Abstract
BackgroundIpilimumab is an antagonistic monoclonal antibody against cytotoxic T-lymphocyte antigen-4 (CTLA-4) that enhances antitumor immunity by inhibiting immunosuppressive activity of regulatory T cells (Treg). In this study, we investigated whether inhibiting Treg activity with ipilimumab during ex vivo T cell expansion could augment anti-CD3-driven T cell proliferation and enhance bispecific antibody (BiAb)-redirected antitumor cytotoxicity of activated T cells (ATC).MethodsPBMC from healthy individuals were stimulated with anti-CD3 monoclonal antibody with or without ipilimumab and expanded for 10-14 days. ATC were harvested and armed with anti-CD3 x anti-EGFR BiAb (EGFRBi) or anti-CD3 x anti-CD20 BiAb (CD20Bi) to test for redirected cytotoxicity against COLO356/FG pancreatic cancer cell line or Burkitt’s lymphoma cell line (Daudi).ResultsIn PBMC from healthy individuals, the addition of ipilimumab at the initiation of culture significantly enhanced T cell proliferation (p = 0.0029). ATC grown in the presence of ipilimumab showed significantly increased mean tumor-specific cytotoxicity at effector:target (E:T) ratio of 25:1 directed at COLO356/FG and Daudi by 37.71% (p < 0.0004) and 27.5% (p < 0.0004), respectively, and increased the secretion of chemokines (CCL2, CCL3, CCL4,CCL5, CXCL9, and granulocyte-macrophage colony stimulating factor(GM-CSF)) and cytokines (IFN-γ, IL-2R, IL-12, and IL-13), while reducing IL-10 secretion.ConclusionsExpansion of ATC in the presence of ipilimumab significantly improves not only the T cell proliferation but it also enhances cytokine secretion and the specific cytotoxicity of T cells armed with bispecific antibodies.
Highlights
Efficacy of cancer immunotherapy using targeted T cells has been limited by tumor-induced immunosuppression or regulatory T cells (Tregs) that interfere with T cell effector functions resulting in failure to induce robust cellular and humoral antitumor responses
Since recent clinical trial data show that cytotoxic T-lymphocyte antigen-4 (CTLA-4) positive Tregs are associated with reduced T cell antitumor activities [1], we hypothesized that treatment with anti-CTLA-4 monoclonal antibody
One approach to avoid immune-related adverse events (irAEs) would be by adding ipilimumab at the initiation of T cell expansion cultures to enhance the proliferation and cytotoxicity mediated by bispecific antibody (BiAb)-armed activated T cells (ATC)
Summary
Efficacy of cancer immunotherapy using targeted T cells has been limited by tumor-induced immunosuppression or regulatory T cells (Tregs) that interfere with T cell effector functions resulting in failure to induce robust cellular and humoral antitumor responses. This study shows that ipilimumab enhances T cell proliferation, tumor-specific cytotoxicity mediated by BiAb, and cytokine secretion without Treg-depletion prior to ATC expansion. These results could be used to optimize antitumor activity in immunotherapeutic approaches for patients with oncological or hematological malignancies. Ipilimumab is an antagonistic monoclonal antibody against cytotoxic T-lymphocyte antigen-4 (CTLA-4) that enhances antitumor immunity by inhibiting immunosuppressive activity of regulatory T cells (Treg). We investigated whether inhibiting Treg activity with ipilimumab during ex vivo T cell expansion could augment anti-CD3-driven T cell proliferation and enhance bispecific antibody (BiAb)-redirected antitumor cytotoxicity of activated T cells (ATC)
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