Fc Effector Function Contributes to the Activity of Human Anti-CTLA-4 Antibodies (original) (raw)
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Proceedings of the National Academy of Sciences, 2018
Anti–CTLA-4 mAb is efficacious in enhancing tumor immunity in humans. CTLA-4 is expressed by conventional T cells upon activation and by naturally occurring FOXP3+CD4+ Treg cells constitutively, raising a question of how anti–CTLA-4 mAb can differentially control these functionally opposing T cell populations in tumor immunity. Here we show that FOXP3high potently suppressive effector Treg cells were abundant in melanoma tissues, expressing CTLA-4 at higher levels than tumor-infiltrating CD8+ T cells. Upon in vitro tumor-antigen stimulation of peripheral blood mononuclear cells from healthy individuals or melanoma patients, Fc-region–modified anti–CTLA-4 mAb with high antibody-dependent cell-mediated cytotoxicity (ADCC) and cellular phagocytosis (ADCP) activity selectively depleted CTLA-4+FOXP3+ Treg cells and consequently expanded tumor-antigen–specific CD8+T cells. Importantly, the expansion occurred only when antigen stimulation was delayed several days from the antibody treatmen...
Journal of Translational Medicine, 2013
Background: CTLA-4 (Cytotoxic T lymphocyte antigen-4) is traditionally known as a negative regulator of T cell activation. The blocking of CTLA-4 using human monoclonal antibodies, such as Ipilimumab, is currently used to relieve CTLA-4-mediated inhibition of anti-tumor immune response in metastatic melanoma. Herein, we have analyzed CTLA-4 expression and Ipilimumab reactivity on melanoma cell lines and tumor tissues from cutaneous melanoma patients. Then, we investigated whether Ipilimumab can trigger innate immunity in terms of antibody dependent cellular cytotoxicity (ADCC) or Tumor Necrosis Factor (TNF)-α release. Finally, a xenograft murine model was set up to determine in vivo the effects of Ipilimumab and NK cells on melanoma.
PLoS ONE, 2013
It has previously been found that combination therapy with anti-CTLA-4 and anti-4-1BB antibodies may enhance tumor immunity. However, this treatment is not efficient against all tumors, and it has been suggested that variations in tumor control may reflect differences in the immunogenicity of different tumors. In the present report, we have formally tested this hypothesis. Comparing the efficiency of combination antibody therapy against two antigenically distinct variants of the B16.F10 melanoma cell line, we observed that antibody therapy delayed the growth of a variant expressing an exogenous antigen (P,0.0001), while this treatment failed to protect against the non-transfected parental line (P = 0.1850) consistent with published observations. As both cell lines are poorly immunogenic in wild type mice, these observations suggested that the magnitude of the tumor targeting T-cell repertoire plays a major role in deciding the efficiency of this antibody treatment. To directly test this assumption, we made use of mice expressing the exogenous antigen as a self-antigen and therefore carrying a severely purged T-cell repertoire directed against the major tumor antigen. Notably, combination therapy completely failed to inhibit tumor growth in the latter mice (P = 0.8584). These results underscore the importance of a functionally intact T-cell population as a precondition for the efficiency of treatment with immunomodulatory antibodies. Clinically, the implication is that this type of antibody therapy should be attempted as an early form of tumor-specific immunotherapy before extensive exhaustion of the tumor-specific T-cell repertoire has occurred.
Cancer Immunology, Immunotherapy, 2009
The management of unresectable metastatic melanoma is a major clinical challenge because of the lack of reliably eVective systemic therapies. Blocking cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) has recently been proposed as a strategy to enhance cell-mediated immune responses to cancer, and clinical trials have demonstrated that anti-CTLA-4 therapy can produce durable outcomes with diVerent response patterns than cytotoxic chemotherapy. We enrolled eight out of 155 patients with advanced melanoma in a multicentre phase II trial that evaluated the activity and tolerability of ipilimumab, a fully human, anti-CTLA-4 monoclonal antibody (www.clinicaltrials.gov; NCT00289627; CA184-008). Here we report our experience with three of these patients, who experienced progressive disease after a variety of previous therapies, including prior immunotherapies, and who achieved good outcomes with ipilimumab. One patient had a partial response ongoing at 17+ months on ipilimumab despite failure with four prior therapies, and the other two patients showed durable stable disease, both still ongoing at 17+ and 20+ months, respectively. The patient achieving a partial response experienced no side eVects while receiving ipilimumab. The other two patients developed immunerelated adverse events (irAEs) including rash (one case; grade 2) and diarrhoea (both cases; grades 1 and 2, respectively); the histopathology of colon biopsy samples from both was suggestive of colitis, with an abundant CD8+ Tcell inWltrate. Nausea, vomiting and acute pancreatitis were also observed in one patient. In addition, immunohistochemical Wndings of a dense CD8+, TIA1+ and granzyme B+ lymphoid inWltrate within a biopsied lesion provide indirect evidence of functional T-cell activation induced by treatment. These case reports highlight the potential for anti-CTLA-4-based therapy in previously treated patients with advanced melanoma. Moreover, because the patterns of response to ipilimumab diVer from chemotherapy, we need to understand how and when patients may respond to treatment so that appropriate clinical decisions can be made.
