No abstract

Oxide dispersion strengthened (ODS) tungsten heavy alloys have been considered as promising candidates for advanced kinetic energy penetrator due to their characteristic fracture mode compared to conventional tungsten heavy alloy. In order to obtain high relative density, the ODS tungsten heavy alloy needs to be sintered at higher temperature for longer time, however, induces growth of tungsten grains. Therefore, it is very difficult to obtain controlled microstructure of ODS tungsten heavy alloy having fine tungsten grains with full densification. In this study, two-stage sintering process, consisted of primary solid-state sintering and followed by secondary liquid phase sintering, was introduced for ODS tungsten heavy alloys. The mechanically alloyed 94W-4.56Ni-1.14Fe-0.3Y 2 O 3 powders are solid-state sintered at 1300-1450 • C for 1 h in hydrogen atmosphere, and followed by liquid phase sintering temperature at 1465-1485 • C for 0-60 min. The microstructure of ODS tungsten heavy alloys showed high relative density above 97%, with contiguous tungsten grains after primary solid-state sintering. The microstructure of solid-state sintered ODS tungsten heavy alloy was changed into spherical tungsten grains embedded in W-Ni-Fe matrix during secondary liquid phase sintering. The twostage sintered ODS tungsten heavy alloy from mechanically alloyed powders showed finer microstructure and higher mechanical properties than conventional liquid phase sintered alloy. The mechanical properties of ODS tungsten heavy alloys are dependent on the microstructural parameters such as tungsten grain size, matrix volume fraction and tungsten/tungsten contiguity, which can be controlled through the two-stage sintering process.

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Chimeric antigen receptors (CARs) combine specificity of antibody to target antigen on cancer cells with the potent cytotoxic activity of T-cells without the need for MHC recognition. Chimeric antigen receptor (CAR) T-cells that were designed to express the single chain variable fragment binding domain of human anti-CEA antibody BW431/26 on mouse splenocytes were able to reduce CEA-expressing pancreatic adenocarcinoma tumor in CEA-transgenic (CEAtg) mice without significant off-target effects (Chmielewski et al., 2012). In this study, an anti-CEA CAR construct derived from murine anti-CEA antibody (T84.66) expressed on human T-cells targeted CEA+ colon carcinoma cells (LS174T/CEA and MC38CEA) with high specificity in vitro. When co-incubated with CEA-positive or CEA-negative mouse cancer cells, anti-CEA CAR expressed on mouse T-cells also specifically targeted CEA-positive cancer cells in vitro. Compared to mock T-cells control, anti-CEA CAR T-cells injected intravenously delayed subcutaneous MC38CEA tumor growth in CEA-transgenic mice (CEAtg). Lymphodepletion via cyclophosphamide injected before anti-CEA T-cells injection further delayed subcutaneous MC38CEA tumor growth and delayed orthotopic CEA+ breast carcinoma (E0771CEA) tumor growth in CEAtg mice. To improve the therapeutic potential of anti-CEA CAR T-cells, IL2 conjugated to humanized anti-CEA antibody (M5A-IL2, ICK) was interperitoneally injected after anti-CEA CAR T-cells into lymphodepleted CEAtg mice. A single injection of ICK after anti-CEA CAR T-cells delayed subcutaneous MC38CEA tumor growth even further. Two injections of ICK after anti-CEA T-cells delayed orthotopic E0771CEA tumor growth. Four injections of ICK after anti-CEA CAR T-cells eradicated subcutaneous MC38CEA tumors. These data show the therapeutic potential of anti-CEA CAR T-cells to target CEA-positive tumors. Citation Format: Seung Cha, Paul Yazaki, Christine Brown, John Shively. Treatment of CEA-positive solid tumors with anti-CEA chimeric antigen receptor T-cells in CEA transgenic mice [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2020 Oct 19-20. Philadelphia (PA): AACR; Cancer Immunol Res 2021;9(2 Suppl):Abstract nr PO083.