Gene expression profile correlates with T-cell infiltration and relative survival in glioblastoma patients vaccinated with dendritic cell immunotherapy.
OBJECTIVE
To assess the feasibility, safety, and toxicity of autologous tumor lysate-pulsed dendritic cell (DC) vaccination and toll-like receptor (TLR) agonists in patients with newly diagnosed and recurrent glioblastoma. Clinical and immune responses were monitored and correlated with tumor gene expression profiles.


METHODS
Twenty-three patients with glioblastoma (WHO grade IV) were enrolled in this dose-escalation study and received three biweekly injections of glioma lysate-pulsed DCs followed by booster vaccinations with either imiquimod or poly-ICLC adjuvant every 3 months until tumor progression. Gene expression profiling, immunohistochemistry, FACS, and cytokine bead arrays were performed on patient tumors and peripheral blood mononuclear cells.


RESULTS
DC vaccinations are safe and not associated with any dose-limiting toxicity. The median overall survival from the time of initial surgical diagnosis of glioblastoma was 31.4 months, with a 1-, 2-, and 3-year survival rate of 91%, 55%, and 47%, respectively. Patients whose tumors had mesenchymal gene expression signatures exhibited increased survival following DC vaccination compared with historic controls of the same genetic subtype. Tumor samples with a mesenchymal gene expression signature had a higher number of CD3(+) and CD8(+) tumor-infiltrating lymphocytes compared with glioblastomas of other gene expression signatures (P = 0.006).


CONCLUSIONS
Autologous tumor lysate-pulsed DC vaccination in conjunction with TLR agonists is safe as adjuvant therapy in newly diagnosed and recurrent glioblastoma patients. Our results suggest that the mesenchymal gene expression profile may identify an immunogenic subgroup of glioblastoma that may be more responsive to immune-based therapies.
Department of Neurosurgery, Brain Research Institute, The Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, California 90095-6901, USA. rprins@mednet.ucla.edu
Robert M
RM
Prins
Horacio
H
Soto
Vera
V
Konkankit
Sylvia K
SK
Odesa
Ascia
A
Eskin
William H
WH
Yong
Stanley F
SF
Nelson
Linda M
LM
Liau
D000328:Adult; D000368:Aged; D017252:CD3 Complex / Q000096:biosynthesis; D016827:CD8 Antigens / Q000096:biosynthesis; D019496:Cancer Vaccines / Q000378:metabolism*; D002469:Cell Separation; D003713:Dendritic Cells / Q000166:cytology*; D005260:Female; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000401:mortality* / Q000628:therapy*; D005910:Glioma; D006801:Humans; D007107:Immune System; D007150:Immunohistochemistry; D007167:Immunotherapy / Q000379:methods*; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008297:Male; D008875:Middle Aged
D017252:CD3 Complex; D016827:CD8 Antigens; D019496:Cancer Vaccines