Phase I study of gene-mediated cytotoxic immunotherapy with AdV-tk as adjuvant to surgery and radiation for pediatric malignant glioma and recurrent ependymoma

Mark W. Kieran*, Liliana Goumnerova, Peter Manley, Susan N. Chi, Karen J. Marcus, Andrea G. Manzanera, Maria Lucia Silva Polanco, Brian W. Guzik, Estuardo Aguilar-Cordova, C. Marcela Diaz-Montero, Arthur J DiPatri, Tadanori Tomita, Rishi Lulla, Lianne Greenspan, Laura K. Aguilar, Stewart Goldman

*Corresponding author for this work

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Background. Gene-mediated cytotoxic immunotherapy (GMCI) is a tumor-specific immune stimulatory strategy implemented through local delivery of aglatimagene besadenovec (AdV-tk) followed by anti-herpetic prodrug. GMCI induces T-cell dependent tumor immunity and synergizes with radiotherapy. Clinical trials in adult malignant gliomas demonstrated safety and potential efficacy. This is the first trial of GMCI in pediatric brain tumors. Methods. This phase I dose escalation study was conducted to evaluate GMCI in patients 3 years of age or older with malignant glioma or recurrent ependymoma. AdV-tk at doses of 1 × 1011 and 3 × 1011 vector particles (vp) was injected into the tumor bed at the time of surgery followed by 14 days of valacyclovir. Radiation started within 8 days of surgery, and if indicated, chemotherapy began after completion of valacyclovir. Results. Eight patients (6 glioblastoma, 1 anaplastic astrocytoma, 1 recurrent ependymoma) were enrolled and completed therapy: 3 on dose level 1 and 5 on dose level 2. Median age was 12.5 years (range 7-17) and Lansky/Karnofsky performance scores were 60-100. Five patients had multifocal/extensive tumors that could not be resected completely and 3 had gross total resection. There were no dose-limiting toxicities. The most common possibly GMCI-related adverse events included Common Terminology Criteria for Adverse Events grade 1-2 fever, fatigue, and nausea/vomiting. Three patients, in dose level 2, lived more than 24 months, with 2 alive without progression 37.3 and 47.7 months after AdV-tk injection. Conclusions. GMCI can be safely combined with radiation therapy with or without temozolomide in pediatric patients with brain tumors and the present results strongly support further investigation. Clinical trial registry. ClinicalTrials.gov NCT00634231.

Original languageEnglish (US)
Pages (from-to)537-546
Number of pages10
JournalNeuro-oncology
Volume21
Issue number4
DOIs
StatePublished - Mar 18 2019

Fingerprint

Ependymoma
Glioma
Immunotherapy
valacyclovir
Radiation
Pediatrics
Genes
temozolomide
Brain Neoplasms
Neoplasms
Radiotherapy
Clinical Trials
Astrocytoma
Prodrugs
Glioblastoma
Ambulatory Surgical Procedures
Terminology
Nausea
Vomiting
Fatigue

Keywords

  • gene therapy
  • glioblastoma
  • immunooncology
  • immunotherapy
  • viral therapy

