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1.
Sci Transl Med ; 7(311): 311ra170, 2015 Oct 28.
Article in English | MEDLINE | ID: mdl-26511507

ABSTRACT

Interleukin-2 (IL-2) is a lymphocyte growth factor that is an important component of many immune-based cancer therapies. The efficacy of IL-2 is thought to be limited by the expansion of T regulatory cells, which express the high-affinity IL-2 receptor subunit IL-2Rα. IL-15 is under investigation as an alternative to IL-2. Although both cytokines signal through IL-2Rßγ, IL-15 does not bind IL-2Rα and therefore induces less T regulatory cell expansion. However, we found that transferred effector CD8(+) T cells induced curative responses in lymphoreplete mice only with IL-2-based therapy. Although conventional in vitro assays showed similar effector T cell responsiveness to IL-2 and IL-15, upon removal of free cytokine, IL-2 mediated sustained signaling dependent on IL-2Rα. Mechanistically, IL-2Rα sustained signaling by promoting a cell surface IL-2 reservoir and recycling of IL-2 back to the cell surface. Our results demonstrate that IL-2Rα endows T cells with the ability to compete temporally for limited IL-2 via mechanisms beyond ligand affinity. These results suggest that strategies to enhance IL-2Rα expression on tumor-reactive lymphocytes may facilitate the development of more effective IL-2-based therapies.


Subject(s)
Immunotherapy/methods , Interleukin-2 Receptor alpha Subunit/metabolism , Interleukin-2/immunology , Animals , CD8-Positive T-Lymphocytes/immunology , Cell Line, Tumor , Cells, Cultured , Interleukin-15/therapeutic use , Interleukin-2/therapeutic use , Interleukin-2 Receptor alpha Subunit/genetics , Melanoma, Experimental/immunology , Melanoma, Experimental/therapy , Mice , Mice, Inbred C57BL , Mice, Transgenic , Microscopy, Confocal , Signal Transduction/physiology , T-Lymphocytes, Regulatory/immunology
2.
J Hematol Oncol ; 6: 75, 2013 Oct 01.
Article in English | MEDLINE | ID: mdl-24279871

ABSTRACT

BACKGROUND: Administration of recombinant G-CSF following cytoreductive therapy enhances the recovery of myeloid cells, minimizing the risk of opportunistic infection. Free G-CSF, however, is expensive, exhibits a short half-life, and has poor biological activity in vivo. METHODS: We evaluated whether the biological activity of G-CSF could be improved by pre-association with anti-G-CSF mAb prior to injection into mice. RESULTS: We find that the efficacy of G-CSF therapy can be enhanced more than 100-fold by pre-association of G-CSF with an anti-G-CSF monoclonal antibody (mAb). Compared with G-CSF alone, administration of G-CSF/anti-G-CSF mAb complexes induced the potent expansion of CD11b+Gr-1+ myeloid cells in mice with or without concomitant cytoreductive treatment including radiation or chemotherapy. Despite driving the dramatic expansion of myeloid cells, in vivo antigen-specific CD8+ T cell immune responses were not compromised. Furthermore, injection of G-CSF/anti-G-CSF mAb complexes heightened protective immunity to bacterial infection. As a measure of clinical value, we also found that antibody complexes improved G-CSF biological activity much more significantly than pegylation. CONCLUSIONS: Our findings provide the first evidence that antibody cytokine complexes can effectively expand myeloid cells, and furthermore, that G-CSF/anti-G-CSF mAb complexes may provide an improved method for the administration of recombinant G-CSF.


Subject(s)
Antibodies, Monoclonal/pharmacology , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/immunology , Granulocyte Colony-Stimulating Factor/pharmacology , Immunoconjugates/pharmacology , Myeloid Cells/drug effects , Myeloid Cells/immunology , Animals , Antibodies, Monoclonal/immunology , Granulocyte Colony-Stimulating Factor/immunology , Humans , Immunoconjugates/immunology , Mice , Mice, Inbred C57BL , Mice, Transgenic
3.
J Am Coll Surg ; 214(4): 700-7; discussion 707-8, 2012 Apr.
Article in English | MEDLINE | ID: mdl-22360982

ABSTRACT

BACKGROUND: Clinical application of adoptive T cell therapy has been hindered by an inability to generate adequate numbers of nontolerized, functionally active, tumor-specific T cells, which can persist in vivo. In order to address this, we evaluated the impact of interleukin (IL)-12 signaling during tumor-specific CD8(+) T cell priming in terms of persistence and antitumor efficacy using an established B16 melanoma tumor adoptive therapy model. STUDY DESIGN: B6 mice were injected subcutaneously with B16 melanoma tumor cells. On day 12 of tumor growth, mice were preconditioned with cyclophosphamide (4mg dose, intraperitoneally), and 1 day later were treated by adoptive transfer of tumor-specific pmel-1 CD8(+) T cells primed ex vivo 3 days earlier with both IL-12 and antigen (hGP100(25-33) peptide) or antigen only. Tumors were measured biweekly, and infused donor T cells were analyzed for persistence, localization to the tumor, phenotype, and effector function. RESULTS: Adoptive transfer of tumor-specific CD8(+) T cells primed with IL-12 was significantly more effective in reducing tumor burden in mice preconditioned with cyclophosphamide compared with transfer of T cells primed without IL-12. This enhanced antitumor response was associated with increased frequencies of infused T cells in the periphery and tumor as well as elevated expression of effector molecules including granzyme B and interferon-γ (IFNγ). CONCLUSIONS: Our findings demonstrate that ex vivo priming of tumor-specific CD8(+) T cells with IL-12 dramatically improves their in vivo persistence and therapeutic ability on transfer to tumor-bearing mice. These findings can be directly applied as novel clinical trial strategies.


Subject(s)
CD8-Positive T-Lymphocytes/transplantation , Immunotherapy, Adoptive/methods , Interleukin-12/immunology , Lymphocyte Activation , Melanoma/therapy , Animals , CD8-Positive T-Lymphocytes/immunology , Cell Line, Tumor , Cyclophosphamide/administration & dosage , Female , Flow Cytometry , Immunosuppressive Agents/administration & dosage , Male , Melanoma/immunology , Melanoma/pathology , Mice , Mice, Inbred C57BL , Treatment Outcome , Tumor Burden
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