Immunotherapy of advanced malignancy by direct gene transfer of an interleukin-2 DNA/DMRIE/DOPE lipid complex: Phase I/II experience

Evanthia Galanis, Evan M Hersh, Alison T Stopeck, R. Gonzalez, P. Burch, Catherine S Perry, E. T. Akporiaye, J. J. Rinehart, J. Edmonson, R. E. Sobol, C. Forscher, V. K. Sondak, B. D. Lewis, Evan C Unger, M. O'Driscoll, L. Selk, J. Rubin

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Abstract

Purpose: We have completed a phase I study, followed by three phase I/II studies, in patients with metastatic melanoma, renal cell carcinoma (RCC), and sarcoma in order to evaluate the safety, toxicity, and antitumor activity of Leuvectin (Vical Inc, San Diego, CA), a gene transfer product containing a plasmid encoding human interleukin (IL)-2 formulated with the cationic lipid 1,2-dimyristyloxypropyl-3-dimethyl-hydroxyethyl ammonium bromide/dioleyl- phosphatidyl-ethanolamine (DMRIE/DOPE) and administered intratumorally. Patients and Methods: Twenty-four patients were treated in the phase I study. Leuvectin doses were 10 μg, 30 μg, or 300 μg weekly for 6 weeks. In three subsequent phase I/II studies, a total of 52 patients (18 with melanoma, 17 with RCC, and 17 with sarcoma) were treated with further escalating doses of Leuvectin: 300 μg twice a week for 3 weeks, 750 μg weekly for 6 weeks, and 1,500 μg weekly for 6 weeks. Results: There were no drug-related grade 4 toxicities and only one grade 3 toxicity, but the majority of patients experienced mild constitutional symptoms after treatment. In the phase I/II studies, 45 patients were assessable for response (14 with RCC, 16 with melanoma, and 15 with sarcoma). Two patients with RCC and one with melanoma have achieved partial responses lasting from 16 to 19 months and continuing. In addition, two RCC, three melanoma, and six sarcoma patients had stable disease lasting from 3 to 18 months and continuing. The plasmid was detected by polymerase chain reaction assay in the posttreatment samples of 29 of 46 evaluated patients. Immunohistochemistry studies on serial biopsy specimens showed increased IL-2 expression and CD8+ infiltration after treatment in the tumor samples of several patients (12 and 16, respectively). Conclusion: Direct intratumoral injection of Leuvectin is a safe and possibly effective immunotherapeutic approach in the treatment of certain tumor types.

Original languageEnglish (US)
Pages (from-to)3313-3323
Number of pages11
JournalJournal of Clinical Oncology
Volume17
Issue number10
StatePublished - Oct 1999

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Ethanolamine
Immunotherapy
Interleukin-2
Lipids
DNA
Renal Cell Carcinoma
Genes
Melanoma
Neoplasms
Sarcoma
Plasmids
ammonium bromide
Therapeutics
Immunohistochemistry
Biopsy
Safety
Polymerase Chain Reaction
Injections

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Immunotherapy of advanced malignancy by direct gene transfer of an interleukin-2 DNA/DMRIE/DOPE lipid complex : Phase I/II experience. / Galanis, Evanthia; Hersh, Evan M; Stopeck, Alison T; Gonzalez, R.; Burch, P.; Perry, Catherine S; Akporiaye, E. T.; Rinehart, J. J.; Edmonson, J.; Sobol, R. E.; Forscher, C.; Sondak, V. K.; Lewis, B. D.; Unger, Evan C; O'Driscoll, M.; Selk, L.; Rubin, J.

In: Journal of Clinical Oncology, Vol. 17, No. 10, 10.1999, p. 3313-3323.