Anti-CTLA-4 therapy in melanoma: role of ipilimumab (MDX-010)
Expert Review of Dermatology, 2009
When the cytotoxic T-lymphocyte-associated protein (CTLA)-4 molecule, present on the surface of a lymphocyte after immune cell activation, binds B7 surface molecules, T-lymphocyte anergy occurs, resulting in cell proliferation and inhibition of IL-2 secretion. Treatment with the anti-CTLA-4 monoclonal antibody ipilimumab (MDX-010) seems to prevent this anergy and permits specific T-lymphocyte activation against tumor antigens. Two Phase I trials on metastatic melanoma have been conducted using doses ranging from 3 to 20 mg/kg, followed by several Phase II trials. Although immune-related adverse events were reported in most of the clinical trials, these were generally manageable with systemic steroids or symptomatic treatments, and anti-tumor efficacy did not appear to be affected. Durable objective response rates were obtained in 4.6-15% of patients, with a further increment in late responses after long-term stable disease or after initial progression. Early and late responses, or stabilizations that are preceded by apparent progressive disease, would seem to indicate that new efficacy criteria are needed to describe the clinical benefit of ipilimumab.
Cell research, 2015
The cytotoxic T lymphocyte antigen-4 (CTLA-4)-blocking antibody ipilimumab induces immune-mediated long-term control of metastatic melanoma in a fraction of patients. Although ipilimumab undoubtedly exerts its therapeutic effects via immunostimulation, thus far clinically useful, immunologically relevant biomarkers that predict treatment efficiency have been elusive. Here, we show that neutralization of IL-2 or blocking the α and β subunits of the IL-2 receptor (CD25 and CD122, respectively) abolished the antitumor effects and the accompanying improvement of the ratio of intratumoral T effector versus regulatory cells (Tregs), which were otherwise induced by CTLA-4 blockade in preclinical mouse models. CTLA-4 blockade led to the reduction of a suppressive CD4(+) T cell subset expressing Lag3, ICOS, IL-10 and Egr2 with a concomitant rise in IL-2-producing effector cells that lost FoxP3 expression and accumulated in regressing tumors. While recombinant IL-2 improved the therapeutic ef...
Cancer immunology research, 2013
CD4(+) T cells provide help to enhance and sustain cytotoxic CD8(+) T cell responses. A direct lytic role for this cell population in mouse models further supports the use of tumor-reactive CD4(+) T cells for cancer immunotherapy. CTLA-4 blockade has been shown to expand antigen-specific cytotoxic CD4(+) T cells in mouse models. We took advantage of spontaneous immunity to the NY-ESO-1 cancer-testis antigen to investigate quantitative and qualitative changes in antigen-specific CD4(+) T cell responses after ipilimumab (anti-CTLA-4 monoclonal antibody) treatment in advanced melanoma patients. Four NY-ESO-1 seropositive melanoma patients were chosen upon the availability of suitable blood specimens for characterizing the functions of NY-ESO-1 antigen-specific CD4(+) T cell response by enzyme-linked immunospot (ELISPOT), intracellular cytokine staining (ICS) and cytotoxicity assays. Multiple NY-ESO-1 antigen-specific CD4(+) T cell responses with Th1 dominance were induced or enhanced a...
CTLA-4 antibodies in cancer immunotherapy
Activating human immune system to battle cancer has been a focus of cancer immunotherapy research from quite some time. After decades of disappointment, the tide has finally changed with some recent successes in clinical trials. The first such approach with clinical success is cytotoxic T lymphocyte antigen-4 (CTLA-4) antibody therapy which aims to relieve the immune suppressive effects of CTLA-4 on T cells which are specifically aimed to fight cancer. CTLA-4 antibody therapy has enhanced the survival of patients suffering from late stage refractory metastatic melanoma. The success of CTLA-4 antibody therapy has cemented cancer immunotherapy potential in patients and even swayed away skeptics.