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Combined immunotherapy with controlled interleukin-12 gene therapy and immune checkpoint blockade in recurrent glioblastoma: An open-label, multi-institutional phase I trial.
Chiocca, E Antonio; Gelb, Arnold B; Chen, Clark C; Rao, Ganesh; Reardon, David A; Wen, Patrick Y; Bi, Wenya Linda; Peruzzi, Pierpaolo; Amidei, Christina; Triggs, Dan; Seften, Leah; Park, Grace; Grant, James; Truman, Kyla; Buck, Jill Y; Hadar, Nira; Demars, Nathan; Miao, John; Estupinan, Taylor; Loewy, John; Chadha, Kamal; Tringali, Joseph; Cooper, Laurence; Lukas, Rimas V.
Afiliação
  • Chiocca EA; Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
  • Gelb AB; Ziopharm Oncology, Inc., Boston, Massachusetts, USA.
  • Chen CC; University of Minnesota, Minneapolis, Minnesota, USA.
  • Rao G; Baylor College of Medicine, Houston, Texas, USA.
  • Reardon DA; Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
  • Wen PY; Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
  • Bi WL; Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
  • Peruzzi P; Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
  • Amidei C; Northwestern Memorial Hospital, Chicago, Illinois, USA.
  • Triggs D; Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
  • Seften L; Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
  • Park G; Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
  • Grant J; Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
  • Truman K; Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
  • Buck JY; Ziopharm Oncology, Inc., Boston, Massachusetts, USA.
  • Hadar N; Ziopharm Oncology, Inc., Boston, Massachusetts, USA.
  • Demars N; Ziopharm Oncology, Inc., Boston, Massachusetts, USA.
  • Miao J; Ziopharm Oncology, Inc., Boston, Massachusetts, USA.
  • Estupinan T; Ziopharm Oncology, Inc., Boston, Massachusetts, USA.
  • Loewy J; Ziopharm Oncology, Inc., Boston, Massachusetts, USA.
  • Chadha K; Ziopharm Oncology, Inc., Boston, Massachusetts, USA.
  • Tringali J; Ziopharm Oncology, Inc., Boston, Massachusetts, USA.
  • Cooper L; Ziopharm Oncology, Inc., Boston, Massachusetts, USA.
  • Lukas RV; Northwestern Memorial Hospital, Chicago, Illinois, USA.
Neuro Oncol ; 24(6): 951-963, 2022 06 01.
Article em En | MEDLINE | ID: mdl-34850166
BACKGROUND: Veledimex (VDX)-regulatable interleukin-12 (IL-12) gene therapy in recurrent glioblastoma (rGBM) was reported to show tumor infiltration of CD8+ T cells, encouraging survival, but also up-regulation of immune checkpoint signaling, providing the rationale for a combination trial with immune checkpoint inhibition. METHODS: An open-label, multi-institutional, dose-escalation phase I trial in rGBM subjects (NCT03636477) accrued 21 subjects in 3 dose-escalating cohorts: (1) neoadjuvant then ongoing nivolumab (1mg/kg) and VDX (10 mg) (n = 3); (2) neoadjuvant then ongoing nivolumab (3 mg/kg) and VDX (10 mg) (n = 3); and (3) neoadjuvant then ongoing nivolumab (3 mg/kg) and VDX (20 mg) (n = 15). Nivolumab was administered 7 (±3) days before resection of the rGBM followed by peritumoral injection of IL-12 gene therapy. VDX was administered 3 hours before and then for 14 days after surgery. Nivolumab was administered every two weeks after surgery. RESULTS: Toxicities of the combination were comparable to IL-12 gene monotherapy and were predictable, dose-related, and reversible upon withholding doses of VDX and/or nivolumab. VDX plasma pharmacokinetics demonstrate a dose-response relationship with effective brain tumor tissue VDX penetration and production of IL-12. IL-12 levels in serum peaked in all subjects at about Day 3 after surgery. Tumor IFNγ increased in post-treatment biopsies. Median overall survival (mOS) for VDX 10 mg with nivolumab was 16.9 months and for all subjects was 9.8 months. CONCLUSION: The safety of this combination immunotherapy was established and has led to an ongoing phase II clinical trial of immune checkpoint blockade with controlled IL-12 gene therapy (NCT04006119).
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Glioblastoma / Antineoplásicos Imunológicos Tipo de estudo: Clinical_trials / Prognostic_studies Limite: Humans Idioma: En Revista: Neuro Oncol Assunto da revista: NEOPLASIAS / NEUROLOGIA Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Glioblastoma / Antineoplásicos Imunológicos Tipo de estudo: Clinical_trials / Prognostic_studies Limite: Humans Idioma: En Revista: Neuro Oncol Assunto da revista: NEOPLASIAS / NEUROLOGIA Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Estados Unidos