Septins promote epithelial motility by reinforcing the crosslinking of lamellar stress fibers and the stability of nascent focal adhesions.

No abstract

Duvortuxizumab (JNJ-64052781 or MGD011) is a CD19 x CD3 DART® protein designed to engage and redirect CD3+ T-cells to eliminate CD19+ B-cells through T-cell-mediated cytotoxicity. Duvortuxizumab displays potent killing activity in lymphoma cell lines and animal models and is currently in clinical development for the treatment of B-cell malignancies. Here we examined duvortuxizumab activity alone and in combination with standard chemotherapy regimens in preclinical lymphoma models. Duvortuxizumab plus bendamustine increased T-cell mediated cytotoxicity of CD19+ Raji and DOHH2 lymphoma cells in the presence of isolated human pan T-cells (effector:target = 10:1). Minimal inhibition of T-cell activation was observed at bendamustine concentrations up to 40 µM. A Burkitt’s lymphoma model was used to evaluate the in vivo effects of duvortuxizumab plus bendamustine. NOD scid gamma mice were subcutaneously implanted with Daudi tumor cells and inoculated with either peripheral blood mononuclear cells or purified, activated human pan T-cells. Duvortuxizumab was dosed at 0.5 mg/kg (x7, twice weekly); bendamustine was dosed once at 25 mg/kg on day 1. Dosing with bendamustine alone inhibited tumor growth by 79% (p=0.0002) whereas duvortuxizumab alone resulted in complete tumor regression with no signs of relapse for up to 90 days. Dosing with duvortuxizumab plus bendamustine resulted in complete and durable tumor regression and elimination. Analysis of tumor-infiltrating lymphocytes (TILs) 3 days after the start of therapy showed that bendamustine inhibited CD3+ T-cell infiltration and activation whereas duvortuxizumab increased both. The combination showed greater activation of CD4+ and CD8+ T-cells. At 48 days after the last duvortuxizumab dose, TILs had a large percentage of CD3+ CD45RA- CCR7- cells, indicative of effector memory T-cells. This activation was accompanied by higher expression of PD-1 on T-cells and PD-L1 on tumor cells. Similar effects were seen when duvortuxizumab was combined with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). In vitro, a decrease in T-cell activation was observed with duvortuxizumab/CHOP, which may have been caused by inclusion of prednisone; however, cytotoxicity against tumor cells was maintained. In a patient sample-derived model of diffuse large B-cell lymphoma, duvortuxizumab (twice weekly for 4 consecutive weeks) in combination with CHOP (given once) resulted in rapid tumor regression that was more sustained than CHOP treatment alone. In summary, duvortuxizumab has potent anti-tumor activity as a single agent and in combination with standard chemotherapy in lymphoma preclinical models. Duvortuxizumab-mediated tumor killing and T-cell activation were maintained or increased in the presence of multiple chemotherapeutics, suggesting the potential clinical utility of combining duvortuxizumab with standard therapies in the treatment of B-cell malignancies. Citation Format: Liat Izhak, Dana E. Cullen, Maha Elgawly, Leopoldo Luistro, Syd Johnson, Jaime Bald, A Kate Sasser, Sriram Balasubramanian. Potent antitumor activity of duvortuxizumab, a CD19 x CD3 DART® molecule, in lymphoma models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3636. doi:10.1158/1538-7445.AM2017-3636