Adenovirus-mediated p53 gene transfer in sequence with cisplatin to tumors of patients with non-small-cell lung cancer

J. Nemunaitis, S. G. Swisher, T. Timmons, D. Connors, M. Mack, L. Doerksen, D. Weill, J. Wait, D. D. Lawrence, B. L. Kemp, F. Fossella, B. S. Glisson, W. K. Hong, F. R. Khuri, J. M. Kurie, J. J. Lee, J. S. Lee, D. M. Nguyen, J. C. Nesbitt, Roman Perez-Soler & 6 others K. M W Pisters, J. B. Putnam, W. R. Richli, D. M. Shin, G. L. Walsh, J. Roth

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Abstract

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 x 106 to 1 x 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 deoxynucleotidyltransferase-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 patients (median age, 64 years) received a total of 83 intratumor injections with Adp53. The maximum dose administered was 1 x 1011 PFU per dose. Transient fever related to Adp53 injection developed in eight of 24 patients. Seventeen patients achieved a best clinical response of stable disease, two patients achieved a partial response, four patients had progressive disease, and one patient was not assessable. A mean apoptotic index between baseline and follow-up measurements increased from 0.010 to 0.044 (P = .011). Intratumor transgene mRNA was identified in 43% of assessable patients. Conclusion: Intratumoral injection with Adp53 in combination with cisplatin is well tolerated, and there is evidence of clinical activity. (C) 2000 by American Society of Clinical Oncology.

Original languageEnglish (US)
Pages (from-to)609-622
Number of pages14
JournalJournal of Clinical Oncology
Volume18
Issue number3
StatePublished - Feb 2000
Externally publishedYes

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p53 Genes
Adenoviridae
Non-Small Cell Lung Carcinoma
Cisplatin
Neoplasms
Injections
DNA Nucleotidylexotransferase
Reverse Transcriptase Polymerase Chain Reaction
Transgenes
Antibody Formation
Fever
Enzyme-Linked Immunosorbent Assay
Apoptosis
Safety
Polymerase Chain Reaction
Messenger RNA

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Nemunaitis, J., Swisher, S. G., Timmons, T., Connors, D., Mack, M., Doerksen, L., ... Roth, J. (2000). Adenovirus-mediated p53 gene transfer in sequence with cisplatin to tumors of patients with non-small-cell lung cancer. Journal of Clinical Oncology, 18(3), 609-622.

Adenovirus-mediated p53 gene transfer in sequence with cisplatin to tumors of patients with non-small-cell lung cancer. / Nemunaitis, J.; Swisher, S. G.; Timmons, T.; Connors, D.; Mack, M.; Doerksen, L.; Weill, D.; Wait, J.; Lawrence, D. D.; Kemp, B. L.; Fossella, F.; Glisson, B. S.; Hong, W. K.; Khuri, F. R.; Kurie, J. M.; Lee, J. J.; Lee, J. S.; Nguyen, D. M.; Nesbitt, J. C.; Perez-Soler, Roman; Pisters, K. M W; Putnam, J. B.; Richli, W. R.; Shin, D. M.; Walsh, G. L.; Roth, J.

In: Journal of Clinical Oncology, Vol. 18, No. 3, 02.2000, p. 609-622.

