The most common malignant primary brain tumor, glioblastoma (GBM), remains uniformly fatal despite surgical resection and incapacitating radiation therapy. Temozolomide (TMZ) chemotherapy has shown a survival benefit in patients with GBM, but median survival remains <15 months. Immunotherapy represents a promising additional approach, but the profound lymphopenia induced by TMZ would curtail the induction of vaccine-induced antitumor immune responses. Recently, however, non-myeloablative lymphodepletion, such as that produced by TMZ, has emerged as a potent adjuvant to adoptive T-cell immunotherapy. Following periods of lymphopenia there is a homeostatic proliferation of lymphocytes designed to recover normal lymphocyte counts. Thus, T-cells that predominate during this recovery period, including those anti-tumor T-cells provided through adoptive transfer, become disproportionately represented in the recovering lymphocyte population. Unfortunately, immunosuppressive regulatory T-cells (TRegs) also undergo homeostatic proliferation after lymphodepletion. Moreover, attempts at eliminating TRegs from adoptively transferred cells are thwarted because these immunosuppressive cells are re-generated de novo from the transferred cells. While antibodies specific for the high-affinity interleukin (IL)-2 receptor alpha (IL-2R1) (CD25) have been shown to abrogate TReg function in animal models, effector T-cell functions are also inhibited. Effector T-cells may not always be dependent on IL-2 signaling, however. During homeostatic proliferation, effector T-cells enjoy a reduced activation threshold and can differentiate into effector memory T-cells directly driven by surges in cytokines that share receptors with IL-2 such as IL-7 and IL-15. Signaling through these cytokines, then, may uniquely bypass the need for IL-2 signaling in effector T-cells in this context. If so, lymphodepletion may provide a unique context wherein adoptively transferred effector T-cells may not require IL-2 signaling and may not be susceptible to inhibition by IL-2R blocking antibodies while TRegs may remain susceptible to this mode of inhibition because of their unique dependence on IL-2 specifically. Consistent with this, our preliminary studies have shown that unarmed IL-2R1-specific antibodies given to mice during recovery from transient lymphopenia, while capable of functionally inactivating TRegs actually dramatically enhance effector T-cell responses. In this proposal, we will test the HYPOTHESIS that during hematopoietic recovery from treatment-induced lymphopenia the generation of de novo TRegs from adoptively transferred anti- tumor T-cells can be selectively inhibited by anti-IL2R1 antibodies leading to enhanced antitumor immunity without induction of limiting autoimmunity. If correct, the translatability of this approach is high because daclizumab, a commercially-available, humanized IL-2R1-specific antibody, functions identically to the antibody used for TReg inactivation studies in mice.
Treatment for brain tumors represents the most expensive medical therapy per quality-adjusted life-year saved currently provided in the United States, and brain tumors remain the most common cause of cancer death among children and account for more deaths in adults than melanoma. Immunotherapy is an attractive alternative approach to therapy for these tumors, but is thwarted by immunosuppressive cells that are over represented in patients with cancer. Antibodies that block a critical receptor on these inhibitory cells, however, may be able to be used to reduce their recovery after chemotherapy.
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