CD137 stimulation enhances the antilymphoma activity of anti-CD20 antibodies

Abstract

Antibody-dependent cell-mediated cytotoxicity (ADCC), which is largely mediated by natural killer (NK) cells, is thought IntroductionMonoclonal antibodies (mAbs) have revolutionized the treatment of cancer. The first approved mAb for this purpose, rituximab, a murine-human chimeric immunoglobulin G1 (IgG1) antibody against CD20, has become a standard treatment for patients with B-cell lymphomas.Despite tumor response rates to rituximab of up to 90% and decreased risk of death by as much as 36%, the majority of patients with advanced lymphoma still die of their disease, including 19 000 patients in the United States in 2009 alone. [1][2][3][4] Enhancing the efficacy of rituximab represents an opportunity to improve patient outcome. We have developed a strategy to enhance the antitumor activity of rituximab by augmenting antibody-induced cell killing.Several mechanisms of rituximab's antitumor action have been proposed, including direct induction of apoptosis, complementdependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity (ADCC), and, possibly, induction of an adaptive immune response (a "vaccinal" effect). 5 Among these mechanisms, ADCC is believed to be of importance, particularly to the initial antitumor response. In vitro studies have shown that rituximab can induce ADCC of human lymphoma cell lines. 6 In murine xenotransplant lymphoma models, a role for ADCC in rituximab's efficacy was confirmed in studies using FcR-␥-chain-deficient mice, 7 as well as a neutralizing antibody against murine Fc␥R. 8 Further murine studies using CD20 mAbs have confirmed that monocyte-mediated ADCC is the primary, if not exclusive, mechanism through which normal and malignant B cells are depleted in vivo. 9-13 Finally, clinical results have shown that patients harboring an Fc␥RIIIA polymorphism with higher affinity for IgG1 have better responses to rituximab, further supporting the hypothesis that ADCC is an important in vivo mechanism of rituximab action in patients with lymphoma. 14,15 Natural killer (NK) cells are known to be important effector cells mediating ADCC. Binding of the NK-cell Fc receptor (Fc␥RIII, CD16) to the constant region of an antibody induces NK-cell activation. On activation, NK cells release cytotoxic granules, promoting tumor cell killing, and up-regulate the expression of several activation markers, including CD137. 16 In this study, we hypothesized that rituximab-induced ADCC could be specifically increased by using an anti-CD137 agonistic mAb to enhance NK-cell function.CD137 (4-1BB) is a surface glycoprotein that belongs to the tumor-necrosis factor receptor superfamily. 17 CD137 is an inducible costimulatory molecule expressed on a variety of immune cells, including activated CD4 and CD8 T cells, NK cells, monocytes, and dendritic cells. 18,19 On T cells specifically, CD137 functions as a costimulatory receptor induced on T-cell receptor stimulation. In this context, ligation of CD137 leads to increased T-cell proliferation, cytokine production, functional maturation, and prolonged ...

4‐1BB ligand modulates direct and Rituximab‐induced NK‐cell reactivity in chronic lymphocytic leukemia

“…Such signals via 4-1BBL influence proliferation, survival and cytokine secretion of various healthy and malignant cell types [18]. As (i) Fc-receptor triggering was recently reported to enhance 4-1BB expression on NK cells [14,19], (ii) 4-1BBL has been reported to be functionally expressed on healthy B cells and tumor cell lines of lymphoid origin [20], and (iii) we recently found that 4-1BB/4-1BBL interaction impairs the reactivity of human NK cells against acute myeloid leukemia (AML) cells [16] we here studied the expression of 4-1BBL in CLL and its influence on direct and Rituximabinduced NK-cell reactivity.…”

NK cell-based immunotherapy for malignant diseases

“…119 Activated NK cells by an agonistic antibody to the activating 4-1BB receptor completely regressed subcutaneous murine lymphoma tumors during Rituximab treatment. 120 Antibodies containing cytokines linked to their Fc terminus, called immunocytokines (ICs), may wield certain advantages over traditional mAbs. 121 ICs enhance synapse formation between the mAb-coated tumor cell and the NK cell by enhancing both Fc and cytokine receptor binding.…”

Perspectives of Fc engineered antibodies in CD19 targeting immunotherapies in pediatric B-cell precursor acute lymphoblastic leukemia

“…Another strategy may be to co-stimulate myeloid effector cells and NK cells, which are absent in our NSG PDX model, but are expected to contribute to antibody-mediated effects in patients. Combining CD19 antibodies with agonistic CD137 antibodies, which were shown to alter the NK cell activation status leading to enhanced ADCC 39 may be warranted. Moreover, Fc engineered antibodies may be combined with immunomodulatory cytokines (e. g. GM-CSF, IFN-γ) or drugs (e. g. lenalidomide) to promote activation of lymphocytes and/or myeloid effector cells (Fig.…”