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Originally published as JCO Early Release 10.1200/JCO.2005.03.4116 on February 27 2006 © 2006 American Society of Clinical Oncology. Multicenter Phase I Study of Repeated Intratumoral Delivery of Adenoviral p53 in Patients With Advanced Non–Small-Cell Lung Cancer
From the Center for Gene and Cell Therapy, Okayama University Hospital; Departments of Surgery and Radiology, Okayama University Graduate School of Medicine and Dentistry, Okayama; Department of Molecular Medicine, Tohoku University Graduate School of Medicine; Department of Respiratory Oncology and Molecular Medicine, Institute of Developing, Aging, and Cancer, Tohoku University, Sendai; Department of Gene Therapy, Institute of DNA Medicine, Department of Respiratory Medicine, Jikei University School of Medicine; Department of Surgery, Tokyo Medical University, Toyko, Japan; and Introgen Therapeutics Inc, Houston, TX Address reprint requests to Toshiyoshi Fujiwara, MD, Center for Gene and Cell Therapy, Okayama University Hospital, 2-5-1 Shikata-cho, Okayama 700-8558, Japan; e-mail: toshi_f{at}md.okayama-u.ac.jp
PURPOSE: To determine the feasibility, safety, humoral immune response, and biologic activity of multiple intratumoral injections of Ad5CMV-p53, and to characterize the pharmacokinetics of Ad5CMV-p53 in patients with advanced non–small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Fifteen patients with histologically confirmed NSCLC and p53 mutations were enrolled onto this phase I trial. Nine patients received escalating dose levels of Ad5CMV-p53 (1 x 109 to 1 x 1011 plaque-forming units) as monotherapy once every 4 weeks. Six patients were treated on a 28-day schedule with Ad5CMV-p53 in combination with intravenous administration of cisplatin (80 mg/m2). Patients were monitored for toxicity, vector distribution, antibody formation, and tumor response. RESULTS: Fifteen patients received a total of 63 intratumoral injections of Ad5CMV-p53 without dose-limiting toxicity. The most common treatment-related toxicity was a transient fever. Specific p53 transgene expression was detected using reverse-transcriptase polymerase chain reaction in biopsied tumor tissues throughout the period of treatment despite of the presence of neutralizing antiadenovirus antibody. Distribution studies revealed that the vector was detected in the gargle and plasma, but rarely in the urine. Thirteen of 15 patients were assessable for efficacy; one patient had a partial response (squamous cell carcinoma at the carina), 10 patients had stable disease, with three lasting at least 9 months, and two patients had progressive disease. CONCLUSION: Multiple courses of intratumoral Ad5CMV-p53 injection alone or in combination with intravenous administration of cisplatin were feasible and well tolerated in advanced NSCLC patients, and appeared to provide clinical benefit.
Lung cancer is the most common cause of cancer related deaths in both men and women worldwide.1 In 2001, 39,880 males and 15,122 females died of lung cancer in Japan, which ranked first among males and third among females in the number of cancer deaths.2 Recent advances in molecular biology have fostered remarkable insights into the molecular basis of lung cancer,3 and suggest that restoration of the function of critical gene products could halt or reverse cancer pathogenesis, thus having a therapeutic effect in cancer. p53 is the most extensively studied tumor suppressor gene, and its mutation has been reported to be one of the most common genetic changes found in malignant tumors.4 p53 gene mutation is reported to occur in 40% to 50% of non–small-cell lung cancer (NSCLC),5 and aberrant p53 expression correlates with an adverse prognosis in lung cancers.6,7 The p53 gene product is involved in multiple pivotal cellular processes as a potent transcriptional regulator, and one of its most important roles is in the regulation of apoptosis.8 We previously reported that the overexpression of the wild-type p53 (wt-p53) gene by recombinant, replication-deficient viral vector, Ad5CMV-p53 (ADVEXIN; Introgen Therapeutics Inc, Houston, TX), triggered apoptosis in a variety of human cancer cells independent of their p53 status.9-13 ADVEXIN in combination with chemotherapeutic drugs, such as cisplatin, showed a profound antitumor effect in vitro and in vivo.14,15 We also found that wt-p53 gene transfer could promote bystander effects to neighboring tumor cells through the multiple mechanisms, including antiangiogenesis and neutrophil-mediated immune responses.16,17 On the basis of these promising preclinical results, a multi-institutional, dose-escalation phase I study of ADVEXIN was conducted in Japanese patients with advanced NSCLC who had failed conventional treatments such as chemotherapy and radiotherapy. We assessed the tolerability of repeated administration of ADVEXIN for more than 6 months, which was not examined in previous phase I and II trials in the United States.18-20
Patient Eligibility Patients were included who met the following criteria: between 15 and 75 years old; histologically confirmed advanced NSCLC, resistant or refractory to standard therapies; lesions accessible for repeated injection; measurable disease; Zubrod performance status of 2 or lower; life expectancy greater than 12 weeks; and adequate bone marrow, liver, and renal function. Pretreatment tumor biopsies must show a p53 mutation by single-strand conformation polymorphism analysis.
