Abstract 5611: Interleukin-2 receptor α (IL-2R α/CD25)-specific antibodies eliminate regulatory T-cells (TRegs) and enhance tumor-specific immune responses

Abstract

Abstract Interleukin-2 Receptor α (IL-2R α / CD25)-specific Antibodies Eliminate Regulatory T-cells (TRegs) and enhance Tumor-specific Immune Responses Duke University Medical Center, Durham, NC, USA Introduction: Immunotherapy is an attractive therapeutic alternative for glioblastoma (GBM), but is limited by the lack of frequent and homogeneously-expressed tumor-specific antigens. The nearly universal presence and homogeneous expression of antigens derived from Cytomegalovirus (CMV) in GBM, but not normal brain, has now been well-established and may provide ideal antigens for tumor-specific immunotherapy. Despite the potential immunogenicity of CMV antigens, CMV immune responses in patients with GBM are blunted which may be a result of immunosuppressive regulatory T cells (TRegs) which are present at high levels in patients with GBM. Monoclonal antibodies (MAbs) that block IL-2Rα have been shown to abrogate TReg function in animal models, but also inhibit effective antitumor immune responses in the context of established tumors and attenuate immune responses in humans with autoimmune disorders or allogeneic organ transplants. Material and Methods: The interleukin-2 receptor α (IL-2R α)-specific MAbs, PC61 (250 µg/mouse) and daclizumab (1 mg/kg), were administered during the recovery from TMZ-induced lymphopenia in mice and humans with GBM, respectively, concurrent with tumor-specific vaccination targeting the model antigen OVA or CMV pp65. Results: As expected, in normal mice, anti-IL2Rα MAb treatment depletes and functionally impairs TRegs, but it also abrogates vaccine-induced immune responses. However, in direct contrast, when IL-2Rα-specific MAbs are administered during recovery from temozolomide (TMZ)-induced lymphopenia, anti-IL2Rα MAb administration depletes TRegs while simultaneously augmenting vaccine-induced effector T-cell responses and antitumor efficacy. Similarly, in a randomized Phase II trial, administration of the humanized IL-2Rα-specific MAb daclizumab after therapeutic TMZ dramatically reduces TReg levels (73.9% + 8.2 S.D.) and increases pp65-specific CD8+ T-cell responses (4.3 fold) in response to vaccination with CMV pp65 mRNA transfected DCs. Time-to-progression in the cohort of patients treated with daclizumab exceeds 24 months with a likelihood of 2 year progression-free survival of 66.7% (CI95 19.5%, 90.4%). Conclusions: Therapeutic TMZ-induced lymphopenia provides a unique window of opportunity in which the presence of anti-IL-2Rα antibodies selectively inhibits TRegs, but potentiates ongoing anti-tumor effector T cell responses. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5611.