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To address these hypotheses, we comprehensively characterized functional and phenotypic immune responses induced by these two combination therapies, which provided insight into the mechanisms associated with efficacious combination therapies. We hypothesized that the proinflammatory signals provided via intratumoral NKTR-262 would enhance the priming of tumor-reactive T cells that would then be supported by systemic BEMPEG treatment, resulting in BEMPEG +NKTR-262 eliciting more robust tumor regression than BEMPEG +RT. Whether the innate stimulation provided by the TLR7/8 agonist NKTR-262 combined with BEMPEG will improve response rates over BEMPEG +RT is unknown. 20 The modest benefit observed may be a result of the immunosuppressive effects elicited by RT, which include inactivating NK cells, recruiting myeloid-derived suppressor cells (MDSCs), and altering macrophage polarization towards an M2 tumor-promoting phenotype. 19 BEMPEG synergizes with RT and provides the greatest benefit to immunologically ‘hot’ (well infiltrated) tumors, 16 but only a modest benefit to immunologically ‘cold’ (poorly infiltrated) tumors. 11 Furthermore, TLR7/8 agonists have demonstrated antitumor activity in preclinical models.
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15 16 TLR7/8 stimulation can induce functional APC differentiation, 17 induce Th1-biased responses, 18 and enhance CD8 + T cell effector functions. 11 12 RT-induced tumor cell death results in increased cross-presentation of tumor antigen, 13 increased numbers of IFN-γ-secreting tumor-specific tumor-infiltrating lymphocytes (TIL), 14 and increased expression of chemokines that promote T and NK cell trafficking to the tumor. Both RT and TLR targeting have innate immunostimulatory effects that can unleash antitumor CD8 + T cell responses. 4īecause BEMPEG supports adaptive immunity, we sought to evaluate BEMPEG in combination with different innate immune agonists capable of boosting antitumor immunity, aiming to enhance overall therapeutic potential. Indeed, BEMPEG-induced T cell activation and expansion activity in vivo increases Teff:Treg ratios in tumor tissue compared with IL-2. These PEG units increase the duration of IL-2 receptor agonism and preferentially reduce binding to IL-2Rα (CD25) 5 compared with IL-2Rβ, supporting effector T cell expansion over Treg expansion, and thereby increasing efficacy and reducing toxicity. 10 One prodrug modified to reduce those toxicities is BEMPEG, an engineered IL-2R agonist with six releasable polyethylene glycol (PEG) units attached to the IL-2Rα binding region. 6–8 However, HD IL-2 efficacy is limited by the expansion of suppressive CD25 + FoxP3 + T regulatory (Treg) cells 9 and by treatment toxicity, which includes vascular leak syndrome, hypotension, and liver toxicities. For example, high-dose IL-2 (HD IL-2) is an FDA-approved cytokine therapy with a 15%–20% objective response rate in metastatic renal cell carcinoma and melanoma. Here, we compare efficacy of two combination therapies, bempegaldesleukin (BEMPEG, immunostimulatory IL-2 cytokine prodrug) 3–5 combined either with radiation therapy (RT) or with NKTR-262, a toll-like receptor (TLR) 7/8 agonist.Ĭytokine-based immunotherapies aim to increase the proliferation and survival of pre-existing antitumor effector T cells.
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Identifying highly efficacious combination therapies will require elucidating the molecular mechanisms by which they induce antitumor responses and an in-depth, side-by-side characterization of different therapies. While applications of immunotherapies, either individually or in combination with other treatments, continue to improve patient outcomes, 1 2 determining which immunotherapy combinations achieve the best possible outcome is a critical and unresolved issue.