GTMB 7 - Gene Therapy & Molecular Biology

Gene Therapy and Molecular Biology Vol 7, page 31adverse events all the patients developed anti-adenovirusantibodies in the course of treatment, but this immuneresponse did not treatment. The most common treatmentrelatedadverse event was pain at injection site. Otherreported adverse events were transient fever, headache,pain, and edema. No evidence of systemic hypersensitivityor allergic reactions was seen, despite the fact that patientsreceived many repeated courses of treatment. In somepatients, adenovirus p53 administration led to objectiveantitumor activity. Two out of 17 patients showedobjective tumor regressions greater than 50% and sixpatients showed stable disease for up to 3.5 months. Inaddition, one patient showed a complete pathologicresponse. The median survival for responding patients was13.6 months, and the overall median survival was 267days, which is about 60% longer than that reported inchemotherapy trials with a similar patient profile(Schornagel et al, 1995). Of course, it is impossible, for aphase-one study with limited numbers of patients to stateanything more than that these results are promising andthat further studies are needed, and are underway, todetermine the actual role of adenovirus-mediated p53intratumoral injections as a treatment option for HNSCC.The next step in the development of p53 treament is toinclude combination therapy with cytotoxic agents.There is also a negative trial published by Schullerand coworkers (2001). Twenty-five patients with nonresectableNSCLC were enrolled in an open-label,multicenter, phase II study of three cycles ofchemotherapeutics with intratumoral injection ofrecombinant adenovirus p53. The main idea of this smallstudy was to compare the isolated responses of a tumorlesion treated by transfer of the adenoviral wild-type p53gene with a comparable lesion not receiving any injectionsin patients undergoing first-line chemotherapy forNSCLC. In the 13 patients receiving carboplatin andpaclitaxel, there was no obvious difference between themean response of gene-therapy-treated and the referencelesions. In contrast, the mean regression of the referencelesions in patients treated with cisplatin and vinorelbinewas 15%, whereas it amounted to 55% in lesions that wereadditionally injected with the gene construct.There was no difference between the responses of lesionstreated with p53 gene therapy in addition to chemotherapy(52%) and those of lesions treated with chemotherapyalone (48%). The authors concluded that, in these patientsthe therapy appears to provide no additional benefit.However, there were several possible shortcomings in theclinical set-up: no injections to the reference lesions,highly restrictive inclusion criteria may result in selectionbias, a higher response rate (50%) than is normallyachieved in this disease, a chance of having a biologicallyinactive virus construct, and insufficient spreading of thereplication-defective adenoviral vectors within the tumorsafter only one central intralesional injection.Recently, attemps have been made to overcome theproblem of ineffective vector spreading by administrationof replication-competent adenoviruses (Heise, Sampson etal, 1997) and encouraging clinical results have beenreported (Khuri et al, 2000). There were concerns aboutthe safety, which, however, turned out to be exaggerated.Khuri et al, (2000) demonstrated an acceptable safetypattern with no sign of any dissemination to theenvironment. A Phase II trial of a combination ofintratumoral ONYX-015 injection with cisplatin and 5-fluorouracil was carried out with patients having recurrentsquamous cell cancer of the head and neck. Only pain atthe injection site (45%), mucous membrane disorder(21%), syncope (5%), kidney failure (5%), and anorexia(3%) could not be ruled out as attributable to Onyx-015.In addition, the injected tumors achieved objectiveresponses at a substantially higher rate (9 of the 11) thanthe non-injected tumors (3 of the 11) within the samepatients. In six patients, the injected tumor responded andthe non injected tumor did not respond. The time to tumorprogression was also longer for the injected tumors thanfor the non-injected tumors. There was no correlationbetween the response and the baseline tumor size, baselineneutralizing antibody titer, p53 gene status, or priortreatment. It was also clear that the efficacy of theintratumoral injection was not prevented by neutralizingantibodies. There has been discussion about whether or notenough evidence about viral replication of ONYX-015 inpatients, as along experience based on 190 patients treatedby a replication-defective adenovirus demonstratingsimilar biodistribution (Clayman et al, 1998; Constenla-Figueiras et al, 1999). It may simple be that Taqman realtimepolymerase chain reaction technology is not sufficientto prove that viral reproduction is taking place (Yver et al,2001).Table 1. Sensitising effect of adenovirus-p53 on chemotherapeutic agents, major clinical treatment resultsDisease Phase Combination n Treatment responses Reference (first author year)NSCLC II no 24 2 PR, 17 SD_ (Swisher et al, 1999)Head & neck II no 17 1CR, 2 PR, 6 SD_ (Clayman et al, 1998)NSCLC II Cisplatin + vinorelbin 25 13 PR* (Schuler et al, 2001)Heach & neck II Cisplatin +5-FU 11 9 PR* (Khuri et al, 2000)(_) on patients(*) on measurable lesions31