Monoclonal antibody blockade of IL-2 receptor α during lymphopenia selectively depletes regulatory T cells in mice and humans

Abstract

IntroductionThe alkylating chemotherapeutic agent temozolomide (TMZ) has been shown to prolong survival in patients with glioblastoma (GBM) and metastatic melanoma; however, patients with these diseases treated with TMZ possess a median survival of Ͻ 15 months. 1,2 Novel approaches are required to treat these devastating malignancies, and the exquisite specificity inherent to immunotherapy makes it an appealing option.Despite the potential of cancer immunotherapy, limited success has been achieved within this field due in large part to difficulties in generating appropriate numbers of high-avidity and persistent antitumor T cells. [3][4][5] A recent and profound advance in immunotherapy is the use of lymphopenia to augment antitumor immunity through adoptive cellular therapy. [6][7][8] Lymphodepletion induces homeostatic proliferation, enabling adoptively transferred activated T cells to become disproportionately overrepresented in the regenerating population and persist for months at high precursor frequencies. [9][10][11][12] Recent studies have primarily examined the lymphodepletive properties of total body irradiation (TBI), and although informative, TBI is not routinely used therapeutically and has a limited clinical context. In contrast, lymphopenia resulting from various standard-of-care chemotherapies, although generally considered an undesirable but inevitable side effect of treatment, could provide a clinically significant means to augment immunotherapy.TMZ is generally considered an immunosuppressive agent that induces lymphopenia in humans and patients receiving TMZ are routinely given prophylaxis to prevent the development of opportunistic infections. [13][14][15][16] Low-dose TMZ has been shown to enhance "cross-priming" against tumor-derived antigens in experimental mice 17 ; however, the direct effects of lymphodepletive doses of TMZ on vaccine-induced immunologic responses and regulatory T cells (T Regs ) has not been examined.Here, we report that lymphodepletive TMZ strongly augments vaccine-induced immune responses in a dose-dependent manner and that combinatorial vaccination and lymphopenia in mice bearing established B16/F10.9-OVA tumors significantly impaired malignant growth despite an increase in the frequency of CD4 ϩ CD25 ϩ Foxp3 ϩ T Regs . This TMZ-induced enhancement of immunity is dramatically augmented when combined with anti-IL-2R␣ monoclonal antibody (mAb)-mediated depletion of CD4 ϩ CD25 ϩ Foxp3 ϩ T Regs , whereas identical treatment in normal mice impaired vaccine-induced effector responses. Anti-IL-2 receptor ␣ (IL-2R␣) mAb treatment can suppress activated T cells in normal mice 18 and can suppress vaccine-induced immune responses in patients with metastatic melanoma. 19 However, to our knowledge, this is the first demonstration that the lymphopenic environment differentially impacts whether vaccination can be successfully combined with systemic antibody-mediated T Reg depletion in the treatment of established Submitted February 3, 2011; accepted July 2, 2011. Prepublished onli...

Phase I/IIa trial of fractionated radiotherapy, temozolomide, and autologous formalin-fixed tumor vaccine for newly diagnosed glioblastoma

“…Some animal studies have indicated that TMZ may enhance antitumor immunity. 10,14,19 In a murine model of an established intracerebral tumor, vaccination-induced immunity in the setting of myeloablative TMZ, but not non-myeloablative TMZ, leads to significantly prolonged survival. 19 These data are consistent with our interesting result that the median OS in patients with Grade 3 lymphopenia was superior to that in patients with Grade 0-2 lymphopenia.…”

“…13 In animal studies, TMZ shows the potential to enhance antitumor immunity. 10,14,19 In our pilot study, AFTV combined with TMZ was used to treat 1 patient with primary GBM and 2 patients with secondary GBM. 17 All patients demonstrated pathological improvement associated with the therapy, and the adverse effects related to AFTV plus TMZ were very minor.…”

Chemokines as adjuvants for immunotherapy: implications for immune activation with CCL3

“…This form of therapy is expected to induce both therapeutic T-cell immunity (in the form of tumor-specific effector T-cells) [47] and protective T-cell immunity (in the form of tumor-specific memory T-cells that can control tumor recurrence) [48]. Various clinical trials are currently evaluating the safety and efficacy of direct vaccination with patient-specific dendritic cells (DCs) [49,50]. Additionally, vaccination with tumor-derived peptides that rely on recruitment and activation of APCs have demonstrated potent immune responses [51–55].…”

Brain cancer immunoediting: novel examples provided by immunotherapy of malignant gliomas

“…In humans, anti-CD25 antibodies such as daclizumab have been developed, but their capacity to deplete human Tregs is questioned by transplantation studies. Recent data suggest that in a mouse model of glioma monoclonal antibodies against IL-2a receptor CD25, when administered during lympho depletion caused by temozolomide, decrease the number of Tregs and increase the anti-tumor efficacy of vaccination [124]. A reduction in Treg frequency was also verified in patients receiving anti-CD25 antibodies after temozolomide-induced lymphodepletion [124].…”