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Open Access Green as soon as Postprint is submitted to ZB.
Selective bispecific T cell recruiting antibody and antitumor activity of adoptive T cell transfer.
J. Natl. Cancer Inst. 107:dju364 (2015)
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.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Engaging Antibody; Therapy; Lymphocytes; Cancer; Tumors; Trial; Immunotherapy; Secretion; Carcinoma; Proteins
ISSN (print) / ISBN
0027-8874
e-ISSN
1460-2105
Quellenangaben
Volume: 107,
Issue: 1,
Article Number: dju364
Publisher
Oxford University Press
Publishing Place
Cary
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Institute of Molecular Immunology (IMI)