Pre-clinical Translation of Regulatory T-cell Inhibition in Brain Tumors

Duke University, Durham NC

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Abstract

DESCRIPTION (provided by applicant): 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.