title: Dendritic cell vaccination combined with temozolomide retreatment: results of a phase I trial in patients with recurrent glioblastoma multiforme.
abstract: There is no standard treatment for recurrent glioblastoma multiforme (GBM). Retreatment with temozolomide (TMZ) is one treatment option. We reasoned this could be more effective if combined with a vaccine that preferentially targeted TMZ-resistant cells. To test the feasibility and safety of such an approach, a phase 1 trial was conducted in which patients with GBM tumors relapsing after standard chemoradiotherapy were retreated with TMZ in combination with a vaccine consisting of monocyte-derived dendritic cells (DC) pulsed with autologous tumor cells that had previously been exposed to TMZ in vivo in the course of primary treatment. Of 14 participants, nine patients completed the initial phase of priming vaccinations and two cycles of TMZ, one proved to have radionecrosis, one rapidly progressed, and in three the yield of DC vaccine was insufficient to proceed with treatment. Other than expected toxicities related to TMZ, there were no adverse events attributable to the combined treatment. Two patients had objective radiological responses. Six month progression-free survival was 22 %, similar to retreatment with TMZ alone. Anti-tumor immune responses were assessed in peripheral blood mononuclear cells using interferon-γ ELISpot, with two patients meeting criteria for a vaccine-induced immune response, one of whom remained disease-free for nearly three years. Another patient with an anti-tumor immune response at baseline that was sustained post-vaccination experienced a 12-month period of progression-free survival. In summary, the combined treatment was safe and well-tolerated but feasibility in the recurrent setting was marginal. Evidence of immune responses in a few patients broadly correlated with better clinical outcome.
authors.affiliation: Malaghan Institute of Medical Research, PO Box 7060, Wellington, 6021, New Zealand, mhunn@malaghan.org.nz.
authors.forename: Martin K
authors.initials: MK
authors.lastname: Hunn
authors.forename: Evelyn
authors.initials: E
authors.lastname: Bauer
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Wood
authors.forename: Olivier
authors.initials: O
authors.lastname: Gasser
authors.forename: Marina
authors.initials: M
authors.lastname: Dzhelali
authors.forename: Lindsay R
authors.initials: LR
authors.lastname: Ancelet
authors.forename: Brigitta
authors.initials: B
authors.lastname: Mester
authors.forename: Katrina J
authors.initials: KJ
authors.lastname: Sharples
authors.forename: Michael P
authors.initials: MP
authors.lastname: Findlay
authors.forename: David A
authors.initials: DA
authors.lastname: Hamilton
authors.forename: Ian F
authors.initials: IF
authors.lastname: Hermans
mesh_terms: D000328:Adult; D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D001921:Brain / Q000473:pathology; D001932:Brain Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D019496:Cancer Vaccines / Q000009:adverse effects / Q000627:therapeutic use*; D003131:Combined Modality Therapy / Q000009:adverse effects; D003606:Dacarbazine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D003713:Dendritic Cells / Q000276:immunology; D018572:Disease-Free Survival; D005240:Feasibility Studies; D005260:Female; D005909:Glioblastoma / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D019233:Retreatment; D000077204:Temozolomide; D016896:Treatment Outcome
chemical_list: D018906:Antineoplastic Agents, Alkylating; D019496:Cancer Vaccines; D003606:Dacarbazine; D000077204:Temozolomide