ASJC Scopus subject areas

  • Oncology
  • Clinical Neurology
  • Cancer Research

Cite this

Kieran, Mark W. ; Goumnerova, Liliana ; Manley, Peter ; Chi, Susan N. ; Marcus, Karen J. ; Manzanera, Andrea G. ; Polanco, Maria Lucia Silva ; Guzik, Brian W. ; Aguilar-Cordova, Estuardo ; Diaz-Montero, C. Marcela ; DiPatri, Arthur J ; Tomita, Tadanori ; Lulla, Rishi ; Greenspan, Lianne ; Aguilar, Laura K. ; Goldman, Stewart. / Phase I study of gene-mediated cytotoxic immunotherapy with AdV-tk as adjuvant to surgery and radiation for pediatric malignant glioma and recurrent ependymoma. In: Neuro-oncology. 2019 ; Vol. 21, No. 4. pp. 537-546.
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abstract = "Background. Gene-mediated cytotoxic immunotherapy (GMCI) is a tumor-specific immune stimulatory strategy implemented through local delivery of aglatimagene besadenovec (AdV-tk) followed by anti-herpetic prodrug. GMCI induces T-cell dependent tumor immunity and synergizes with radiotherapy. Clinical trials in adult malignant gliomas demonstrated safety and potential efficacy. This is the first trial of GMCI in pediatric brain tumors. Methods. This phase I dose escalation study was conducted to evaluate GMCI in patients 3 years of age or older with malignant glioma or recurrent ependymoma. AdV-tk at doses of 1 × 1011 and 3 × 1011 vector particles (vp) was injected into the tumor bed at the time of surgery followed by 14 days of valacyclovir. Radiation started within 8 days of surgery, and if indicated, chemotherapy began after completion of valacyclovir. Results. Eight patients (6 glioblastoma, 1 anaplastic astrocytoma, 1 recurrent ependymoma) were enrolled and completed therapy: 3 on dose level 1 and 5 on dose level 2. Median age was 12.5 years (range 7-17) and Lansky/Karnofsky performance scores were 60-100. Five patients had multifocal/extensive tumors that could not be resected completely and 3 had gross total resection. There were no dose-limiting toxicities. The most common possibly GMCI-related adverse events included Common Terminology Criteria for Adverse Events grade 1-2 fever, fatigue, and nausea/vomiting. Three patients, in dose level 2, lived more than 24 months, with 2 alive without progression 37.3 and 47.7 months after AdV-tk injection. Conclusions. GMCI can be safely combined with radiation therapy with or without temozolomide in pediatric patients with brain tumors and the present results strongly support further investigation. Clinical trial registry. ClinicalTrials.gov NCT00634231.",
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Kieran, MW, Goumnerova, L, Manley, P, Chi, SN, Marcus, KJ, Manzanera, AG, Polanco, MLS, Guzik, BW, Aguilar-Cordova, E, Diaz-Montero, CM, DiPatri, AJ, Tomita, T, Lulla, R, Greenspan, L, Aguilar, LK & Goldman, S 2019, 'Phase I study of gene-mediated cytotoxic immunotherapy with AdV-tk as adjuvant to surgery and radiation for pediatric malignant glioma and recurrent ependymoma', Neuro-oncology, vol. 21, no. 4, pp. 537-546. https://doi.org/10.1093/neuonc/noy202

Phase I study of gene-mediated cytotoxic immunotherapy with AdV-tk as adjuvant to surgery and radiation for pediatric malignant glioma and recurrent ependymoma. / Kieran, Mark W.; Goumnerova, Liliana; Manley, Peter; Chi, Susan N.; Marcus, Karen J.; Manzanera, Andrea G.; Polanco, Maria Lucia Silva; Guzik, Brian W.; Aguilar-Cordova, Estuardo; Diaz-Montero, C. Marcela; DiPatri, Arthur J; Tomita, Tadanori; Lulla, Rishi; Greenspan, Lianne; Aguilar, Laura K.; Goldman, Stewart.

In: Neuro-oncology, Vol. 21, No. 4, 18.03.2019, p. 537-546.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Phase I study of gene-mediated cytotoxic immunotherapy with AdV-tk as adjuvant to surgery and radiation for pediatric malignant glioma and recurrent ependymoma

AU - Kieran, Mark W.

AU - Goumnerova, Liliana

AU - Manley, Peter

AU - Chi, Susan N.

AU - Marcus, Karen J.

AU - Manzanera, Andrea G.

AU - Polanco, Maria Lucia Silva

AU - Guzik, Brian W.

AU - Aguilar-Cordova, Estuardo

AU - Diaz-Montero, C. Marcela

AU - DiPatri, Arthur J

AU - Tomita, Tadanori

AU - Lulla, Rishi

AU - Greenspan, Lianne

AU - Aguilar, Laura K.

