PURPOSE: To determine the safety, humoral immune response replication, and activity of multiple intratumoral injections of ONYX-015 (replication selective adenovirus) in patients with recurrent squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: This phase II trial enrolled patients with SCCHN who had recurrence/relapse after prior conventional treatment. Patients received ONYX-015 at a dose of 2 × 1011 particles via intratumoral injection for either 5 consecutive days (standard) or twice daily for 2 consecutive weeks (hyperfractionated) during a 21-day cycle. Patients were monitored for tumor response, toxicity, and antibody formation. RESULTS: Forty patients (30 standard and 10 hyperfractionated) received 533 injections of ONYX-015. Standard treatment resulted in 14% partial to complete regression, 41% stable disease, and 45% progressive disease rates. Hyperfractionated treatment resulted in 10% complete response, 62% stable disease, and 29% progressive disease rates. Treatment-r...

https://ascopubs.org/doi/pdfdirect/10.1200/JCO.2001.19.2.289

Phase II Trial of Intratumoral Administration of ONYX-015, a Replication-Selective Adenovirus, in Patients With Refractory Head and Neck Cancer

OVER THE PAST DECADE, gene therapy has been increasingly applied in clinical trials. According to data published by the Journal of Gene Medicine (http://www.wiley.co.uk/genetherapy/ clinical/), there were a total of 1020 approved gene therapy clinical trials in the world at the end of January 2005. Among these clinical trials, 66% were for the treatment of cancer. Of these cancer gene therapy trials, 58 used recombinant adenovirus encoding human p53 tumor suppressor gene (rAd-p53). More than 20 kinds of cancer indications have been treated with rAd-p53 agent, such as head and neck squamous cell carcinoma (HNSCC), lung cancer, breast cancer, liver cancers. Various clinical treatment regimens have been evaluated, including administration of rAd-p53 agent alone or in combination with conventional therapies such as radiotherapy, chemotherapy, and surgery. Encouraging clinical responses have been reported by a number of study groups. Lang et al. (2003) reported the results of a phase I clinical trial study in which rAd-p53 was administered to 15 patients with recurrent glioma. rAd-p53 was injected intratumorally at doses between 3 1010 and 3 1012 viral particles (VP). Three days after rAd-p53 injection the tumor was resected and more rAd-p53 was injected into the tumor bed. Of the 15 patients treated, 1 survived more than 3 years without evidence of recurrence, 4 patients experienced no recurrence for more than 6 months after treatment, and 2 of these 4 patients survived for more than 1 year. In a multicenter phase II trial study involving 25 patients with non-small cell lung cancer, 7.5 1012 VP of rAd-p53 was injected intratumorally in combination with cisplatin and vinorelbine. No significant difference in tumor response was observed from rAd-p53-injected lesions and noninjected lesions (52 versus 48%, respectively); however, the rAd-p53-treated lesions appeared to be smaller than the nontreated controls (Schuler et al., 2001). In a separate clinical study of 24 patients with non-small cell lung cancer (Nemunaitis et al., 2000), rAd-p53 was injected intratumorally at doses between 1 106 and 1 1011 plaque-forming units (PFU)/injection in combination with cisplatin. Seventeen patients achieved stable disease, 2 patients achieved partial response, and 4 patients had progressive disease. Intratumoral injection of rAd-p53 in combination with cisplatin was well tolerated and there was evidence of clinical efficacy. rAd-p53 was also used for non-small cell lung cancer treatment in combination with radiation therapy (Swisher et al., 2003). The rAd-p53 dose ranged from 3 1011 to 3 1012 VP/injection. Radiation was given concurrently over 6 weeks to a total of 60 Gy. Of the 19 patients treated, 1 showed complete regression (5%), 11 demonstrated partial regression (58%), 3 showed stable disease (16%), 2 showed progressive disease (11%), and 2 were unevaluable (11%). In a bladder carcinoma trial, 12 patients received either intratumoral or intravesicular injections of rAdp53 at doses of 7.5 1011 to 7.5 1013 VP (Kuball et al., 2002). Higher transduction efficiency was observed when using the intravesicular delivery method. Seven of the 11 evaluable patients had evidence of p53 expression by reverse transcription-polymerase chain reaction (RT-PCR). Nine of the 12 patients were alive at a median follow-up of 30 months. Pagliaro et al. (2003) reported a similar phase I study in which rAd-p53 was instilled intravesicularly at 1 1012 VP/dose in 13 patients with locally advanced transitional cell carcinoma of the bladder. A preliminary antitumor effect was observed at a treatment dose of 1 1012 VP on days 1 and 4. Clayman et al. (1998) reported the results of a clinical study in which rAd-p53 was applied as a single agent to treat advanced recurrent head and neck squamous cell carcinoma. Thirty-three patients received an intratumoral injection of rAd-p53 at doses up to 1 1011 PFU/injection. Of the 17 evaluable patients, 2 patients showed objective tumor regression of greater than 50%, 6 patients presented stable disease for up to 3.5 months, and 9 patients showed progressive disease. In all the reported clinical studies, the most common side effects were pain at the injection site, fatigue, and development of self-limited fever. Overall, rAd-p53 treatment was well tolerated by patients, without serious side effects. On the basis of

