Glioblastoma-mediated Immune Dysfunction Limits CMV-specific T Cells and Therapeutic Responses: Results from a Phase I/II Trial

Clin Cancer Res. 2020 Jul 15;26(14):3565-3577. doi: 10.1158/1078-0432.CCR-20-0176. Epub 2020 Apr 16.

Abstract

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.

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • CD8-Positive T-Lymphocytes / immunology*
  • Cytomegalovirus / immunology
  • Cytomegalovirus / isolation & purification
  • Cytomegalovirus Infections / immunology
  • Cytomegalovirus Infections / mortality
  • Cytomegalovirus Infections / therapy*
  • Cytomegalovirus Infections / virology
  • Female
  • Glioblastoma / immunology
  • Glioblastoma / mortality
  • Glioblastoma / therapy*
  • Glioblastoma / virology
  • Humans
  • Immunotherapy, Adoptive / methods*
  • Leukapheresis
  • Lymphocyte Depletion / methods
  • Male
  • Middle Aged
  • Progression-Free Survival
  • Temozolomide / administration & dosage
  • Transplantation, Autologous / methods
  • Tumor Microenvironment / immunology
  • Viral Matrix Proteins / immunology*

Substances

  • Viral Matrix Proteins
  • cytomegalovirus matrix protein 65kDa
  • Temozolomide