DSP107 combines inhibition of CD47/SIRPα axis with activation of 4-1BB to trigger anticancer immunity

BACKGROUND: Treatment of Diffuse Large B Cell Lymphoma (DLBCL) patients with rituximab and the CHOP treatment regimen is associated with frequent intrinsic and acquired resistance. However, treatment with a CD47 monoclonal antibody in combination with rituximab yielded high objective response rates in patients with relapsed/refractory DLBCL in a phase I trial. Here, we report on a new bispecific and fully human fusion protein comprising the extracellular domains of SIRPα and 4-1BBL, termed DSP107, for the treatment of DLBCL. DSP107 blocks the CD47:SIRPα ‘don’t eat me’ signaling axis on phagocytes and promotes innate anticancer immunity. At the same time, CD47-specific binding of DSP107 enables activation of the costimulatory receptor 4-1BB on activated T cells, thereby, augmenting anticancer T cell immunity. METHODS: Using macrophages, polymorphonuclear neutrophils (PMNs), and T cells of healthy donors and DLBCL patients, DSP107-mediated reactivation of immune cells against B cell lymphoma cell lines and primary patient-derived blasts was studied with phagocytosis assays, T cell activation and cytotoxicity assays. DSP107 anticancer activity was further evaluated in a DLBCL xenograft mouse model and safety was evaluated in cynomolgus monkey. RESULTS: Treatment with DSP107 alone or in combination with rituximab significantly increased macrophage- and PMN-mediated phagocytosis and trogocytosis, respectively, of DLBCL cell lines and primary patient-derived blasts. Further, prolonged treatment of in vitro macrophage/cancer cell co-cultures with DSP107 and rituximab decreased cancer cell number by up to 85%. DSP107 treatment activated 4-1BB-mediated costimulatory signaling by HT1080.4-1BB reporter cells, which was strictly dependent on the SIRPα-mediated binding of DSP107 to CD47. In mixed cultures with CD47-expressing cancer cells, DSP107 augmented T cell cytotoxicity in vitro in an effector-to-target ratio-dependent manner. In mice with established SUDHL6 xenografts, the treatment with human PBMCs and DSP107 strongly reduced tumor size compared to treatment with PBMCs alone and increased the number of tumor-infiltrated T cells. Finally, DSP107 had an excellent safety profile in cynomolgus monkeys. CONCLUSIONS: DSP107 effectively (re)activated innate and adaptive anticancer immune responses and may be of therapeutic use alone and in combination with rituximab for the treatment of DLBCL patients. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13046-022-02256-x

When we want them to fear us: The motivation to influence outgroup emotions in collective action

Prior work has shown that the experience of group-based emotions can motivate disadvantaged group members to engage in collective action. In the current research, we tested whether such action can also be driven by the motivation to induce certain emotions among the outgroup to the extent that disadvantaged group members believe this would help them attain their social change goals. We tested this hypothesis in three studies (two correlational and one experimental) within the context of the Israeli-Palestinian conflict. Study 1 showed that individuals' motivation to induce outgroup regret was associated with nonviolent collective action tendencies, whereas the motivation to induce outgroup fear was related to violent action. Study 2 moved beyond Study 1 by assessing corrective and punitive goals of social change. We found that preferences for inducing outgroup regret mediated the relationship between endorsement of corrective goals and nonviolent action tendencies, whereas preferences for outgroup fear mediated the relationship between punitive goals and violent action. Study 3 provided experimental support for the causal effect of goals on emotion motivations and collective action tendencies. Together, our findings are in line with the notion of instrumental emotion regulation as applied to collective action

Can Fetal Echocardiographic Measurements of the Left Ventricular Outflow Tract Angle Detect Fetuses with Conotruncal Cardiac Anomalies?

Objectives: The angle between the inter-ventricular septum and the ascending aorta can be measured during a sonographic fetal survey while viewing the left ventricular outflow tract (LVOT angle). Our aim was to compare the LVOT angle between fetuses with and without conotruncal cardiac anomaliesrmations. Methods: In this prospective observational study, we compared the LVOT angle between normal fetuses, at different gestational age, and fetuses with cardiac malformations. Results: The study included 302 fetuses screened at gestational age of 12–39 weeks. The LVOT angle ranged from 127 to 163 degrees (mean 148.2), in 293 fetuses with normal hearts, and was not correlated with gestational age. The LVOT angle was significantly wider in fetuses with D-transposition of the great arteries (D-TGA, eight fetuses) and valvar aortic stenosis (AS, three fetuses), than in fetuses with normal hearts (164.8 ± 5.0 vs. 148.2 ± 5.4, respectively, p p < 0.001). On ROC analysis, an angle of 159.6 degrees or higher had a sensitivity of 100% and a specificity of 97.3% for the detection of TGA or AS, whereas an angle of 128.8 degrees or lower had a sensitivity of 100% and a specificity of 99.7% for the detection of AVC defect. Conclusions: The LVOT angle is constant during pregnancy, and differs significantly in fetuses with TGA/AS, and AVC, compared to fetuses with normal hearts (wider and narrower, respectively)

SupplementaryMaterial – Supplemental material for When we want them to fear us: The motivation to influence outgroup emotions in collective action

<p>Supplemental material, SupplementaryMaterial for When we want them to fear us: The motivation to influence outgroup emotions in collective action by Siwar Hasan-Aslih, Liat Netzer, Martijn van Zomeren, Tamar Saguy, Maya Tamir and Eran Halperin in Group Processes & Intergroup Relations</p