Systemic Administration of IL-15 Augments the Antigen-Specific Primary CD8+ T Cell Response Following Vaccination with Peptide-Pulsed Dendritic Cells (original) (raw)
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IL-15 and a Two-Step Maturation Process Improve Bone Marrow-Derived Dendritic Cell Cancer Vaccine
Cancers
In the last 20 years, dendritic cells (DCs) have been largely used as a platform for therapeutic vaccination in cancer patients. However, despite its proven safety and ability to induce cancer specific immune responses, the clinical benefits of DC-based immunotherapy are currently very limited. Thus, novel approaches are still needed to boost its efficacy. Our group recently showed that squaric acid treatment of antigens is an important adjuvant that can increase vaccine-induced downstream immune responses and therapeutic outcomes. Here we further improved this dendritic cell vaccine formulation by developing a new method for differentiating and maturing DCs from their bone marrow precursors. Our data demonstrate that bone marrow-derived DCs differentiated with GM-CSF and IL-15 and matured with a maturation cocktail in two steps present a more mature and immunogenic phenotype, compared to standard DC preparations. Further suppression of the prostaglandin E2 pathway achieved even mor...
IL-15 enhances the in vivo antitumor activity of tumor-reactive CD8+ T Cells
Proceedings of the National Academy of Sciences, 2004
IL-15 and IL-2 possess similar properties, including the ability to induce T cell proliferation. However, whereas IL-2 can promote apoptosis and limit CD8 ؉ memory T cell survival and proliferation, IL-15 helps maintain a memory CD8 ؉ T cell population and can inhibit apoptosis. We sought to determine whether IL-15 could enhance the in vivo function of tumor͞self-reactive CD8 ؉ T cells by using a T cell receptor transgenic mouse (pmel-1) whose CD8 ؉ T cells recognize an epitope derived from the self͞melanoma antigen gp100. By removing endogenous IL-15 by using tumor-bearing IL-15 knockout hosts or supplementing IL-15 by means of exogenous administration, as a component of culture media or as a transgene expressed by adoptively transferred T cells, we demonstrate that IL-15 can improve the in vivo antitumor activity of adoptively transferred CD8 ؉ T cells. These results provide several avenues for improving adoptive immunotherapy of cancer in patients.
Dendritic cell-derived interleukin-15 is crucial for therapeutic cancer vaccine potency
Oncoimmunology, 2014
IL-15 supports improved antitumor immunity. How to best incorporate IL-15 into vaccine formulations for superior cancer immunotherapy remains a challenge. DC-derived IL-15 (DCIL-15) notably has the capacity to activate DC, to substitute for CD4(+) Th and to potentiate vaccine efficacy making IL-15-based therapies attractive treatment options. We observed in transplantable melanoma, glioma and metastatic breast carcinoma models that DCIL-15-based DNA vaccines in which DC specifically express IL-15 and simultaneously produce tumor Aghsp70 were able to mediate potent therapeutic efficacy that required both host Batf3(+) DC and CD8(+) T cells. In an inducible Braf(V600E)/Pten-driven murine melanoma model, DCIL-15 (not rIL-15)-based DNA vaccines elicited durable therapeutic CD8(+) T cell-dependent antitumor immunity. DCIL-15 was found to be superior to rIL-15 in "licensing" both mouse and human DC, and for activating CD8(+) T cells. Such activation occurred even in the presence...
Journal of Translational Medicine, 2009
Background: Optimization of the current dendritic cell (DC) culture protocol in order to promote the therapeutic efficacy of DC-based immunotherapy is warranted. Alternative differentiation of monocytederived DCs using granulocyte macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-15 has been propagated as an attractive strategy in that regard. The applicability of these so-called IL-15 DCs has not yet been firmly established. We therefore developed a novel pre-clinical approach for the generation of IL-15 DCs with potent immunostimulatory properties.
Cancer Research, 2008
Tumors often escape immune-mediated destruction by suppressing lymphocyte infiltration or effector function. New approaches are needed that overcome this suppression and thereby augment the tumoricidal capacity of tumor-reactive lymphocytes. The cytokine interleukin-15 (IL-15) promotes proliferation and effector capacity of CD8(+) T cells, natural killer (NK) cells, and NKT cells; however, it has a short half-life and high doses are needed to achieve functional responses in vivo. The biological activity of IL-15 can be dramatically increased by complexing this cytokine to its soluble receptor, IL-15R alpha. Here, we report that in vivo delivery of IL-15/IL-15R alpha complexes triggers rapid and significant regression of established solid tumors in two murine models. Despite a marked expansion of IL-2/IL-15R beta(+) cells in lymphoid organs and peripheral blood following treatment with IL-15/IL-15R alpha complexes, the destruction of solid tumors was orchestrated by tumor-resident rather than newly infiltrating CD8(+) T cells. Our data provide novel insights into the use of IL-15/IL-15R alpha complexes to relieve tumor-resident T cells from functional suppression by the tumor microenvironment and have significant implications for cancer immunotherapy and treatment of chronic infections.
