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. 2021 Jul 5;12:690437. doi: 10.3389/fimmu.2021.690437

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Copyright © 2021 Thakur, Scholler, Kubicka, Bliemeister, Schalk, June and Lum

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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hCART_41BBζ: (A) Specific Cytotoxicity by HER2 hCART_41BBζ and EGFR hCART_41BBζ Directed at Solid Tumor Cell Lines. The four panels show cytotoxicity of unarmed COATC (Control), CD20 hCART_41BBζ (irrelevant control), EGFR hCART_41BBζ and HER2 hCART_41BBζ in ⁵¹Cr release assay at E:T of 10:1. Cytotoxicity was measured against breast (Upper left), pancreas/GI (Upper right), prostate (Lower left) and glioblastoma (Lower right) cell lines. Data is presented as mean ± SD (n=3) and analyzed using Two-way ANOVA and Turkey’s multiple comparisons test (****p < 0.00001). (B) Sequential Targeting of MCF-7 with HER2 hCART_41BBζ and EGFR hCART_41BBζ. Upper panel shows the sequential cytotoxicity against MCF-7 cell line with either HER2 hCART_41BBζ followed by (f/b) EGFR hCART_41BBζ or EGFR_41BBζ (f/b) HER2 hCART_41BBζ using RTCA up to 96 hours at E:T of 1:1. The dashed lines denote single antigen targeting by HER2 hCART_41BBζ or EGFR hCART_41BBζ and solid lines show the double sequential killing mediated by effectors from 2 normal donors (ND1 =Normal Donor 1 and ND2 = Normal Donor 2). Lower panel shows the significant killing at 72 hours with sequential antigen targeting by HER2 hCART_41BBζ f/b EGFR hCART_41BBζ or EGFR hCART_41BBζ f/b HER2 hCART_41BBζ of MCF-7 compared to single antigen targeting by HER2 hCART_41BBζ (p<0.007) and EGFR hCART_41BBζ (p<0.003). Data is presented as mean ± SD (n=3) and analyzed using Two-way ANOVA and Turkey’s multiple comparisons test (**p < 0.001*). Right panel shows the sequential targeting schema. (C) Show Sequential Targeting of Two Antigens in SKBR3 and MB231 Cell Lines. The hCART_41BBζ induced significantly higher cytotoxicity against SKBR3 cells by sequential targeting of HER2 f/b EGFR (p<0.03) or EGFR f/b HER2 (p<0.02) compared to single antigen targeting. COATC and BATs also showed significantly enhanced killing by sequential targeting of EGFR f/b HER2 (p<0.03), HER2 f/b EGFR (p<0.004) compared single antigen targeting on SKBR3 cell line (Left panels of C and D). Significantly higher cytotoxicity after sequential targeting of EGFR f/b HER2 by hCART_41BBζ compared to single antigen targeting of HER2 (p<0.001) or EGFR (p<0.0002) was observed for MB231 cells (Right panels of C, D). Data is presented as mean ± SD (n=3) and analyzed using Two-way ANOVA and Turkey’s multiple comparisons test (***p < 0.0001, **p < 0.001, *p < 0.01).