Research output: Contribution to journalArticle

Nemunaitis, J, Swisher, SG, Timmons, T, Connors, D, Mack, M, Doerksen, L, Weill, D, Wait, J, Lawrence, DD, Kemp, BL, Fossella, F, Glisson, BS, Hong, WK, Khuri, FR, Kurie, JM, Lee, JJ, Lee, JS, Nguyen, DM, Nesbitt, JC, Perez-Soler, R, Pisters, KMW, Putnam, JB, Richli, WR, Shin, DM, Walsh, GL & Roth, J 2000, 'Adenovirus-mediated p53 gene transfer in sequence with cisplatin to tumors of patients with non-small-cell lung cancer', Journal of Clinical Oncology, vol. 18, no. 3, pp. 609-622.
Nemunaitis J, Swisher SG, Timmons T, Connors D, Mack M, Doerksen L et al. Adenovirus-mediated p53 gene transfer in sequence with cisplatin to tumors of patients with non-small-cell lung cancer. Journal of Clinical Oncology. 2000 Feb;18(3):609-622.
Nemunaitis, J. ; Swisher, S. G. ; Timmons, T. ; Connors, D. ; Mack, M. ; Doerksen, L. ; Weill, D. ; Wait, J. ; Lawrence, D. D. ; Kemp, B. L. ; Fossella, F. ; Glisson, B. S. ; Hong, W. K. ; Khuri, F. R. ; Kurie, J. M. ; Lee, J. J. ; Lee, J. S. ; Nguyen, D. M. ; Nesbitt, J. C. ; Perez-Soler, Roman ; Pisters, K. M W ; Putnam, J. B. ; Richli, W. R. ; Shin, D. M. ; Walsh, G. L. ; Roth, J. / Adenovirus-mediated p53 gene transfer in sequence with cisplatin to tumors of patients with non-small-cell lung cancer. In: Journal of Clinical Oncology. 2000 ; Vol. 18, No. 3. pp. 609-622.
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abstract = "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 x 106 to 1 x 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 deoxynucleotidyltransferase-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 patients (median age, 64 years) received a total of 83 intratumor injections with Adp53. The maximum dose administered was 1 x 1011 PFU per dose. Transient fever related to Adp53 injection developed in eight of 24 patients. Seventeen patients achieved a best clinical response of stable disease, two patients achieved a partial response, four patients had progressive disease, and one patient was not assessable. A mean apoptotic index between baseline and follow-up measurements increased from 0.010 to 0.044 (P = .011). Intratumor transgene mRNA was identified in 43{\%} of assessable patients. Conclusion: Intratumoral injection with Adp53 in combination with cisplatin is well tolerated, and there is evidence of clinical activity. (C) 2000 by American Society of Clinical Oncology.",
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T1 - Adenovirus-mediated p53 gene transfer in sequence with cisplatin to tumors of patients with non-small-cell lung cancer

AU - Nemunaitis, J.

AU - Swisher, S. G.

AU - Timmons, T.

AU - Connors, D.

AU - Mack, M.

AU - Doerksen, L.

AU - Weill, D.

AU - Wait, J.

AU - Lawrence, D. D.

AU - Kemp, B. L.

AU - Fossella, F.

AU - Glisson, B. S.

AU - Hong, W. K.

AU - Khuri, F. R.

AU - Kurie, J. M.

AU - Lee, J. J.

AU - Lee, J. S.

AU - Nguyen, D. M.

AU - Nesbitt, J. C.

AU - Perez-Soler, Roman

AU - Pisters, K. M W

AU - Putnam, J. B.

AU - Richli, W. R.

AU - Shin, D. M.

AU - Walsh, G. L.

AU - Roth, J.

PY - 2000/2

Y1 - 2000/2

N2 - 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 x 106 to 1 x 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 deoxynucleotidyltransferase-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 patients (median age, 64 years) received a total of 83 intratumor injections with Adp53. The maximum dose administered was 1 x 1011 PFU per dose. Transient fever related to Adp53 injection developed in eight of 24 patients. Seventeen patients achieved a best clinical response of stable disease, two patients achieved a partial response, four patients had progressive disease, and one patient was not assessable. A mean apoptotic index between baseline and follow-up measurements increased from 0.010 to 0.044 (P = .011). Intratumor transgene mRNA was identified in 43% of assessable patients. Conclusion: Intratumoral injection with Adp53 in combination with cisplatin is well tolerated, and there is evidence of clinical activity. (C) 2000 by American Society of Clinical Oncology.

AB - 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 x 106 to 1 x 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 deoxynucleotidyltransferase-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 patients (median age, 64 years) received a total of 83 intratumor injections with Adp53. The maximum dose administered was 1 x 1011 PFU per dose. Transient fever related to Adp53 injection developed in eight of 24 patients. Seventeen patients achieved a best clinical response of stable disease, two patients achieved a partial response, four patients had progressive disease, and one patient was not assessable. A mean apoptotic index between baseline and follow-up measurements increased from 0.010 to 0.044 (P = .011). Intratumor transgene mRNA was identified in 43% of assessable patients. Conclusion: Intratumoral injection with Adp53 in combination with cisplatin is well tolerated, and there is evidence of clinical activity. (C) 2000 by American Society of Clinical Oncology.

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