Study Design
Treatment Plan
Toxicity and Response Criteria
Determinations of Antibody Titer
Analysis of Tumor Biopsy Tissues
Analysis of Vector Dissemination and Biodistribution
Patient Characteristics Fifteen patients with advanced NSCLC who had failed prior conventional therapies were enrolled onto this clinical trial from February 1999 to April 2003 (Table 1). Patients were primarily male (14 males and 1 female), with median age of 58 years (range, 46 to 71 years). Nine patients (60%) had prior chemoradiotherapy and six patients (40%) had prior chemotherapy. Fourteen patients (93.3%) were treated with platinum-based regimens containing either cisplatin or carboplatin. The median number of courses per patient was three (average, 4.2), and the range was one to 14 courses.
Adverse Events Toxicities and adverse events (AE) that occurred in all patients are presented in Table 2. Among the 15 treated patients, none withdrew from the study as a result of toxicity, and no grade 4 toxicities classified as being possibly, probably, or definitely related to the vector were observed. The most frequent vector-related AE was a transient fever. In most patients (93.3%), self-limited fever developed 6 to 24 hours after ADVEXIN injection regardless of dose, with a highest reported grade of 3. Patients generally recovered within 48 hours, although four patients (26.7%; patients 3, 7, 8, and 13) developed grade 2 or 3 obstructive pneumonia categorized as not related or probably not related to study medication. Hematologic toxicity was limited, with one incidence of grade 1 leukopenia (6.7%) and three incidences of grade 2 or 3 anemia (20%). Transient, mild increases in liver ALT and AST were noted in one patient treated with ADVEXIN alone. Liver enzymes recovered to pretreatment values within 10 days.
Clinical Outcome Thirteen of 15 patients (86.7%) were assessable for response with CT scan, broncoscopic, and clinical findings. Objective responses were a partial response in one patient (7.7%), stable disease (SD) in 10 patients (76.9%), and progressive disease in two patients (15.4%; Table 1). The median time of SD was 4.4 months (range, 1 to 11 months). Two patients (13.3%) were not assessable because their tumor sizes could not be measured due to obstructive pneumonia. Of 13 assessable patients, three patients assessed as having partial response or SD received more than six cycles of ADVEXIN injection alone (patients 1 and 2) or in combination with cisplatin (patient 4) before disease progression. Symptomatic improvement, including reduction in dyspnea, cough, or hemoptysis was observed in four patients (26.7%) with refractory disease. One patient (patient 10) received additional external radiation therapy to 60 Gy over 6 weeks after two intratumoral injections of ADVEXIN and systemic administration of cisplatin, and survived for 3.9 months with evidence of the tumor in the right upper lobe. Overall survival analysis by Kaplan and Meier is 40% at 1 year, 13% at 2 years, and 7% at 3 years (Fig 1).
The first responding patient (patient 1) was a 58-year-old male with locally advanced squamous cell carcinoma at the tracheal bifurcation. He was unable to undergo surgery because of poor pulmonary function and received standard chemoradiotherapy. At the time of enrollment, he had relapsed endobronchial tumor in the area from the carina to the left mainstem bronchus, and received ADVEXIN at the 109 PFU dose level every 28 days. Four courses of bronchoscopic injection of ADVEXIN at the 109 PFU dose level every 4 weeks resulted in a marked tumor regression (Fig 2A) and relief of his symptoms such as hemoptysis, cough, and dyspnea. Pathologic examination demonstrated squamous metaplasia in most lesions, although there was a microscopic residual tumor in the left mainstem bronchus. He received a total of 14 courses of treatment, during which time no tumor progression was noted for approximately 11 months. His treatment was finally discontinued because of additonal local tumor progression.
