The First Approved Gene Therapy Product for Cancer Ad-p53 (Gendicine): 12 Years in the Clinic.

Zhang WW1,2, Li L3, Li D4, Liu J5, Li X6, Li W7, Xu X7, Zhang MJ8, Chandler LA2, Lin H7, Hu A7, Xu W7, Lam DM1.

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Abstract

Gendicine (recombinant human p53 adenovirus), developed by Shenzhen SiBiono GeneTech Co. Ltd., was approved in 2003 by the China Food and Drug Administration (CFDA) as a first-in-class gene therapy product to treat head and neck cancer, and entered the commercial market in 2004. Gendicine is a biological therapy that is delivered via minimally invasive intratumoral injection, as well as by intracavity or intravascular infusion. The wild-type (wt) p53 protein expressed by Gendicine-transduced cells is a tumor suppressor that is activated by cellular stress, and mediates cell-cycle arrest and DNA repair, or induces apoptosis, senescence, and/or autophagy, depending upon cellular stress conditions. Based on 12 years of commercial use in >30,000 patients, and >30 published clinical studies, Gendicine has exhibited an exemplary safety record, and when combined with chemotherapy and radiotherapy has demonstrated significantly higher response rates than for standard therapies alone. In addition to head and neck cancer, Gendicine has been successfully applied to treat various other cancer types and different stages of disease. Thirteen published studies that include long-term survival data showed that Gendicine combination regimens yield progression-free survival times that are significantly longer than standard therapies alone. Although the p53 gene is mutated in >50% of all human cancers, p53 mutation status did not significantly influence efficacy outcomes and long-term survival rate for Ad-p53-treated patients. To date, Shenzhen SiBiono GeneTech has manufactured 41 batches of Gendicine in compliance with CFDA QC/QA requirements, and 169,571 vials (1.0 × 1012 vector particles per vial) have been used to treat patients. No serious adverse events have been reported, except for vector-associated transient fever, which occurred in 50-60% of patients and persisted for only a few hours. The manufacturing accomplishments and clinical experience with Gendicine, as well as the understanding of its cellular mechanisms of action and implications, could provide valuable insights for the international gene therapy community and add valuable data to promote further developments and advancements in the gene therapy field.

In de Indiase The Telegraph van 4 juli wordt melding gemaakt van een opzienbarende gentherapie onder de naam Gendincine in China. 400 terminale en ongeneeslijk verklaarde kankerpatiënten zouden hiermee al in remissie zijn gekomen. Ook 20 patiënten uit Europa en Amerika. Wat de Chinese artsen doen is het gen p53 inbrengen bij een bepaald virus en het daarna rechtstreeks inspuiten bij de tumoren zelf. Daarna plegen de kankercellen zelfmoord. Dit lijkt veel op wat recent ook is gepubliceerd door Engelse onderzoekers die een genbewerkt adenovirus inbrengen in de tumorcellen en daarmee ook zeer opmerkelijke resultaten hebben. Zie bericht hierover onder kankernieuws no. 10. Of het allemaal waar is durven we niet te zeggen, maar desalniettemin toch maar het artikel ook hier gepubliceerd. Virussen zoals ook het bekendere Newcastle virus lijken toch een zeer interessante optie voor kankerpatiënten.

Gene therapy for cancer in China
ADAM LUCK Hong Kong, July 4: Terminally ill cancer patients from Europe and America are travelling to China for treatment with a revolutionary anti-tumour drug — the world’s first officially licenced “gene therapy”.

The Chinese government approved the manufacture and use of the drug at the end of last year after clinical trials found that it markedly improved the survival rate for patients with cancer of the head and neck. Doctors are now extending the treatment, named Gendicine, to patients with lung and stomach cancer.

Injected directly into the tumour, Gendicine works by, in effect, programming cancer cells to commit suicide.
About 400 patients — 20 of them from abroad — have been treated with the drug in eight-week courses which cost the equivalent of £1,800.

Peng Zhaohui, a medical scientist who helped develop Gendicine, said: “I believe this revolutionary form of gene therapy represents the future for treating cancer patients. There is still a lot of work to be done, but the results have been very promising so far and — unlike experimental forms of gene therapy attempted elsewhere — there is no evidence of serious side-effects. We have treated foreign patients successfully and word is beginning to spread.”

