Redirected T-Cell Killing of Solid Cancers Targeted with an Anti-CD3/Trop-2–Bispecific Antibody Is Enhanced in Combination with Interferon-α

Abstract

Trop-2 has limited presence on normal tissues but is highly expressed in diverse epithelial cancers. (E1)-3s is a T-cell-redirecting trivalent bispecific antibody (bsAb), comprising an anti-CD3 scFv covalently linked to a stabilized dimer of a Trop-2-targeting Fab using Dock-and-Lock. We show for the first time that bsAbmediated bidirectional trogocytosis occurs between target and T cells and involves immunologic synapses. We studied the effects of interferon-a (INFa) on (E1)-3s-mediated T-cell killing of human gastric and pancreatic cancer cell lines. T-cell activation, cytokine induction, and cytotoxicity were evaluated ex vivo using peripheral blood mononuclear cells (PBMC) or T cells with NCI-N87 gastric cancer as target cells. In vivo activity was assayed with NCI-N87 and Capan-1 (pancreatic) xenografts. In the presence of target cells and PBMCs, (E1)-3s did not cause excess cytokine production. When combined with (E1)-3s, peginterferonalfa-2a-which alone did not increase T-cell activation or raise cytokine levels over baseline-increased CD69 expression but did not significantly increase cytokine induction. (E1) 3s mediated a highly potent T-cell lysis of NCI-N87 target cells in vitro. Inclusion of peginterferonalfa-2a or a more potent form of INFa, 20 Ã -2b, significantly potentiated the activity of (E1)-3s by more than 2.5-or 7-fold, respectively. In vivo, combining peginterferonalfa-2a with (E1)-3s delayed Capan-1 growth longer than each single agent. Similarly, combination therapy delayed tumor proliferation of NCI-N87 compared with (E1)-3s or peginterferonalfa-2a single-treatment groups. (E1)-3s effectively induced T-cell-mediated killing of Trop-2-expressing pancreatic and gastric cancers, which was enhanced with INFa.

Prevention of Vγ9Vδ2 T Cell Activation by a Vγ9Vδ2 TCR Nanobody

“…Because these processes are inhibited by VHH 5E7, it is likely that VHH 5E7 inhibits the formation of immunological synapses between Vg9Vd2 T cells and target cells. This is supported by our observation that VHH 5E7, but not a nonspecific control VHH, dose-dependently inhibited trogocytosis, an active, rapid, and polarized bidirectional exchange of membrane patches in the immunological synapse that forms between immune effector and target cells (50)(51)(52)(53), that is, between Vg9Vd2 T cells and phosphoantigen-expressing target cells (Supplemental Fig. 1).…”

Combination Therapy with Bispecific Antibodies and PD-1 Blockade Enhances the Antitumor Potency of T Cells

“…21). We have also demonstrated in a follow-on study with (E1)-3s, a representative (X)-3s with specificity for Trop-2-expressing epithelial cancer cells, that the addition of interferon-a (IFN-a) further enhanced the potency of redirected T cells in vitro without a significant increase in cytokine production, and that the combination of (E1)-3s with peginterferon alfa-2a more effectively delayed the growth of Trop-2-expressing NCI-N87 human gastric cancer xenografts in vivo than single treatments with either (E1)-3s or peginterferon alfa-2a (28). In the current study, we provide evidence that the combination of a novel PD-1-blocking antibody (cPD-1) with (E1)-3s or the CEACAM5targeting (14)-3s could potentiate the antitumor activity of redirected T cells against target human cancer cells grown in vitro as monolayer cultures or three-dimensional (3D) multicellular tumor spheroids (MCTS; ref.…”

ISG15 in the tumorigenesis and treatment of cancer: An emerging role in malignancies of the digestive system

“…Clinical studies have demonstrated the benefit of IFN-α as an adjuvant to chemotherapy and radiation treatments following the resection of malignant tumors, including cancers of the digestive system [10-13]. Cell culture and animal studies have also shown that treatments that included IFN-α inhibited the proliferation and metastasis of hepatocellular carcinoma [14], gastric cancer, and pancreatic cancer cells [15]. However, recent studies have shown that IFN signaling is also involved in immunosuppression [16].…”