The second responding patient (patient 2) presented with locally advanced unresectable squamous cell carcinoma that was completely obstructing the left lower lobe. After two courses of broncoscopic ADVEXIN injection at 109 PFU, radiographic tumor destruction was observed at the central portion (Fig 2B), resulting in reopening of the airway. He showed a significant improvement in breathing; treatment was, however, discontinued after nine courses of injections when distant bone metastasis was diagnosed. A long-term SD was documented in a 46-year-old female with adenocarcinoma at the left upper lobe with multiple intrapulmonary metastasis (patient 4). She had disease progression during chemotherapy using cisplatin, vincristine, and etoposide as noted by a radiographic increase during the preceding 3 months, and received CT-guided injection of ADVEXIN at 109 PFU after systemic administration of cisplatin at 80 mg/m2 every 28 days. Her primary adenocarcinoma in the left upper lobe as well as multiple pulmonary metastases were stable for approximately 10 months during the period of treatment (Fig 2C).
Immune Response to Adenovirus and p53
Vector Shedding and Biodistribution A total of 624 gargle and urine samples from 12 patients were examined for virus shedding by DNA-PCR using vector-specific primers (Table 4, Fig 2). Samples were collected just before vector injection and daily thereafter for 15 days in each course. Vector DNA was detectable in 29 of 39 (74.4%) gargle samples obtained at day 1 after vector injection, regardless of dose level or treatment course, and declined to undetectable levels within 15 days for most patients. One patient (patient 11) was continuously positive for vector DNA until day 15 or beyond, probably due to the shedding of infected tumor cells. In total, 90 gargle samples (14.4%) were positive for vector DNA, whereas vector was detected in only 13 urine specimens (2.1%). The presence of ADVEXIN was assayed in the plasma obtained before and 30, 60, 90 minutes after vector injection (Fig 3). In all 12 patients tested, vector was detected in plasma 30 minutes after injection either by the DNA-PCR or CPE method, and the titers decreased over the next 60 minutes. No correlation was noted between systemic virus titer and AEs or clinical response.
Pathologic and Molecular Analysis of Tumor Biopsy Tissues Tumor biopsy samples obtained before and 48 hours after vector injection in 12 patients were assessed for p53 mRNA expression by RT-PCR analysis using vector-specific primers (Table 5). All pretreatment samples were negative for p53 transgene expression because the primers can distinguish exogenous wt-p53 from pre-existing mutant p53 in tumor specimens. Vector-specific p53 mRNA expression was detectable in 9 of 12 patients (75%) after the first vector injection. Overall, 11 of 12 patients (91.7%) demonstrated positive p53 transgene expression during the treatment. Of note, p53 mRNA expression was consistently positive in 52 of 57 serial postinjection samples (91.2%) obtained from patients who received more than six courses of injection (patients 1, 2, and 4). To evaluate the biologic activity of ADVEXIN-induced p53 expression, we performed quantitative analysis of p53-targeted gene expression by a real-time RT-PCR method. Paired biopsy samples obtained before and 48 hours after injection at courses 1, 5, 8, and 11 were analyzed in patient 1 for expression of exogenous p53, p21, Noxa, and p53AIP1 mRNAs. We found that apoptosis-related gene expression such as Noxa and p53AIP1 was consistently higher in postinjection samples than that in preinjection biopsies throughout the study (Fig 4). The expression patterns of these mRNAs almost paralleled that of exogenous p53. In contrast, p21 expression pattern varied on courses.
Autopsy results were obtained from two patients (patients 3 and 7) who died 25 and 151 days after receiving their fourth and second injection of the vector, respectively. DNA-PCR assay indicated that ADVEXIN was present in tumor tissue as well as proximal lymph nodes, suggesting regional spread of the vector via the lymphatic vessels. In contrast, viral distribution was not detected in other organs including liver, kidney, testis, and distal lymph nodes.
