Changes in Dendritic Cell Phenotype After a New High-dose Weekly Schedule of Interleukin-2 Therapy for Kidney Cancer and Melanoma
High-dose intravenous interleukin-2 (IL-2) therapy (14 doses/course, 2 courses/cycle) for metastatic melanoma or kidney cancer induces infrequent, although major responses. In this trial, we evaluated a new schedule (dose of 600,000 IU/kg, 8 h between doses, 5 doses/course, 4 courses at weekly intervals/cycle) of high-dose IL-2, in which we inserted more planned breaks while maintaining high cumulative dose delivery, and investigated the relationship between dendritic cells (DC) and response to treatment. Target dose delivery was attained: median IL-2 cumulative dose per patient was 11.4 and 10.8 million units/kg (cycles 1 and 2, respectively). Major responses were observed in patients with kidney cancer (n=20; 3 complete and 2 partial responses) and melanoma (n=16; 1 partial response). Adverse events appeared comparable with those typically associated with high-dose IL-2. From this data set, we introduce the hypothesis-generating observation that patients who had more favorable outcomes had high pretreatment DC-to-myeloid-derived suppressor cell (MDSC) ratios, similar to the ratio observed in healthy individuals. However, even in patients with the most favorable outcome, after treatment, there were IL-2-induced changes in the DC-to-MDSC ratio, specifically increases in MDSCs. This modified IL-2 schedule is a feasible option, with a more uniform dose delivery over the treatment cycle, a similar toxicity profile, and observed complete, durable response in patients with renal cancer. Pretreatment assessment of DC phenotypic or maturational status may be a starting point to predicting response to high-dose IL-2 cytokine immunotherapy in patients with melanoma and kidney cancer.
Available from: PubMed Central
- "As tumor antigens are weakly immunogenic, dendritic cell vaccination and IL-2 treatment are usually used to increase CTL activity clinically
. Using our B16 tumor model, we co-administered pmel-1 CTLs, Ad-USP18, IL-2 and dendritic cells into tumor. "
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Interferon (IFN)-γ-mediated immune response plays an important role in tumor immunosurveillance. However, the regulation of IFN-γ-mediated tumorigenesis and immune response remains elusive. USP18, an interferon stimulating response element, regulates IFN-α-mediated signaling in anti-viral immune response, but its role in IFN-γ-mediated tumorigenesis and anti-tumor immune response is unknown.
In this study, USP18 in tumorigenesis and anti-tumor immune response was comprehensively appraised in vivo by overexpression or downregulation its expression in murine B16 melanoma tumor model in immunocompetent and immunodeficient mice.
Ectopic expression or downregulation of USP18 in B16 melanoma tumor cells inhibited or promoted tumorigenesis, respectively, in immunocompetent mice. USP18 expression in B16 melanoma tumor cells regulated IFN-γ-mediated immunoediting, including upregulating MHC class-I expression, reducing tumor cell-mediated inhibition of T cell proliferation and activation, and suppressing PD-1 expression in CD4+ and CD8+ T cells in tumor-bearing mice. USP18 expression in B16 melanoma tumor cells also enhanced CTL activity during adoptive immunotherapy by prolonging the persistence and enhancing the activity of adoptively transferred CTLs and by reducing CTL exhaustion in the tumor microenvironment. Mechanistic studies demonstrated that USP18 suppressed tumor cell-mediated immune inhibition by activating T cells, inhibiting T-cell exhaustion, and reducing dendritic cell tolerance, thus sensitizing tumor cells to immunosurveillance and immunotherapy.
These findings suggest that stimulating USP18 is a feasible approach to induce B16 melanoma specific immune response.
Available from: Magali Terme
- "These results may suggest that bevacizumab could modulate not all MDSC subsets but only immature MDSC [18, 58]. The impact of IL-2 on MDSC proportion could also not be excluded . In a mouse model of melanoma, one study showed a critical role for tumor-expressed iNOS in the recruitment of MDSC via the modulation of VEGF secretion . "
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ABSTRACT: In the last decades a new class of therapeutic drugs have been developed that block tumor angiogenesis. These antiangiogenic molecules, which target VEGF or VEGFR, PDGFR, and c-kit, can act not only on endothelial cells but also on immune cells. Some antiangiogenic molecules inhibit the development of immunosuppressive mechanisms developed by the tumors to escape the immune system (such as regulatory T cells, myeloid-derived suppressor cells, and immunosuppressive cytokines). These immunomodulatory effects must be characterized in detail to enable a better prescription of these treatments. In this paper we will focus on the impact of anti-angiogenic drugs on immunosuppression and their potential combination with immunotherapeutic strategies. Interestingly, immune parameters or their modulation during treatment could serve as potential biomarkers of response or resistance to anti-angiogenic therapies.
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ABSTRACT: Renal cell carcinoma (RCC) is a chemo-resistant malignancy. For many years the only treatment for advanced disease was immunotherapy; the cytokines IFN-α and IL-2 were widely used but offered limited objective response rates of 10-20% and only modest survival benefits in the majority of cases. The last decade has witnessed a marked increase in the availability of novel targeted therapies demonstrating anti-tumor activity and, more importantly, providing a meaningful impact on overall survival. However, to date, immunotherapy, in the form of high-dose IL-2, remains the only treatment modality able to induce durable complete remissions and/or cure in metastatic RCC, albeit in a small minority of patients. A priority for immunotherapy research should be to investigate strategies that may augment the effectiveness of immunomodulation and enable a greater proportion of patients with advanced RCC to benefit from this treatment. A number of approaches are discussed; combinations with molecularly targeted agents may potentiate response and survival, immune checkpoint inhibitors such as CTLA-4 and PD1 antibodies are showing encouraging activity in early clinical trials and vaccines are of renewed interest. Taking these and other novel immunomodulatory agents forward will require the use of immune-related response criteria in clinical trial design and, most importantly, the ability to identify reliable predictors of benefit so that appropriate patients may be selected for immunotherapeutic treatments.
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