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The immunomodulatory effects of bevacizumab on systemic immunity in patients with metastatic melanoma.

ABSTRACT: Metastatic melanoma is near-to-invariably a fatal disease. As novel therapeutic strategies against metastatic melanoma are urgently needed, we have tested a combinatorial regimen consisting of conventional chemotherapy coupled to bevacizumab, a monoclonal antibody that inhibit angiogenesis, demonstrating some clinical benefit. A preliminary assessment of one of our clinical trials points to a previously unrecognized immunomodulatory effect of bevacizumab. Herein, we evaluate the immunomodulatory effect of bevacizumab when administered together with conventional chemotherapy to patients with metastatic melanoma. To this aim, we measured the abundance of various lymphocyte subsets among peripheral blood mononuclear cells (PBMCs) as well as the circulating levels of 42 cytokines, chemokines and growth factors in patients with metastatic melanoma who received albumin-bound paclitaxel plus carboplatin, either as a standalone intervention (AC, 55 subjects) or combined with bevacizumab (ACB, 39 individuals), in the context of clinical trials N057e and N0775, respectively. Relative shifts in PBMC subsets and cytokine levels were calculated (relative to baseline levels) when patients underwent restaging evaluation after two cycles of therapy. The Mann-Whitney U test was used to compare responses between the groups. Bevacizumab failed to affect the T_H1/T_H2 cell ratio in this patient cohort. However, we observed a significant increase in CD8⁺ lymphocytes in patients who received ACB (+38%) but not in subjects treated with AC only (-10%) (p = 0.03). Moreover, circulating interleuikin-6 (IL-6) levels were reduced in patients treated with ACB (-42%) but not in individuals receiving AC only (28%) (p = 0.0018). Thus, the addition of bevacizumab to chemotherapy for the treatment of metastatic melanoma exerts immunomodulatory effects.

SUBMITTER: Mansfield AS

PROVIDER: S-EPMC3667915 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundRecent clinical advances in cancer immuno-therapeutics underscore the need for improved understanding of the complex relationship between cancer and the multiple, multi-functional, inter-dependent, cellular and humoral mediators/regulators of the human immune system. This interdisciplinary effort exploits engineering analysis methods utilized to investigate anomalous physical system behaviors to explore immune system behaviors. Cancer Immune Control Dynamics (CICD), a systems analysis approach, attempts to identify differences between systemic immune homeostasis of 27 healthy volunteers versus 14 patients with metastatic malignant melanoma based on daily serial measurements of conventional peripheral blood biomarkers (15 cell subsets, 35 cytokines). The modeling strategy applies engineering control theory to analyze an individual's immune system based on the biomarkers' dynamic non-linear oscillatory behaviors. The reverse engineering analysis uses a Singular Value Decomposition (SVD) algorithm to solve the inverse problem and identify a solution profile of the active biomarker relationships. Herein, 28,605 biologically possible biomarker interactions are modeled by a set of matrix equations creating a system interaction model. CICD quantifies the model with a participant's biomarker data then computationally solves it to measure each relationship's activity allowing a visualization of the individual's current state of immunity.ResultsCICD results provide initial evidence that this model-based analysis is consistent with identified roles of biomarkers in systemic immunity of cancer patients versus that of healthy volunteers. The mathematical computations alone identified a plausible network of immune cells, including T cells, natural killer (NK) cells, monocytes, and dendritic cells (DC) with cytokines MCP-1 [CXCL2], IP-10 [CXCL10], and IL-8 that play a role in sustaining the state of immunity in advanced cancer.ConclusionsWith CICD modeling capabilities, the complexity of the immune system is mathematically quantified through thousands of possible interactions between multiple biomarkers. Therefore, the overall state of an individual's immune system regardless of clinical status, is modeled as reflected in their blood samples. It is anticipated that CICD-based capabilities will provide tools to specifically address cancer and treatment modulated (immune checkpoint inhibitors) parameters of human immunity, revealing clinically relevant biological interactions.

Project description:The cyclic VHCDR3-derived peptide (Rb9) from RebMab200 antibody, directed to a NaPi2B phosphate-transport protein, displayed anti-metastatic melanoma activity at 50-300 ?g intraperitoneally injected in syngeneic mice. Immune deficient mice failed to respond to the peptide protective effect. Rb9 induced increased CD8+ T and low Foxp3+ T cell infiltration in lung metastases and high IFN-? and low TGF-? in lymphoid organs. The peptide co-localized with F-actin and a nuclear site in dendritic cells and specifically bound to MIF and CD74 in a dot-blot setting. Murine bone-marrow dendritic cells preincubated with Rb9 for 6 h were treated with MIF for short time periods. The modulated responses showed stimulation of CD74 and inhibition of pPI3K, pERK, and pNF-?B as compared to MIF alone. Rb9 in a melanoma-conditioned medium, stimulated the M1 type conversion in bone marrow-macrophages. Functional aspects of Rb9 in vivo were studied in therapeutic and prophylactic protocols using a melanoma metastatic model. In both protocols Rb9 exhibited a marked anti-melanoma protection. Human dendritic cells were also investigated showing increased expression of surface markers in response to Rb9 incubation. Rb9 either stimulated or slightly inhibited moDCs submitted to inhibitory (TGF-? and IL-10) or activating (LPS) conditions, respectively. Lymphocyte proliferation was obtained with moDCs stimulated by Rb9 and tumor cell lysate. In moDCs from cancer patients Rb9 exerted immunomodulatory activities depending on their functional status. The peptide may inhibit over-stimulated cells, stimulate poorly activated and suppressed cells, or cause instead, little phenotypic and functional alterations. Recently, the interaction MIF-CD74 has been associated to PD-L1 expression and IFN-?, suggesting a target for melanoma treatment. The effects described for Rb9 and the protection against metastatic melanoma may suggest the possibility of a peptide reagent that could be relevant when associated to modern immunotherapeutic procedures.

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The immunomodulatory effects of bevacizumab on systemic immunity in patients with metastatic melanoma.

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