Peng has been inundated with requests from overseas, including Britain, from patients desperate to try Gendicine. Arthur Winiarski, 48, a Polish-American businessman based in Warsaw, who was diagnosed with squamous cell carcinoma in his sinuses after a routine medical check-up 18 months ago, was one of them.
After operations, radiotherapy and chemotherapy in Poland, America and Germany, he was told by doctors at a hospital in Berlin that he had almost no hope. “They wanted to get rid of me. The only thing they could suggest was chemotherapy but they and I both knew this does not work with this kind of cancer,” he said.
Then a friend saw a sentence about the new drug on the internet, which mentioned Peng. Winiarski e-mailed a short history of his case to the scientist. To his astonishment, within three hours came a reply: “I think I will be able to help you.”
Still sceptical about his prospects, Winiarski travelled to China and presented himself to Niu Qi, an oncologist at Beijing’s elite Tongren hospital, in April. He was told he needed surgery as well as the drug treatment.
He said: “They inject the drug into the tumour and it goes bananas: it invades itself and commits suicide. My tumour was so big — the size of a fist — that they had to use the drug to shrink it first.”
After further doses of Gendicine, Winiarski was given the all-clear. He said: “To have a life like mine, to be a successful businessman, with everything going well and then all of sudden be told you have months to live — you cannot understand. This experience has been incredible and you could not believe the care I have had. I came here in desperation and they have treated me like a king.”
Gendicine works by inserting a gene, called p53, into a virus, which is then injected into patients. The gene is naturally present in healthy cells but is “switched off” or mutated in many cancer patients. When reinserted into tumour cells by the virus, it triggers their self-destruction.

our results demonstrated that CRT/RT combined with rAd-p53 therapy can result in enhanced survival and better clinical responses of patients with NPC. Therefore, rAd-p53 has great potential as an effective therapy for NPC.

. 2016; 5(1): 1885.

Published online 2016 Oct 27. doi: 10.1186/s40064-016-3574-6

PMCID: PMC5083707

PMID: 27843742

Recombinant human adenovirus-p53 therapy for the treatment of nasopharyngeal carcinoma: a meta-analysis

Cheng Yuan,1 Xin-Hua Xu, corresponding author

2 and Zhuo Chen1

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Abstract

To compare clinical curative effects and toxicity of recombinant human adenovirus-p53 injection (rAd-p53, Gendicine) combining chemoradiotherapy (CRT)/radiotherapy (RT) with those obtained with CRT/RT alone in nasopharyngeal carcinoma (NPC). We searched all the eligible studies from the Pubmed, Cochran Library, Embase, Web of science, Wanfang database and Chinese National Knowledge Infrastructure (CNKI). A total of twelve studies including 566 participants met the criteria to perform a meta-analysis. The results indicated the complete remission (CR) and overall response (OR) in the combination therapy group were significantly improved compared with the CRT/RT group (CR:RR = 2.03, 95% CI 1.66–2.48, p < 0.00001; OR:RR = 1.23, 95% CI 1.13–1.33, p < 0.00001), and patients who received the combination therapy showed significantly prolonged 1- and 2-year overall survival (OS), 2 year disease-free survival (DFS) rate and 2 year recurrence-free survival (RFS) rate (1 year OS:RR = 1.08, 95% CI 1.00–1.17, p = 0.04; 2 year OS:RR = 1.12, 95% CI 1.00–1.26, p = 0.04; 2 year DFS:RR = 1.41, 95% CI 1.09–1.83, p = 0.008; 2 year RFS:RR = 1.16, 95% CI 1.03–1.31, p = 0.02), but there was no significance in 3 year OS rate and 2 year distant metastases-free survival (DMFS) rate (3 year OS:RR = 1.28, 95% CI 1.00–1.62, p = 0.05; 2 year DMFS:RR = 1.05, 95% CI 0.89–1.24, p = 0.55). Furthermore, CRT/RT combined with rAd-p53 could not aggravate the myelosuppression versus CRT/RT alone (RR = 0.79, 95% CI 0.51–1.23, p = 0.30). The results demonstrated CRT/RT combined with rAd-p53 can result in enhanced survival and better clinical responses of patients with NPC. Therefore, rAd-p53 has great potential as an effective therapy for NPC.

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