Therapeutic effect of CD137 immunomodulation in lymphoma and its enhancement by Treg depletion

Abstract

Despite the success of passive immunotherapy with monoclonal antibodies (mAbs), many lymphoma patients eventually relapse. Induction of an adaptive immune response may elicit active and longlasting antitumor immunity, thereby preventing or delaying recurrence. Immunomodulating mAbs directed against immune cell targets can be used to enhance the immune response to achieve efficient antitumor immunity. Anti-CD137 agonistic mAb has demonstrated antitumor efficacy in various tumor models and has now entered clinical trials for the treatment of solid tumors. Here, we investigate the therapeutic potential of anti-CD137 mAb in lymphoma. We found that human primary lymphoma tumors are infiltrated with CD137 ؉ T cells. We therefore hypothesized that lymphoma would be susceptible to treatment with anti-CD137 agonistic mAb. Using a mouse model, we demonstrate that anti-CD137 therapy has potent antilymphoma activity in vivo. The antitumor effect of anti-CD137 therapy was mediated by both natural killer (NK) and CD8 T cells and induced long-lasting immunity. Moreover, the antitumor activity of anti-CD137 mAb could be further enhanced by depletion of regulatory T cell (T regs ). These results support the evaluation of anti-CD137 therapy in clinical trials for patients with lymphoma. (Blood. 2009;114:3431-3438) IntroductionLymphoma is responsive to immunotherapy. 1 Despite the success of passive immunotherapy with monoclonal antibodies (mAbs) directed against tumor cells (eg, anti-CD20, rituximab), many lymphoma patients eventually relapse. Active immunotherapy for the treatment of lymphoma aims to induce an adaptive and long-lasting antitumor immune response to prevent or prolong time to recurrence. Although antitumor immune cells can be found in cancer patients, these cells may be rendered ineffective in eradicating cancer due to tumor-induced immunosuppression. 2 Monoclonal antibodies that target and modulate the function of tumor-reactive immune cells may enhance antitumor immune responses to therapeutic levels. 3 Targeting the immune environment of the tumor as opposed to the malignant cells presents unique advantages. Whereas targeting tumor cells with mAbs requires a tumor-specific antigen (Ag), stimulating or inhibiting nonmalignant immune cells is expected to be applicable across different patients and cancer types. Further, unlike tumor cells that may mutate into therapy-resistant clones under selective pressure of mAb treatment, normal immune cells are not expected to be clonally selected for such mutations. Finally, whereas tumor-directed mAbs are considered passive immunotherapy and therefore offer only transient efficacy, targeting the immune system with mAbs aims to induce and/or potentiate an active and long-lasting immune response against cancer.Antibody-mediated T-cell modulation can be accomplished in several ways, including (1) enhancing costimulation on conventional T cells (T convs ; eg, agonistic anti-CD137 and anti-OX40 mAbs); (2) blocking negative signals on T convs (eg, antagonistic anti-CTLA4 mAb); o...

Enhancement of Anti-Tumor Immunity Through Local Modulation of CTLA-4 and GITR by Dendritic Cells

“…Additional murine studies have demonstrated that co-administration of anti-GITR and anti-CTLA-4 mAbs have a synergistic effect, leading to eradication of tumors in a murine tumor model [11,13,50]. Mitsui Based on the results presented in this report, we have initiated a Phase I clinical trial in subjects with metastatic melanoma (ClinicalTrials.gov ID# NCT01216436).…”

Le double visage des anticorps monoclonaux en oncologie

“…Il a été montré -dans un modèle de souris immunocompétentes -qu'un anticorps agoniste anti-CD137 permet d'inhiber la croissance d'un lymphome in vivo et d'améliorer la survie des animaux, grâce au développement d'une immunité antitumorale s'inscrivant dans la durée. De plus, cet effet est renforcé par la déplétion des cellules Treg grâce à un anticorps dirigé contre le récepteur du folate-4 (FR4) [15]. Une autre stratégie actuellement explorée consiste à réévaluer l'effet thérapeutique de cytokines dont le déve-loppement a été arrêté du fait d'effets secondaires sévères aux doses utilisées, en les combinant avec des anticorps antagonistes.…”

Is Absolute Lymphocyte Count Just Another Prognostic Factor in Cancer?

“…These clinical observations suggest that new treatment modalities to enhance host immunity (i.e., NK cells) might improve survival in cancer patients. One of those new treatments that it is currently undergoing clinical trials is anti CD 137 monoclonal antibody [53,54]. CD 137 is a surface glycoprotein that belongs to the tumor-necrosis factor receptor superfamily (TNFRSF) and is expressed by activated natural killer cells, T cells, and dendritic cells [53,54].…”

“…One of those new treatments that it is currently undergoing clinical trials is anti CD 137 monoclonal antibody [53,54]. CD 137 is a surface glycoprotein that belongs to the tumor-necrosis factor receptor superfamily (TNFRSF) and is expressed by activated natural killer cells, T cells, and dendritic cells [53,54]. In vivo studies have shown that anti CD137 enhances cytotoxicity of NK cells and induces a CD4+Th1 response [53].…”

“…In vivo studies have shown that anti CD137 enhances cytotoxicity of NK cells and induces a CD4+Th1 response [53]. Furthermore, anti CD137 effect of immunomodulation can be enhanced by depletion of regulatory T-cells (T-regs) [54], which has been associated with T-cell mediated immunosuppression and correlated with tumor progression in NHL patients [55]. Thus, new therapy to deplete or inhibit T-reg-might also enhance host anti-tumor immunity, translating into improved survival in cancer patients [56] .…”