In an effort to determine the feasibility of p53 gene therapy in human cancer treatments, several clinical trials of locoregional administration of adenoviral p53 have been conducted in patients with a variety of advanced malignancies such as NSCLC,18-20,22 head and neck cancer,23 bladder cancer,24,25 recurrent glioma,26 and ovarian cancer.27 No available data, however, has been reported yet evaluating this agent in Japanese patients. As clinical trials of the epidermal growth factor receptor tyrosine kinase inhibitor, gefitinib (Iressa; AstraZeneca, London, United Kingdom), revealed significant variability in the response to this drug, with higher responses seen in Japanese patients than in a predominantly European-derived population,28 it is important to evaluate variations in the response and safety profiles of novel therapeutic agents in Japanese patients. The results of the present multicenter phase I trial indicate that intratumoral administration of ADVEXIN is feasible, safe, and well tolerated in Japanese patients. Fever was observed as the most common treatment-related AE, which could be due to the transient systemic spread of the vector itself. In fact, flu-like symptoms, such as chills, fatigue or lethargy, and diarrhea, frequently occurred in patients who received replication-competent adenovirus29,30; these symptoms, however, are rarely seen in patients treated with ADVEXIN. Although the frequency of fever (affecting 93.3% of the patients) was slightly higher in our trial than those in the United States (79%) or European (76%) trials,20,22 the observation that most episodes recovered within 48 hours after injection suggests that ADVEXIN-related AEs are limited, and only mild to moderate in severity. The vector was shed into gargle specimens especially when bronchoscopically injected as expected, whereas vector was rarely detectable in urine despite of the systemic spread of the vector. Most PCR-positive gargle samples were negative by CPE assay (data not shown), indicating that secondary infection through vector shedding into gargle is unlikely to occur. The observation of systemic dissemination of ADVEXIN, which was maximal at 30 minutes after injection, is consistent with that observed in the United States trial, although the highest vector titer in the plasma was approximately log1 to log2 lower in Japanese patients.21 The organ distribution of virus found in two deceased patients is clearly of interest, because, to the best of our knowledge, this is the first evidence of virus spread in the regional lymphatic tissues in humans. It has been reported that replication-deficient adenovirus expressing the lacZ gene could be transferred into regional lymph nodes of the stomach in dogs after intratumoral injection31; no lymph node tissues, however, were analyzed in any published clinical trials. This finding suggests that intratumorally administered ADVEXIN can spread not only into the blood circulation, but also into the lymphatic vessels, and potentially kill metastatic tumor cells in regional lymph nodes. Schuler et al22 have reported that intratumoral adenoviral p53 gene therapy provides no additional benefit in NSCLC patients receiving systemic chemotherapy by comparing the responses of injected lesions with those of noninjected comparator lesions, such as hilar metastatic tumors. According to our biodistribution data, the possibility that their virus spread into comparator lesions and showed antitumor effect cannot be ruled out. Despite the presence of neutralizing antibodies for adenovirus, we found that p53 transgene expression was detected in most patients throughout the period of treatment. In addition, quantitative real-time RT-PCR analysis demonstrated that the expression patterns of apoptosis-related p53-targeted genes such as Noxa and p53AIP1 paralleled that of exogenous p53 (Fig 4), demonstrating that exogenous p53 produced after ADVEXIN treatment has biologic activity. These findings further demonstrate that circulating neutralizing anti-Ad5 antibodies do not inhibit vector-mediated transgene expression when ADVEXIN is directly injected into the tumors. Two of 13 patients (15.4%) had pre-existing anti-p53 antibodies, which is consistent with previous studies reporting that p53 autoantibodies were detected in 10% to 20% of patients with lung cancer.32 Most patients, however, did not exhibit an increase of anti-p53 titers after ADVEXIN injection, presumably because of the short half-life of wt-p53 protein or due to lack of overcoming tolerance to this self protein. As predicted by our preclinical and other clinical studies,10-20 sustained antitumor effect was seen with tumor regression or stabilization of tumor growth in 11 of 13 assessable patients. Patient 1 exhibited a 50% or greater reduction in tumor size after ADVEXIN injection and this response was maintained with monthly injections; the growth rate of tumor, however, suddenly increased at 11 months after the time of entry, leading to the uncontrollable progressive disease. Although the molecular mechanism of this resistance to treatment is still under investigation, increasing the frequency of administration beyond once per month may be an approach to improve efficacy in such patients. Previous experience with ADVEXIN has shown that patients with airway stenosis or obstruction may be suitable candidates for this locoregional therapy.18-20 Indeed, three patients (patients 1, 2, and 15) exhibited significant reopening of the airway after bronchoscopic injection of ADVEXIN, and resulted in the marked improvement of symptoms such as cough, hemoptysis, and dyspnea. It is of interest that three of six patients who were assigned to the cohort with the lowest dose of ADVEXIN could receive more than six courses of treatment, whereas no patients treated with higher doses completed six cycles of injections. There was a possible selection bias of patients related to the dose levels and the centers; this finding, however, suggests that 109 PFU of ADVEXIN appears to be sufficient to induce local effect without toxicities in certain patients. Another surprising observation from this study is that there was no apparent difference in clinical activity between the groups with ADVEXIN alone and ADVEXIN plus cisplatin. One possible explanation for this result is that cisplatin may affect induction of systemic immune response against mutant-p53–expressing tumor cells triggered by ADVEXIN. Support for this hypothesis is found in the reduced levels of anti-Ad5 antibodies in the high- dose ADVEXIN plus cisplatin group compared with high-dose ADVEXIN as monotherapy. Furthermore, the study was not powered to identify differences in these groups.
