member of a family of phylogenetically related microtubule-destabilizing phosphoproteins critically involved in the construction and function of the mitotic spindle. A threshold level of STMN1 is required for orderly progression through mitosis in a variety of cell types. STMN1 is overexpressed across a broad range of human malignancies (leukemia, lymphoma, neuroblastoma; ovarian, prostatic, breast and lung cancers and mesothelioma). It is also upregulated in normally proliferating cell lines but is only rarely upregulated in nonproliferating cell lines with the exception of neurons, anterior pituitary cells and glial cells. Its expression is also upregulated in hepatocytes during regeneration and in lymphoid cells when they are signaled to proliferate. In this review, we summarize available data as rationale for the therapeutic manipulation of STMN1 in cancer patients.

In a previous dose escalation trial we demonstrated dose related survival correlation to Belagenpumatucel-L. In order to further evaluate safety and response at the previously defined optimal dose and schedule and to gain preliminary evidence on a hypothesis that the level of circulating tumor cells (CTCs) in blood may correlate with the overall survival of patients with stage IV NSCLC, we initiated a phase II trial. Patients received intradermal immunization of 2.5 Â 10 7 transfected allogeneic tumor cells (Belagenpumatucel-L, supplied by NovaRx) 1 Â every month for a total of 16 months. Circulating tumor cells (Veridex, Raritan, NJ) were measured every 4 weeks. Twenty-one advanced NSCLC patients were enrolled on this study. No significant toxic effect was observed. Overall survival was 562 days. The median survival was 660 days in patients having less than 2 CTCs at baseline compared to 150 days in patients with 2 or more CTCs (P ¼ 0.025). Phase II results of safety and response are consistent with prior experience following treatment with Belagenpumatucel-L and there is a suggestion that the number of circulating tumor cells at baseline appears to correlate with overall survival. A larger clinical trial is warranted to further explore this observation.