title: Vaccination with Irradiated Autologous Tumor Cells Mixed with Irradiated GM-K562 Cells Stimulates Antitumor Immunity and T Lymphocyte Activation in Patients with Recurrent Malignant Glioma.
abstract: Recurrent malignant glioma carries a dismal prognosis, and novel therapies are needed. We examined the feasibility and safety of vaccination with irradiated autologous glioma cells mixed with irradiated GM-K562 cells in patients undergoing craniotomy for recurrent malignant glioma.
  
  
  
  We initiated a phase I study examining the safety of 2 doses of GM-K562 cells mixed with autologous cells. Primary endpoints were feasibility and safety. Feasibility was defined as the ability for 60% of enrolled subjects to initiate vaccination. Dose-limiting toxicity was assessed via a 3+3 dose-escalation format, examining irradiated tumor cells mixed with 5 × 10(6) GM-K562 cells or 1 × 10(7) GM-K562 cells. Eligibility required a priori indication for resection of a recurrent high-grade glioma. We measured biological activity by measuring delayed type hypersensitivity (DTH) responses, humoral immunity against tumor-associated antigens, and T-lymphocyte activation.
  
  
  
  Eleven patients were enrolled. Sufficient numbers of autologous tumor cells were harvested in 10 patients, all of whom went on to receive vaccine. There were no dose-limiting toxicities. Vaccination strengthened DTH responses to irradiated autologous tumor cells in most patients, and vigorous humoral responses to tumor-associated angiogenic cytokines were seen as well. T-lymphocyte activation was seen with significantly increased expression of CTLA-4, PD-1, 4-1BB, and OX40 by CD4(+) cells and PD-1 and 4-1BB by CD8(+) cells. Activation was coupled with vaccine-associated increase in the frequency of regulatory CD4(+) T lymphocytes.
  
  
  
  Vaccination with irradiated autologous tumor cells mixed with GM-K562 cells is feasible, well tolerated, and active in patients with recurrent malignant glioma. Clin Cancer Res; 22(12); 2885-96. ©2016 AACR.
authors.affiliation: Department of Neurosurgery, Massachusetts General Hospital, Boston, Massachusetts. Cancer Center, Massachusetts General Hospital, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts. wcurry@mgh.harvard.edu.
authors.forename: William T
authors.initials: WT
authors.lastname: Curry
authors.affiliation: Department of Neurosurgery, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Ramana
authors.initials: R
authors.lastname: Gorrepati
authors.affiliation: Department of Medicine, Dana Farber Cancer Institute, Boston, Massachusetts. Department of Biomedicine, Aarhus University, Aarhus, Denmark.
authors.forename: Matthias
authors.initials: M
authors.lastname: Piesche
authors.affiliation: Cancer Vaccine Center, Dana Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Sasada
authors.affiliation: Department of Neurosurgery, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Pankaj
authors.initials: P
authors.lastname: Agarwalla
authors.affiliation: Department of Neurosurgery, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Pamela S
authors.initials: PS
authors.lastname: Jones
authors.affiliation: Cancer Center, Massachusetts General Hospital, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts.
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Gerstner
authors.affiliation: Harvard Medical School, Boston, Massachusetts. Department of Neurosurgery, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Alexandra J
authors.initials: AJ
authors.lastname: Golby
authors.affiliation: Cancer Center, Massachusetts General Hospital, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts.
authors.forename: Tracy T
authors.initials: TT
authors.lastname: Batchelor
authors.affiliation: Harvard Medical School, Boston, Massachusetts. Division of Neuro-oncology, Dana Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Patrick Y
authors.initials: PY
authors.lastname: Wen
authors.affiliation: Harvard Medical School, Boston, Massachusetts. Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Martin C
authors.initials: MC
authors.lastname: Mihm
authors.affiliation: Harvard Medical School, Boston, Massachusetts. Department of Medicine, Dana Farber Cancer Institute, Boston, Massachusetts. Cancer Vaccine Center, Dana Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Glenn
authors.initials: G
authors.lastname: Dranoff
mesh_terms: D053330:4-1BB Ligand / Q000096:biosynthesis; D000328:Adult; D000368:Aged; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D060908:CTLA-4 Antigen / Q000096:biosynthesis; D019496:Cancer Vaccines / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D005260:Female; D005909:Glioblastoma / Q000628:therapy*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis*; D006801:Humans; D020014:K562 Cells; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000628:therapy; D009368:Neoplasm Transplantation / Q000379:methods; D053278:OX40 Ligand / Q000096:biosynthesis; D061026:Programmed Cell Death 1 Receptor / Q000096:biosynthesis; D014182:Transplantation, Autologous; D014611:Vaccination
chemical_list: D053330:4-1BB Ligand; D060908:CTLA-4 Antigen; D019496:Cancer Vaccines; C000593794:GVAX vaccine; D053278:OX40 Ligand; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; C089251:TNFSF4 protein, human; D016178:Granulocyte-Macrophage Colony-Stimulating Factor