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Glioblastoma-mediated Immune Dysfunction Limits CMV-specific T Cells and Therapeutic Responses: Results from a Phase I/II Trial.
Weathers, Shiao-Pei; Penas-Prado, Marta; Pei, Be-Lian; Ling, Xiaoyang; Kassab, Cynthia; Banerjee, Pinaki; Bdiwi, Mustafa; Shaim, Hila; Alsuliman, Abdullah; Shanley, Mayra; de Groot, John F; O'Brien, Barbara J; Harrison, Rebecca; Majd, Nazanin; Kamiya-Matsuoka, Carlos; Fuller, Gregory N; Huse, Jason T; Chi, Linda; Rao, Ganesh; Weinberg, Jeffrey S; Lang, Frederick F; Sawaya, Raymond; Shpall, Elizabeth J; Rezvani, Katayoun; Heimberger, Amy B.
Afiliação
  • Weathers SP; Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • Penas-Prado M; Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • Pei BL; Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • Ling X; Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • Kassab C; Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • Banerjee P; Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • Bdiwi M; Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • Shaim H; Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • Alsuliman A; Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • Shanley M; Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • de Groot JF; Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • O'Brien BJ; Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • Harrison R; Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • Majd N; Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • Kamiya-Matsuoka C; Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • Fuller GN; Department of Neuropathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • Huse JT; Department of Neuropathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • Chi L; Department of Radiology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • Rao G; Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • Weinberg JS; Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • Lang FF; Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • Sawaya R; Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • Shpall EJ; Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • Rezvani K; Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas. aheimber@mdanderson.org krezvani@mdanderson.org.
  • Heimberger AB; Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas. aheimber@mdanderson.org krezvani@mdanderson.org.
Clin Cancer Res ; 26(14): 3565-3577, 2020 07 15.
Article em En | MEDLINE | ID: mdl-32299815
PURPOSE: Cytomegalovirus (CMV) antigens occur in glioblastoma but not in normal brains, making them desirable immunologic targets. PATIENTS AND METHODS: Highly functional autologous polyclonal CMV pp65-specific T cells from patients with glioblastoma were numerically expanded under good manufacturing practice compliant conditions and administered after 3 weeks of lymphodepleting dose-dense temozolomide (100 mg/m2) treatment. The phase I component used a 3+3 design, ascending through four dose levels (5 × 106-1 × 108 cells). Treatment occurred every 6 weeks for four cycles. In vivo persistence and effector function of CMV-specific T cells was determined by dextramer staining and multiparameter flow cytometry in serially sampled peripheral blood and in the tumor microenvironment. RESULTS: We screened 65 patients; 41 were seropositive for CMV; 25 underwent leukapheresis; and 20 completed ≥1 cycle. No dose-limiting toxicities were observed. Radiographic response was complete in 1 patient, partial in 2. Median progression-free survival (PFS) time was 1.3 months [95% confidence interval (CI), 0-8.3 months]; 6-month PFS was 19% (95% CI, 7%-52%); and median overall survival time was 12 months (95% CI, 6 months to not reached). Repeated infusions of CMV-T cells paralleled significant increases in circulating CMV+ CD8+ T cells, but cytokine production showing effector activity was suppressed, especially from T cells obtained directly from glioblastomas. CONCLUSIONS: Adoptive infusion of CMV-specific T cells after lymphodepletion with dose-dense temozolomide was well tolerated. But apparently CMV seropositivity does not guarantee tumor susceptibility to CMV-specific T cells, suggesting heterogeneity in CMV antigen expression. Moreover, effector function of these T cells was attenuated, indicating a requirement for further T-cell modulation to prevent their dysfunction before conducting large-scale clinical studies.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Proteínas da Matriz Viral / Imunoterapia Adotiva / Infecções por Citomegalovirus / Glioblastoma / Linfócitos T CD8-Positivos Limite: Adult / Female / Humans / Male / Middle aged Idioma: En Ano de publicação: 2020 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Proteínas da Matriz Viral / Imunoterapia Adotiva / Infecções por Citomegalovirus / Glioblastoma / Linfócitos T CD8-Positivos Limite: Adult / Female / Humans / Male / Middle aged Idioma: En Ano de publicação: 2020 Tipo de documento: Article