Current status of gendicine in China: recombinant human Ad-p53 agent for treatment of cancers.

Purpose: Advances in brain tumor biology indicate that transfer of p53 is an alternative therapy for human gliomas. Consequently, we undertook a phase I clinical trial of p53 gene therapy using an adenovirus vector (Ad-p53, INGN 201). Materials and Methods: To obtain molecular information regarding the transfer and distribution of exogenous p53 into gliomas after intratumoral injection and to determine the toxicity of intracerebrally injected Ad-p53, patients underwent a two-stage approach. In stage 1, Ad-p53 was stereotactically injected intratumorally via an implanted catheter. In stage 2, the tumor-catheter was resected en bloc, and the postresection cavity was treated with Ad-p53. This protocol provided intact Ad-p53–treated biologic specimens that could be analyzed for molecular end points, and because the resection cavity itself was injected with Ad-p53, patients could be observed for clinical toxicity. Results: Of fifteen patients enrolled, twelve underwent both treatment stages. In all patients, e...

Phase I Trial of Adenovirus-Mediated p53 Gene Therapy for Recurrent Glioma: Biological and Clinical Results

Direct targeting of cancer cells with gene therapy has the potential to treat cancer on the basis of its molecular characteristics. But although laboratory results have been extremely encouraging, many practical obstacles need to be overcome before gene therapy can fulfil its goals in the clinic. These issues are not trivial, but seem less formidable than the challenge of killing cancers selectively and rationally--a challenge that has been successfully addressed.

Cancer gene therapy: fringe or cutting edge?

Recent knowledge on apoptosis has made it possible to devise novel approaches, which exploit this process to treat cancer. In this review, we discuss in detail approaches to induce tumor cell apoptosis, their mechanism of action, stage of development, and possible drawbacks. Finally, the obstacles yet to be overcome and the perspectives for potential clinical use of apoptosis-triggering approaches in cancer therapy in the future are assessed.

/pdf/apoptosis-target-of-cancer-therapy-4m1mfuxo0y.pdf

Apoptosis: Target of cancer therapy

PURPOSE: To determine the safety and tolerability of adenovirus-mediated p53 (Adp53) gene transfer in sequence with cisplatin when given by intratumor injection in patients with non–small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with advanced NSCLC and abnormal p53 function were enrolled onto cohorts receiving escalating dose levels of Adp53 (1 × 106 to 1 × 1011 plaque-forming units [PFU]). Patients were administered intravenous cisplatin 80 mg/m2 on day 1 and study vector on day 4 for a total of up to six courses (28 days per course). Apoptosis was determined by the terminal deoxynucleotidyl- transferase-dUTP nick–end labeling assay. Evidence of vector-specific sequences were determined using reverse-transcriptase polymerase chain reaction. Vector dissemination and biodistribution was monitored using a series of assays (cytopathic effects assay, Ad5 hexon enzyme-linked immunosorbent assay, vector-specific polymerase chain reaction assay, and antibody response assay). RESULTS: Twenty-four ...

D. Connors

Papers

Adenovirus-Mediated p53 Gene Transfer in Sequence With Cisplatin to Tumors of Patients With Non–Small-Cell Lung Cancer