Selective bispecific T cell recruiting antibody and antitumor activity of adoptive T cell transfer
- 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
- Bourquin, Carole Chair of Pharmacology, Department of Medicine, University of Fribourg, Fribourg, Switzerland
- Endres, Stefan
-
01.01.2015
Published in:
- Journal of the National Cancer Institute. - 2014, vol. 107, no. 1, p. dju364
English
Background: 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.Methods: 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.Results: 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.Conclusions: BiAb recruitment of tumor-specific T cells transduced with a marker antigen to tumor cells may enhance efficacy of ACT.
- Faculty
- Faculté des sciences et de médecine
- Department
- Département de Médecine
- Language
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- English
- Classification
- Biological sciences
- License
- License undefined
- Identifiers
-
- RERO DOC 234246
- DOI 10.1093/jnci/dju364
- Persistent URL
- https://folia.unifr.ch/unifr/documents/304170
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