Universität zu Köln

Kobold, Sebastian, Steffen, Julius, Chaloupka, Michael, Grassmann, Simon, Henkel, Jonas, Castoldi, Raffaella, Zeng, Yi, Chmielewski, Markus, Schmollinger, Jan C., Schnurr, Max, Rothenfusser, Simon, Schendel, Dolores J., Abken, Hinrich, Sustmann, Claudio, Niederfellner, Gerhard, Klein, Christian ORCID: 0000-0001-7594-7280, Bourquin, Carole ORCID: 0000-0003-3862-4583 and Endres, Stefan (2015). Selective Bispecific T Cell Recruiting Antibody and Antitumor Activity of Adoptive T Cell Transfer. JNCI-J. Natl. Cancer Inst., 107 (1). CARY: OXFORD UNIV PRESS INC. ISSN 1460-2105

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Abstract

One bottleneck for adoptive T cell therapy (ACT) is recruitment of T cells into tumors. We hypothesized that combining tumor-specific T cells, modified with a marker antigen and a bispecific antibody (BiAb) that selectively recognizes transduced T cells and tumor cells would improve T cell recruitment to tumors and enhance therapeutic efficacy. SV40 T antigen-specific T cells from T cell receptor (TCR)-I-transgenic mice were transduced with a truncated human epidermal growth factor receptor (EGFR) as a marker protein. Targeting and killing by combined ACT and anti-EGFR-anti-EpCAM BiAb therapy was analyzed in C57Bl/6 mice (n = six to 12 per group) carrying subcutaneous tumors of the murine gastric cancer cell line GC8 (SV40(+) and EpCAM(+)). Anti-EGFR x anti-c-Met BiAb was used for targeting of human tumor-specific T cells to c-Met(+) human tumor cell lines. Differences between experimental conditions were analyzed using the Student's t test, and differences in tumor growth with two-way analysis of variance. Overall survival was analyzed by log-rank test. All statistical tests were two-sided. The BiAb linked EGFR-transduced T cells to tumor cells and enhanced tumor cell lysis. In vivo, the combination of ACT and Biab produced increased T cell infiltration of tumors, retarded tumor growth, and prolonged survival compared with ACT with a control antibody (median survival 95 vs 75 days, P < .001). In human cells, this strategy enhanced recruitment of human EGFR-transduced T cells to immobilized c-Met and recognition of tyrosinase(+) melanoma cells by TCR-, as well as of CEA(+) colon cancer cells by chimeric antigen receptor (CAR)-modified T cells. BiAb recruitment of tumor-specific T cells transduced with a marker antigen to tumor cells may enhance efficacy of ACT.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Kobold, Sebastian UNSPECIFIED UNSPECIFIED UNSPECIFIED Steffen, Julius UNSPECIFIED UNSPECIFIED UNSPECIFIED Chaloupka, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Grassmann, Simon UNSPECIFIED UNSPECIFIED UNSPECIFIED Henkel, Jonas UNSPECIFIED UNSPECIFIED UNSPECIFIED Castoldi, Raffaella UNSPECIFIED UNSPECIFIED UNSPECIFIED Zeng, Yi UNSPECIFIED UNSPECIFIED UNSPECIFIED Chmielewski, Markus UNSPECIFIED UNSPECIFIED UNSPECIFIED Schmollinger, Jan C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schnurr, Max UNSPECIFIED UNSPECIFIED UNSPECIFIED Rothenfusser, Simon UNSPECIFIED UNSPECIFIED UNSPECIFIED Schendel, Dolores J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Abken, Hinrich UNSPECIFIED UNSPECIFIED UNSPECIFIED Sustmann, Claudio UNSPECIFIED UNSPECIFIED UNSPECIFIED Niederfellner, Gerhard UNSPECIFIED UNSPECIFIED UNSPECIFIED Klein, Christian UNSPECIFIED orcid.org/0000-0001-7594-7280 UNSPECIFIED Bourquin, Carole UNSPECIFIED orcid.org/0000-0003-3862-4583 UNSPECIFIED Endres, Stefan UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-417153
DOI:	10.1093/jnci/dju364
Journal or Publication Title:	JNCI-J. Natl. Cancer Inst.
Volume:	107
Number:	1
Date:	2015
Publisher:	OXFORD UNIV PRESS INC
Place of Publication:	CARY
ISSN:	1460-2105
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language ENGAGING ANTIBODY; THERAPY; LYMPHOCYTES; CANCER; TUMORS; TRIAL; IMMUNOTHERAPY; SECRETION; CARCINOMA; PROTEINS Multiple languages Oncology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/41715