Tafasitamab mediates killing of B-cell non-Hodgkin’s lymphoma in combination with γδ T cell or allogeneic NK cell therapy

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• Tafasitamab (MOR208) is an Fc-modified, humanized monoclonal antibody that binds to the human B-cell surface antigen CD19

• Tafasitamab has two amino acid substitutions in the Fc region (S239D/I332E) that increase its affinity for Fcγ receptors, including FcγRIIIa (CD16)

• FcγRIIIa plays a key role in mediating ADCC and is expressed on the surface of natural killer (NK) cells and most γδ T cells

• The ADCC potency of tafasitamab in vitro is 100- to 1000-fold higher relative to an unmodified anti-CD19 IgG1 analogue [2], suggesting an important role for CD16-positive immune effector cells in ADCC-mediated antitumor activity.

• Tafasitamab and XmAb5603, an anti-CD19 analogue of tafasitamab with a wild-type IgG1 Fc region,

• Furthermore, γδ T cells in cancer patients have been found in reduced numbers and with a diminished proliferative capacity relative to healthy donors

• . A Phase I clinical study of patients with malignant lymphoma or advanced solid tumors who were treated with healthy human donor–derived, ex vivo-expanded allogeneic NK cells (MG4101) reported stable disease in 8 of 17 evaluable patients (47.1%) and a promising safety profile

• [11].

• Similarly, adoptive immune cell therapy with autologous γδ T cells demonstrated a low toxicity profile with modest therapeutic efficacy as monotherapy in several clinical trials [10].

• Therefore, combination of tafasitamab with adoptive NK or γδ T cell therapy may potentially be a promising novel approach to increase the number of immune effector cells in the tumor microenvironment and enhance the antitumor effects of tafasitamab. Prior studies have shown enhanced cytotoxicity of γδ T cells or allogeneic NK cells against a variety of tumor types upon combination with therapeutic antibodies, including rituximab and trastuzumab [12–15].

• To explore this concept for tafasitamab, we confirmed the ability of ex vivo-expanded γδ T or allogeneic NK cells (MG4101) to mediate tafasitamab-induced ADCC against lymphoma cells in vitro. In addition, we investigated the potential of adoptive cell therapy in combination with tafasitamab by supplementing tafasitamab treatment with MG4101 ex vivo-expanded NK cells in disseminated tumor mouse models of NHL.