In conclusion, this study demonstrates that repeated intratumoral injections of ADVEXIN in combination with or without cisplatin are feasible and well tolerated in Japanese patients. Despite undergoing more treatment cycles than other trials, patients experienced no severe toxicities and exhibited a long-term clinical activity (
Although all authors completed the disclosure declaration, the following author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)
Adenoviral p53: The E1- and E3-deleted, replication-deficient adenovirus vector encoding for the wild-type p53 tumor suppressor gene. Apoptosis: Also called programmed cell death, it is a signaling pathway that leads to cellular suicide in an organized manner. Several factors and receptors are specific to the apoptotic pathway. The net result is that cells shrink, develop blebs on their surface, and their DNA undergoes fragmentation. Bystander effect: The biologically positive response observed in untreated cells when neighboring cells are treated. Because of the bystander effect, the magnitude of the therapeutic response exceeds the effect expected from direct target-cell treatment, illustrating that the treatment not only induces direct cytotoxic effects against the individual target cell but also causes the growth suppression of bystander, untreated cells via other mechanisms. CPE (cytopathic effect): Viruses can infect target cells and cause cell death, referred to as the CPE. A CPE assay can be used to determine the titer of viral stocks. Noxa: Noxa is a proapoptotic member of the Bcl-2 family, which contains the Bcl-2 homology 3 (BH3) region, but lacks other BH domains. Noxa functions as an early response gene and a mediator of p53-induced apoptosis. In human cells, Noxa is also designated as PMA-induced protein 1 or APR. p21: The cyclin-dependent kinase inhibitor p21Cip1 inhibits cell-cycle progression by binding to cyclin/CDK complexes and arresting cells in the G1 phase of the cell cycle. p53: The normal function of p53 is to act as a transcriptional activator of genes with a p53-binding site and an inhibitor of genes lacking a p53 binding site. Expression of high levels of wild-type p53 is associated with cell cycle arrest and apoptosis. Mutations in p53 are seen in several tumors. p53AIP1 (p53-regulated, apoptosis-inducing protein 1): p53AIP1 is a tumor suppressor gene that localizes to the mitochondria and regulates mitochondrial membrane potential. RT-PCR (reverse-transcriptase polymerase chain reaction): PCR is a method that allows logarithmic amplification of short DNA sequences within a longer, double-stranded DNA molecule. Gene expression can be measured after extraction of total RNA and preparation of cDNA by a reverse-transcription step. Thus, RT-PCR enables the detection of PCR products on a real-time basis, making it a sensitive technique for quantitating changes in gene expression. Tumor suppressor gene: A gene whose protein product is responsible for antiproliferative signals. The retinoblastoma gene product and the product of the p53 gene are two examples of tumor suppressor genes.
We thank Masafumi Kataoka, MD, Kazuhiko Kataoka, MD, and Osamu Kawamata, MD, for study support; Yoshiko Shirakiya for technical assistance; and Atsushi Nakamura and Takeo Ozawa for study management and monitoring. More importantly, we thank all patients for their courage and cooperation.
