Targeting and killing of glioblastoma with activated T cells armed with bispecific antibodies

Abstract Background Since most glioblastomas express both wild-type EGFR and EGFRvIII as well as HER2/neu, they are excellent targets for activated T cells (ATC) armed with bispecific antibodies (BiAbs) that target EGFR and HER2. Methods ATC were generated from PBMC activated for 14 days with anti-CD3 monoclonal antibody in the presence of interleukin-2 and armed with chemically heteroconjugated anti-CD3×anti-HER2/neu (HER2Bi) and/or anti-CD3×anti-EGFR (EGFRBi). HER2Bi- and/or EGFRBi-armed ATC were examined for in vitro cytotoxicity using MTT and 51Cr-release assays against malignant glioma lines (U87MG, U118MG, and U251MG) and primary glioblastoma lines. Results EGFRBi-armed ATC killed up to 85% of U87, U118, and U251 targets at effector:target ratios (E:T) ranging from 1:1 to 25:1. Engagement of tumor by EGFRBi-armed ATC induced Th1 and Th2 cytokine secretion by armed ATC. HER2Bi-armed ATC exhibited comparable cytotoxicity against U118 and U251, but did not kill HER2-negative U87 cells. HER2Bi- or EGFRBi-armed ATC exhibited 50—80% cytotoxicity against four primary glioblastoma lines as well as a temozolomide (TMZ)-resistant variant of U251. Both CD133– and CD133+ subpopulations were killed by armed ATC. Targeting both HER2Bi and EGFRBi simultaneously showed enhanced efficacy than arming with a single BiAb. Armed ATC maintained effectiveness after irradiation and in the presence of TMZ at a therapeutic concentration and were capable of killing multiple targets. Conclusion High-grade gliomas are suitable for specific targeting by armed ATC. These data, together with additional animal studies, may provide the preclinical support for the use of armed ATC as a valuable addition to current treatment regimens

Simulating the Growth of Articular Cartilage Explants in a Permeation Bioreactor to Aid in Experimental Protocol Design

Recently a cartilage growth finite element model (CGFEM) was developed to solve nonhomogeneous and time-dependent growth boundary-value problems (Davol et al., 2008, “A Nonlinear Finite Element Model of Cartilage Growth,” Biomech. Model. Mechanobiol., 7, pp. 295–307). The CGFEM allows distinct stress constitutive equations and growth laws for the major components of the solid matrix, collagens and proteoglycans. The objective of the current work was to simulate in vitro growth of articular cartilage explants in a steady-state permeation bioreactor in order to obtain results that aid experimental design. The steady-state permeation protocol induces different types of mechanical stimuli. When the specimen is initially homogeneous, it directly induces homogeneous permeation velocities and indirectly induces nonhomogeneous solid matrix shear stresses; consequently, the steady-state permeation protocol is a good candidate for exploring two competing hypotheses for the growth laws. The analysis protocols were implemented through the alternating interaction of the two CGFEM components: poroelastic finite element analysis (FEA) using ABAQUS and a finite element growth routine using MATLAB. The CGFEM simulated 12 days of growth for immature bovine articular cartilage explants subjected to two competing hypotheses for the growth laws: one that is triggered by permeation velocity and the other by maximum shear stress. The results provide predictions for geometric, biomechanical, and biochemical parameters of grown tissue specimens that may be experimentally measured and, consequently, suggest key biomechanical measures to analyze as pilot experiments are performed. The combined approach of CGFEM analysis and pilot experiments may lead to the refinement of actual experimental protocols and a better understanding of in vitro growth of articular cartilage

Modeling of traffic signal control and transit signal priority strategies in the MITSIMLab

Thesis (S.M.)--Massachusetts Institute of Technology, Dept. of Civil and Environmental Engineering, 2001.Includes bibliographical references (p. 117-118).by Angus P. Davol.S.M