Authors:
J. Rech, R. Mick, A. Recio, A. DeMichele, C. K. Tweed, K. R. Fox, S. M. Domchek, & R. H. Vonderheide
Summary:
Background - CD4+ regulatory T cells (Tregs) inhibit tumor immunity and represent an obstacle for cancer immunotherapy, but an effective strategy to deplete Tregs in pts has not been identified. In mice, anti-CD25 mAb depletes CD25+ FoxP3+ Tregs and promotes immunity. We therefore evaluated the FDA-approved anti-CD25 mab daclizumab for its effect on Tregs in a phase I clinical study.
Methods - Ten HLA-A2+ pts with progressive MBC received an intravenous infusion (1 mg/kg) of daclizumab one week before an experimental vaccine consisting of 4 telomerase and survivin peptides and a cytomegalovirus (CMV) control peptide, emulsified in incomplete Freund's adjuvant (Montanide ISA-51-VG) and administered subcutaneously with GM-CSF every other week (x4) then monthly until disease progression. The pneumococcal-conjugate vaccine (Prevnar), containing CRM-197 antigen to engage T cell help, was also administered. Immune assessment was performed using blood samples obtained at baseline and regularly thereafter.
Results - Daclizumab and vaccines were extremely well-tolerated. A median of 4 vaccines per pt (range 2 to 17) were given. Five pts had stable disease as the best response. Both percentage and absolute counts of CD25+ FoxP3+ CD4+ T cells decreased dramatically after daclizumab (p<0.001), based on monitoring with a CD25 antibody not blocked by daclizumab. Total FoxP3+ CD4+ T cells also decreased (p<0.001) but total CD4+ cells did not. The decrease of CD25+ FoxP3+ T cells was rapid (<1 week), marked (mean decrease of 83%), and prolonged (at least 7 weeks). Despite CD25 expression on effector T cells, 80% of pts exhibited CD8 responses to one or more tumor peptides, and 80% had CRM197-specific T cell responses. Two of five CMV seronegative pts exhibited CD8 T cell priming to CMV peptide.
Conclusions - A single infusion of anti- CD25 mab daclizumab results in rapid, marked, and prolonged loss of CD25+ FoxP3+ CD4+ Tregs without toxicity in pts with MBC. Robust T cell priming and boosting to all vaccine antigens was observed despite CD25 blockade. These results demonstrate the utility of anti-CD25 mab for achieving extensive depletion of Tregs in patients.
Source:
2010 American Society of Clinical Oncology Annual Meeting; 2508, 9:30AM-12:30PM (06/08/10)