Supported by grants from the Ministry of Education, Science, and Culture, Japan; and by grants from the Ministry of Health, Labour, and Welfare, Japan. Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Waku T, Fujiwara T, Shao J, et al: Contribution of CD95 ligand-induced neutrophil infiltration to the bystander effect in p53 gene therapy for human cancer. J Immunol 165:5884-5890, 2000 18. Swisher SG, Roth JA, Nemunaitis J, et al: Adenovirus-mediated p53 gene transfer in advanced non–small-cell lung cancer. J Natl Cancer Inst 91:763-771, 1999 19. Nemunaitis J, Swisher SG, Timmons T, et al: Adenovirus-mediated p53 gene transfer in sequence with cisplatin to tumors of patients with non–small-cell lung cancer. J Clin Oncol 18:609-622, 2000 20. Swisher SG, Roth JA, Komaki R, et al: Induction of p53-regulated genes and tumor regression in lung cancer patients after intratumoral delivery of adenoviral p53 (INGN 201) and radiation therapy. Clin Cancer Res 9:93-101, 2003 21. Zhang WW, Fang X, Mazur W, et al: High efficiency gene transfer and high-level expression of wildtype p53 in human lung cancer cells mediated by recombinant adenovirus. Cancer Gene Ther 1:5-13, 1994 22. Schuler M, Herrmann R, De Greve JL, et al: Adenovirus-mediated wild-type p53 gene transfer in patients receiving chemotherapy for advanced non-small-cell lung cancer: Results of a multicenter phase II study. J Clin Oncol 19:1750-1758, 2001 23. Clayman GL, el-Naggar AK, Lippman SM, et al: Adenovirus-mediated p53 gene transfer in patients with advanced recurrent head and neck squamous cell carcinoma. J Clin Oncol 16:2221-2232, 1998[Abstract] 24. Kuball J, Wen SF, Leissner J, et al: Successful adenovirus-mediated wild-type p53 gene transfer in patients with bladder cancer by intravesical vector instillation. J Clin Oncol 20:957-965, 2002 25. Pagliaro LC, Keyhani A, Williams D, et al: Repeated intravesical instillations of an adenoviral vector in patients with locally advanced bladder cancer: A phase I study of p53 gene therapy. J Clin Oncol 21:2247-2253, 2003 26. Lang FF, Bruner JM, Fuller GN, et al: Phase I trial of adenovirus-mediated p53 gene therapy for recurrent glioma: Biological and clinical results. J Clin Oncol 21:2508-2518, 2003 27. Buller RE, Runnebaum IB, Karlan BY, et al: A phase I/II trial of rAd/p53 (SCH 58500) gene replacement in recurrent ovarian cancer. Cancer Gene Ther 9:553-566, 2002[CrossRef][Medline] 28. Fukuoka M, Yano S, Giaccone G, et al: Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (The IDEAL 1 Trial). J Clin Oncol 21:2237-2246, 2003 29. Vasey PA, Shulman LN, Campos S, et al: Phase I trial of intraperitoneal injection of the E1B-55-kd-gene-deleted adenovirus ONYX-015 (dl1520) given on days 1 through 5 every 3 weeks in patients with recurrent/refractory epithelial ovarian cancer. J Clin Oncol 20:1562-1569, 2002 30. Hamid O, Varterasian ML, Wadler S, et al: Phase II trial of intravenous CI-1042 in patients with metastatic colorectal cancer. J Clin Oncol 21:1498-1504, 2003 31. Matsukura N, Hoshino A, Igarashi T, et al: In situ gene transfer and suicide gene therapy of gastric cancer induced by N-ethyl-N'-nitro-N-nitrosoguanidine in dogs. Jpn J Cancer Res 90:1039-1049, 1999 32. Mitsudomi T, Suzuki S, Yatabe Y, et al: Clinical implications of p53 autoantibodies in the sera of patients with non-small-cell lung cancer. J Natl Cancer Inst 90:1563-1568, 1998 Submitted August 1, 2005; accepted December 8, 2005.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
1:20) neutralizing antibody titers, and the other eight patients had titers ranging from 1:20 to 1:320. Titers of specimens collected at 4 weeks after the first injection of ADVEXIN were higher than the titers at baseline in 13 of 14 (92.9%) assessable patients, although the magnitude of increase in titer varied (
9 months in 20% of patients). Therefore, it seems to be reasonable to explore the antitumor effect of this virus in patients with earlier-stage disease. This study provides support for the ongoing randomized phase III trials to identify the therapeutic benefit of ADVEXIN in squamous cell carcinoma of the head and neck and suggest that additional evaluations for NSCLC in phase II/III trials with appropriate controls are warranted. 
B activity and synergizes with aspirin to induce apoptosis in human colon cancer cells. Oncogene 19:726-736, 2000