Research output: Contribution to journalArticle

Galanis, E, Hersh, EM, Stopeck, AT, Gonzalez, R, Burch, P, Perry, CS, Akporiaye, ET, Rinehart, JJ, Edmonson, J, Sobol, RE, Forscher, C, Sondak, VK, Lewis, BD, Unger, EC, O'Driscoll, M, Selk, L & Rubin, J 1999, 'Immunotherapy of advanced malignancy by direct gene transfer of an interleukin-2 DNA/DMRIE/DOPE lipid complex: Phase I/II experience', Journal of Clinical Oncology, vol. 17, no. 10, pp. 3313-3323.
Galanis, Evanthia ; Hersh, Evan M ; Stopeck, Alison T ; Gonzalez, R. ; Burch, P. ; Perry, Catherine S ; Akporiaye, E. T. ; Rinehart, J. J. ; Edmonson, J. ; Sobol, R. E. ; Forscher, C. ; Sondak, V. K. ; Lewis, B. D. ; Unger, Evan C ; O'Driscoll, M. ; Selk, L. ; Rubin, J. / Immunotherapy of advanced malignancy by direct gene transfer of an interleukin-2 DNA/DMRIE/DOPE lipid complex : Phase I/II experience. In: Journal of Clinical Oncology. 1999 ; Vol. 17, No. 10. pp. 3313-3323.
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abstract = "Purpose: We have completed a phase I study, followed by three phase I/II studies, in patients with metastatic melanoma, renal cell carcinoma (RCC), and sarcoma in order to evaluate the safety, toxicity, and antitumor activity of Leuvectin (Vical Inc, San Diego, CA), a gene transfer product containing a plasmid encoding human interleukin (IL)-2 formulated with the cationic lipid 1,2-dimyristyloxypropyl-3-dimethyl-hydroxyethyl ammonium bromide/dioleyl- phosphatidyl-ethanolamine (DMRIE/DOPE) and administered intratumorally. Patients and Methods: Twenty-four patients were treated in the phase I study. Leuvectin doses were 10 μg, 30 μg, or 300 μg weekly for 6 weeks. In three subsequent phase I/II studies, a total of 52 patients (18 with melanoma, 17 with RCC, and 17 with sarcoma) were treated with further escalating doses of Leuvectin: 300 μg twice a week for 3 weeks, 750 μg weekly for 6 weeks, and 1,500 μg weekly for 6 weeks. Results: There were no drug-related grade 4 toxicities and only one grade 3 toxicity, but the majority of patients experienced mild constitutional symptoms after treatment. In the phase I/II studies, 45 patients were assessable for response (14 with RCC, 16 with melanoma, and 15 with sarcoma). Two patients with RCC and one with melanoma have achieved partial responses lasting from 16 to 19 months and continuing. In addition, two RCC, three melanoma, and six sarcoma patients had stable disease lasting from 3 to 18 months and continuing. The plasmid was detected by polymerase chain reaction assay in the posttreatment samples of 29 of 46 evaluated patients. Immunohistochemistry studies on serial biopsy specimens showed increased IL-2 expression and CD8+ infiltration after treatment in the tumor samples of several patients (12 and 16, respectively). Conclusion: Direct intratumoral injection of Leuvectin is a safe and possibly effective immunotherapeutic approach in the treatment of certain tumor types.",
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T1 - Immunotherapy of advanced malignancy by direct gene transfer of an interleukin-2 DNA/DMRIE/DOPE lipid complex

T2 - Phase I/II experience

AU - Galanis, Evanthia

AU - Hersh, Evan M

AU - Stopeck, Alison T

AU - Gonzalez, R.

AU - Burch, P.

AU - Perry, Catherine S

AU - Akporiaye, E. T.

AU - Rinehart, J. J.

AU - Edmonson, J.

AU - Sobol, R. E.

AU - Forscher, C.

AU - Sondak, V. K.

AU - Lewis, B. D.

AU - Unger, Evan C

AU - O'Driscoll, M.

AU - Selk, L.

AU - Rubin, J.

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N2 - Purpose: We have completed a phase I study, followed by three phase I/II studies, in patients with metastatic melanoma, renal cell carcinoma (RCC), and sarcoma in order to evaluate the safety, toxicity, and antitumor activity of Leuvectin (Vical Inc, San Diego, CA), a gene transfer product containing a plasmid encoding human interleukin (IL)-2 formulated with the cationic lipid 1,2-dimyristyloxypropyl-3-dimethyl-hydroxyethyl ammonium bromide/dioleyl- phosphatidyl-ethanolamine (DMRIE/DOPE) and administered intratumorally. Patients and Methods: Twenty-four patients were treated in the phase I study. Leuvectin doses were 10 μg, 30 μg, or 300 μg weekly for 6 weeks. In three subsequent phase I/II studies, a total of 52 patients (18 with melanoma, 17 with RCC, and 17 with sarcoma) were treated with further escalating doses of Leuvectin: 300 μg twice a week for 3 weeks, 750 μg weekly for 6 weeks, and 1,500 μg weekly for 6 weeks. Results: There were no drug-related grade 4 toxicities and only one grade 3 toxicity, but the majority of patients experienced mild constitutional symptoms after treatment. In the phase I/II studies, 45 patients were assessable for response (14 with RCC, 16 with melanoma, and 15 with sarcoma). Two patients with RCC and one with melanoma have achieved partial responses lasting from 16 to 19 months and continuing. In addition, two RCC, three melanoma, and six sarcoma patients had stable disease lasting from 3 to 18 months and continuing. The plasmid was detected by polymerase chain reaction assay in the posttreatment samples of 29 of 46 evaluated patients. Immunohistochemistry studies on serial biopsy specimens showed increased IL-2 expression and CD8+ infiltration after treatment in the tumor samples of several patients (12 and 16, respectively). Conclusion: Direct intratumoral injection of Leuvectin is a safe and possibly effective immunotherapeutic approach in the treatment of certain tumor types.

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