Effect of daclizumab on TReg counts and EGFRvIII-specific immune responses in GBM.

Published

Journal Article

2034 Background: TRegs are increased in patients with GBM and constitutively express the high affinity interleukin-2 receptor (IL-2Rα). Treatment with an antibody that blocks IL-2Rα signaling functionally inactivates and eliminates TRegs without inducing autoimmune toxicity in murine models. We hypothesized that daclizumab, a commercially-available, IL-2Rα-specific antibody would function identically. METHODS: A randomized phase II clinical trial assessed the effects of daclizumab in the context of the cancer vaccine, CDX-110, which is comprised of an EGFRvIII-specific peptide sequence linked to KLH. EGFRvIII is a constitutively activated and immunogenic mutation not expressed in normal tissues, but widely expressed in GBMs and other neoplasms. In patients with newly-diagnosed, EGFRvIII+ GBM, after resection and radiation/TMZ, patients received CDX-110 vaccinations biweekly x 3, then monthly until tumor progression in combination with TMZ (200 mg/m(2) x 5/28 days). Half the patients were randomized to receive daclizumab (1mg/Kg x1) at the first vaccine. The others received saline in a double-blinded fashion. RESULTS: There were no drug related SAEs. EGFRvIII-specific immune responses were generated in all patients, and all immune responses were sustained or enhanced during subsequent TMZ cycles. Preliminary analysis (n = 4) suggests that daclizumab reduces Treg (CD4(+)CD25(+)CD45RO(+)FOXP3(+)) numbers [change 82.4 ± 7.1% from baseline (p = 0.011; t-test)] without reducing overall CD8(+) or CD4(+) T-cell counts. Tregs decreased only 3.7 + 11.0% after vaccination in the saline treated group during the same interval. Preliminary analysis (n = 4) also suggest that daclizumab enhanced EGFRvIII-specific immune responses (p = 0.01; t-test) and enhanced the titer of cytotoxic EGFRvIII-specific IgG1 isotype antibodies compared to the saline treated group (p = 0.003; t-test) and compared to previously vaccinated patients who did not receive daclizumab (p = 0.0015; t-test). TTP and OS survival in both arms has not been reached. CONCLUSIONS: Daclizumab may reduce Treg counts in patients with GBM. TMZ and daclizumab may enhance EGFRvIII-targeted immune responses despite lymphodepletion. These combinations are currently under further investigation. [Table: see text].

Full Text

Duke Authors

Cited Authors

  • Sampson, JH; Archer, GE; Bigner, DD; Schmittling, RJ; Herndon, JE; Davis, T; Friedman, HS; Keler, T; Reardon, DA; Mitchell, DA

Published Date

  • May 20, 2009

Published In

Volume / Issue

  • 27 / 15_suppl

Start / End Page

  • 2034 -

PubMed ID

  • 27964629

Pubmed Central ID

  • 27964629

Electronic International Standard Serial Number (EISSN)

  • 1527-7755

Language

  • eng

Conference Location

  • United States