Dendritic cell vaccination in glioblastoma patients induces systemic and intracranial T-cell responses modulated by the local central nervous system tumor microenvironment.
OBJECTIVE
We previously reported that autologous dendritic cells pulsed with acid-eluted tumor peptides can stimulate T cell-mediated antitumor immune responses against brain tumors in animal models. As a next step in vaccine development, a phase I clinical trial was established to evaluate this strategy for its feasibility, safety, and induction of systemic and intracranial T-cell responses in patients with glioblastoma multiforme.


METHODS
Twelve patients were enrolled into a multicohort dose-escalation study and treated with 1, 5, or 10 million autologous dendritic cells pulsed with constant amounts (100 mug per injection) of acid-eluted autologous tumor peptides. All patients had histologically proven glioblastoma multiforme. Three biweekly intradermal vaccinations were given; and patients were monitored for adverse events, survival, and immune responses. The follow-up period for this trial was almost 5 years.


RESULTS
Dendritic cell vaccinations were not associated with any evidence of dose-limiting toxicity or serious adverse effects. One patient had an objective clinical response documented by magnetic resonance imaging. Six patients developed measurable systemic antitumor CTL responses. However, the induction of systemic effector cells did not necessarily translate into objective clinical responses or increased survival, particularly for patients with actively progressing tumors and/or those with tumors expressing high levels of transforming growth factor beta(2) (TGF-beta(2)). Increased intratumoral infiltration by cytotoxic T cells was detected in four of eight patients who underwent reoperation after vaccination. The magnitude of the T-cell infiltration was inversely correlated with TGF-beta(2) expression within the tumors and positively correlated with clinical survival (P = 0.047).


CONCLUSIONS
Together, our results suggest that the absence of bulky, actively progressing tumor, coupled with low TGF-beta(2) expression, may identify a subgroup of glioma patients to target as potential responders in future clinical investigations of dendritic cell-based vaccines.
Liau
Linda M
LM
Division of Neurosurgery, Department of Surgery, The Brain Research Institute, David Geffen School of Medicine at University of California at Los Angeles, University of California Los Angeles, Los Angeles, California 90095, USA. lliau@mednet.ucla.edu
Prins
Robert M
RM
Kiertscher
Sylvia M
SM
Odesa
Sylvia K
SK
Kremen
Thomas J
TJ
Giovannone
Adrian J
AJ
Lin
Jia-Wei
JW
Chute
Dennis J
DJ
Mischel
Paul S
PS
Cloughesy
Timothy F
TF
Roth
Michael D
MD
D000328:Adult; D000368:Aged; D019496:Cancer Vaccines / Q000378:metabolism*; D002490:Central Nervous System / Q000378:metabolism*; D016543:Central Nervous System Neoplasms / Q000473:pathology* / Q000628:therapy*; D015331:Cohort Studies; D003713:Dendritic Cells / Q000166:cytology* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D010455:Peptides / Q000737:chemistry; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053781:Transforming Growth Factor beta2; D016896:Treatment Outcome
D019496:Cancer Vaccines; D010455:Peptides; D012333:RNA, Messenger; C509041:TGFB2 protein, human; D016212:Transforming Growth Factor beta; D053781:Transforming Growth Factor beta2