Cancer Gene Therapy, 2002
Purpose: Triggering of CD40 on antigen-presenting cells via its ligand CD154 is an important event in the initial phase of an immune response against cancer cells. In this study, we investigated the effects of adenoviral CD154 immunomodulatory gene therapy on the activation of human dendritic cells (DCs) in a well-defined in vitro system. Experimental design: Human bladder cancer cell lines and tumor cells from patients with renal cell carcinoma (RCC) were transduced with Ad-CD154 vectors or control vectors. Activation of human in vitro generated DCs after coculture with transduced tumor cells was analyzed. Therapeutic efficacy and cytotoxic Tlymphocyte (CTL) activity were assessed in a subcutaneous (s.c.) murine bladder cancer model. Results: Human bladder cancer cell lines expressing CD154 showed a decreased growth rate, increased apoptosis, and modulated expression of molecules important for recognition by cytotoxic lymphocytes. Further, CD154-expressing allogeneic bladder tumor cell lines and autologous tumor cells from patients with renal cell cancer induced maturation of DCs and stimulated IFN-g production from lymphocytes cocultured with mature DCs. In vivo studies showed that CD154 gene therapy was highly effective in wild-type mice but only minimally effective in nude mice. Consequently, strong tumor-specific CTL activity was detected in mice vaccinated with tumor cells expressing CD154. Conclusions: Using tumor cell lines as well as patient-derived material, we could show that tumor cells expressing CD154 efficiently induce maturation and activation of DCs as well as activation of lymphocytes. Our murine in vivo studies demonstrate that lymphocytes contribute to the observed antitumor effect in a s.c. bladder tumor model. These studies should stimulate CD154 gene therapy approaches for the treatment of urologic malignancies.
Clinical Cancer Research, 2011
Purpose: We compared the efficacy of human Langerhans cells (LC) as tumor immunogens in vivo with monocyte-derived dendritic cells (moDC) and investigated how interleukin 15 (IL15) supports optimal DC-stimulated antitumor immunity. Experimental Design: American Joint Committee on Cancer stage III/IV melanoma patients participated in this first clinical trial comparing melanoma peptide-pulsed LC with moDC vaccines (NCT00700167, www.ClinicalTrials.gov). Correlative studies evaluated mechanisms mediating IL15 support of DC-stimulated antitumor immunity. Results: Both DC vaccines were safe and immunogenic for melanoma antigens. LC-based vaccines stimulated significantly greater tyrosinase-HLA-A*0201 tetramer reactivity than the moDC-based vaccines. The two DC subtypes were otherwise statistically comparable, in contrast to extensive prior data in vitro showing LC superiority. LCs synthesize much more IL15 than moDCs and stimulate significantly more antigen-specific lymphocytes with a cytolytic IFN-g profile even without exogenous IL15. When supplemented by low-dose IL15, instead of IL2, moDCs stimulate 5 to 6 logs more tumor antigen-specific effector memory T cells (T EMRA) over 3 to 4 weeks in vitro. IL2 and IL15 can be synergistic in moDC stimulation of cytolytic T cells. IL15 promotes T-cell expression of the antiapoptotic bcl-2 and inhibits candidate regulatory T-cell (Treg) expansion after DC stimulation, countering two effects of IL2 that do not foster tumor immunity. Conclusions: MoDC-based vaccines will require exogenous IL15 to achieve clinical efficacy. Alternatively, LCs can couple the endogenous production of IL15 with potent T-cell stimulatory activity. Optimization of full-length tumor antigen expression for processing into multiple immunogenic peptides for presentation by both class I and II MHC therefore merits emphasis to support more effective antitumor immunity stimulated by LCs. Clin Cancer Res; 17(7); 1984-97. Ó2011 AACR.
IL15 and T-cell Stemness in T-cell-Based Cancer Immunotherapy
Cancer research, 2015
Preclinical models revealed that the immune system can mediate rejection of established tumors, but direct evidence in humans has been limited to largely immunogenic tumors, such as melanoma. The recent success of immune checkpoint inhibitors and adoptive T-cell transfer immunotherapy in clinical trials has instilled new hope for the use of T-cell immunotherapy in the treatment of cancer. IL15, a potent immunostimulatory cytokine, both potentiates host T-cells and natural killer (NK) cell immune responses and promotes the generation of long-lived memory T cells with superior functional capacity, with potential use in adoptive T-cell transfer protocols. IL15 has been recently tested in the clinic and showed dramatic effects at the level of responding NK and CD8(+) memory T cells. The recent advances in the knowledge of IL15-dependent regulation of T-cell responses, gene expression, and metabolic adaptation have important implications for the use of IL15 in T-cell-based immunotherapy ...
International Journal of Cancer, 2000
IL-15 is an immunostimulatory cytokine with IL-2-like activities. To exploit the potential role of IL-15 in cancer immuno-/gene therapy, we engineered murine TS/A cells with different IL-15 cDNA constructs. Significant IL-15 secretion was achieved only by the use of a modified cDNA encoding for an IL-15 pre-protein bearing the IgK light chain signal peptide. Different TS/A clones (TS/A IL-15 C6, C23, C29) producing 390 to 1,600 pg/ml biologically active IL-15 showed reduced tumorigenicity when implanted s.c. in syngeneic mice and significantly reduced metastatic potential by i.v.
Clinical Cancer Research, 2016
Purpose: Adoptive cell transfer (ACT) is a promising immunotherapeutic approach for cancer. Host lymphodepletion is associated with favorable ACT therapy outcomes, but it may cause detrimental effects in humans. We tested the hypothesis that IL15 administration enhances ACT in the absence of lymphodepletion. We previously showed that bioactive IL15 in vivo comprises a stable complex of the IL15 chain with the IL15 receptor alpha chain (IL15Rα), termed heterodimeric IL15 (hetIL15). Experimental Design: We evaluated the effects of the combination regimen ACT + hetIL15 in the absence of lymphodepletion by transferring melanoma-specific Pmel-1 T cells into B16 melanoma-bearing mice. Results: hetIL15 treatment delayed tumor growth by promoting infiltration and persistence of both adoptively transferred Pmel-1 cells and endogenous CD8+ T cells into the tumor. In contrast, persistence of Pmel-1 cells was severely reduced following irradiation in comparison with mice treated with hetIL15. I...