CEA/CD3-bispecific T cell-engaging (BiTE) antibody-mediated T lymphocyte cytotoxicity maximized by inhibition of both PD1 and PD-L1 View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2015-06

AUTHORS

Takuya Osada, Sandip P. Patel, Scott A. Hammond, Koya Osada, Michael A. Morse, H. Kim Lyerly

ABSTRACT

Bispecific T cell-engaging (BiTE) antibodies recruit polyclonal cytotoxic T cells (CTL) to tumors. One such antibody is carcinoembryonic antigen (CEA) BiTE that mediates T cell/tumor interaction by simultaneously binding CD3 expressed by T cells and CEA expressed by tumor cells. A widely operative mechanism for mitigating cytotoxic T cell-mediated killing is the interaction of tumor-expressed PD-L1 with T cell-expressed PD-1, which may be partly reversed by PD-1/PD-L1 blockade. We hypothesized that PD-1/PD-L1 blockade during BiTE-mediated T cell killing would enhance CTL function. Here, we determined the effects of PD-1 and PD-L1 blockade during initial T cell-mediated killing of CEA-expressing human tumor cell lines in vitro, as well as subsequent T cell-mediated killing by T lymphocytes that had participated in tumor cell killing. We observed a rapid upregulation of PD-1 expression and diminished cytolytic function of T cells after they had engaged in CEA BiTE-mediated killing of tumors. T cell cytolytic activity in vitro could be maximized by administration of anti-PD-1 or anti-PD-L1 antibodies alone or in combination if applied prior to a round of T cell killing, but T cell inhibition could not be fully reversed by this blockade once the T cells had killed tumor. In conclusion, our findings demonstrate that dual blockade of PD-1 and PD-L1 maximizes T cell killing of tumor directed by CEA BiTE in vitro, is more effective if applied early, and provides a rationale for clinical use. More... »

PAGES

677-688

Identifiers

URI

http://scigraph.springernature.com/pub.10.1007/s00262-015-1671-y

DOI

http://dx.doi.org/10.1007/s00262-015-1671-y

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1004023478

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/25742933


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Download the RDF metadata as:  json-ld nt turtle xml License info

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RDF/XML is a standard XML format for linked data.

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293 Department of Medicine, Duke University Medical Center, 403 MSRB, Research Drive, 27710, Durham, NC, USA
294 Duke Comprehensive Cancer Center, Duke University Medical Center, 403 MSRB, Research Drive, 27710, Durham, NC, USA
295 Section of Applied Therapeutics, Department of Surgery, Duke University Medical Center, 403 MSRB, Research Drive, 27710, Durham, NC, USA
296 rdf:type schema:Organization
297 https://www.grid.ac/institutes/grid.418152.b schema:alternateName AstraZeneca (United States)
298 schema:name MedImmune LLC, One MedImmune Way, 20878, Gaithersburg, MD, USA
299 rdf:type schema:Organization
 




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