Bispecific antibody-activated T cells enhance NK cell-mediated antibody-dependent cellular cytotoxicity

Abstract

Resistance to anti-cancer monoclonal antibody (mAb) therapy remains a clinical challenge. Previous work in our laboratory has shown that T cell help in the form of interleukin-2 maintains long-term NK cell viability and NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC). Lack of such T cell help may be a potential mechanism for resistance to mAb therapy. Here, we evaluate whether concomitant treatment with anti-CD3 × anti-cancer bispecific antibodies (bsAbs) can overcome this resistance by enhancing T cell help, and thereby maintaining long-term NK cell-mediated ADCC. Normal donor peripheral blood mononuclear cells were depleted of T cells, replenished with defined numbers of autologous T cells (from 0.75 to 50%) and co-cultured with mono-/bispecific antibody-treated target tumor cells for up to 7 days. At low T cell concentrations, bsAb-activated T cells (mainly CD4+ T cells) were more effective than resting T cells at maintaining NK cell viability and ADCC. Brief (4 h to 2 day) bsAb exposure was sufficient to enhance long-term ADCC by NK cells. These findings raise the hypothesis that local T cell activation mediated by systemic treatment with anti-CD3 X anti-cancer bsAb may enhance the anti-tumor efficacy of monospecific mAbs that mediate their primary therapeutic effect via NK-mediated ADCC.

A Pathogenic Role for FcγRI in the Immune Response against Chlamydial Respiratory Infection

“…As target cells of FcR, NK cells are one of the key components of innate immunity to invading pathogens [ 23 , 24 , 25 , 26 ]. In determining the contribution of FcγRI to host defense against chlamydial infection, we also observed potential modulation of FcγRI on this cell population.…”

Amino acid metabolism in immune cells: essential regulators of the effector functions, and promising opportunities to enhance cancer immunotherapy

“…First, they can recognize and respond to cancer cells lacking MHCI expression [178]. ADCC is another important mechanism by which NK cells function to restrict tumor growth and survival, and thus several studies have sought out ways to enhance ADCC such as assessing synergistic effects with anti-PD-L1, cytokine stimulation, and intercellular interactions [179][180][181]. NK cells also produce pro-inflammatory cytokines such as IFNγ and TNFα to promote anti-tumor activity of other immune cells or to directly inhibit tumor cells.…”

Flow cytometric assessment for minimal/measurable residual disease in B lymphoblastic leukemia/lymphoma in the era of immunotherapy

“…Blinatumomab is a bispecific anti‐CD19/CD3 T cell engager (BiTE) that consists of a small molecule with a physical bridge between fragments of antibodies directed against CD3‐expressing T cells and CD19‐expressing neoplastic cells to enable optimal interaction between these two cell types and thereby facilitate the anti‐leukemia T cell mediated immune response. By bringing CD19‐expressing leukemic blasts in close proximity with T cells, blinatumomab induces T cell engagement and ADCC to eliminate CD19‐positive leukemic blasts (Franquiz & Short, 2020; Wang et al, 2021). In pediatric and adult patients with R/R B‐LL, blinatumomab resulted in significantly improved survival rates compared with standard chemotherapy (Kantarjian et al, 2017; Locatelli et al, 2020; Locatelli et al, 2021).…”