AU - Goldman, Stewart

PY - 2019/3/18

Y1 - 2019/3/18

N2 - Background. Gene-mediated cytotoxic immunotherapy (GMCI) is a tumor-specific immune stimulatory strategy implemented through local delivery of aglatimagene besadenovec (AdV-tk) followed by anti-herpetic prodrug. GMCI induces T-cell dependent tumor immunity and synergizes with radiotherapy. Clinical trials in adult malignant gliomas demonstrated safety and potential efficacy. This is the first trial of GMCI in pediatric brain tumors. Methods. This phase I dose escalation study was conducted to evaluate GMCI in patients 3 years of age or older with malignant glioma or recurrent ependymoma. AdV-tk at doses of 1 × 1011 and 3 × 1011 vector particles (vp) was injected into the tumor bed at the time of surgery followed by 14 days of valacyclovir. Radiation started within 8 days of surgery, and if indicated, chemotherapy began after completion of valacyclovir. Results. Eight patients (6 glioblastoma, 1 anaplastic astrocytoma, 1 recurrent ependymoma) were enrolled and completed therapy: 3 on dose level 1 and 5 on dose level 2. Median age was 12.5 years (range 7-17) and Lansky/Karnofsky performance scores were 60-100. Five patients had multifocal/extensive tumors that could not be resected completely and 3 had gross total resection. There were no dose-limiting toxicities. The most common possibly GMCI-related adverse events included Common Terminology Criteria for Adverse Events grade 1-2 fever, fatigue, and nausea/vomiting. Three patients, in dose level 2, lived more than 24 months, with 2 alive without progression 37.3 and 47.7 months after AdV-tk injection. Conclusions. GMCI can be safely combined with radiation therapy with or without temozolomide in pediatric patients with brain tumors and the present results strongly support further investigation. Clinical trial registry. ClinicalTrials.gov NCT00634231.

AB - Background. Gene-mediated cytotoxic immunotherapy (GMCI) is a tumor-specific immune stimulatory strategy implemented through local delivery of aglatimagene besadenovec (AdV-tk) followed by anti-herpetic prodrug. GMCI induces T-cell dependent tumor immunity and synergizes with radiotherapy. Clinical trials in adult malignant gliomas demonstrated safety and potential efficacy. This is the first trial of GMCI in pediatric brain tumors. Methods. This phase I dose escalation study was conducted to evaluate GMCI in patients 3 years of age or older with malignant glioma or recurrent ependymoma. AdV-tk at doses of 1 × 1011 and 3 × 1011 vector particles (vp) was injected into the tumor bed at the time of surgery followed by 14 days of valacyclovir. Radiation started within 8 days of surgery, and if indicated, chemotherapy began after completion of valacyclovir. Results. Eight patients (6 glioblastoma, 1 anaplastic astrocytoma, 1 recurrent ependymoma) were enrolled and completed therapy: 3 on dose level 1 and 5 on dose level 2. Median age was 12.5 years (range 7-17) and Lansky/Karnofsky performance scores were 60-100. Five patients had multifocal/extensive tumors that could not be resected completely and 3 had gross total resection. There were no dose-limiting toxicities. The most common possibly GMCI-related adverse events included Common Terminology Criteria for Adverse Events grade 1-2 fever, fatigue, and nausea/vomiting. Three patients, in dose level 2, lived more than 24 months, with 2 alive without progression 37.3 and 47.7 months after AdV-tk injection. Conclusions. GMCI can be safely combined with radiation therapy with or without temozolomide in pediatric patients with brain tumors and the present results strongly support further investigation. Clinical trial registry. ClinicalTrials.gov NCT00634231.

KW - gene therapy

KW - glioblastoma

KW - immunooncology

KW - immunotherapy

KW - viral therapy

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U2 - 10.1093/neuonc/noy202

DO - 10.1093/neuonc/noy202

M3 - Article

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SP - 537

EP - 546

JO - Neuro-Oncology

JF - Neuro-Oncology

SN - 1522-8517

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