Immunotherapy using genetically modified T lymphocytes to target CLEC14A on the tumor vasculature

Xiaodong Zhuang, Baksho Kaul, Michael Bentley, Zsuzsanna Nagy, Enrico Giraudo, Gavin Bendle, David Gilham, Roy Bicknell, Steven P. Lee

Research output: Contribution to journalAbstractpeer-review

Abstract

Chimeric antigen receptor (CAR) therapy combines the specificity of a monoclonal antibody with the potent cytotoxic and immune regulatory activity of self-replicating T cells. This approach has shown remarkable efficacy in recent clinical trials targeting T cells to hematological cancers. More limited benefit has been reported with solid tumors, possibly because of lack of suitable target antigens, immune evasion mechanisms in the malignant cells and/or lack of T cell infiltration into the tumor tissue. An alternative approach that avoids some of these problems is to use a CAR that targets the tumor vasculature rather than the malignant cells directly.

CLEC14A is a glycoprotein recently identified to be selectively overexpressed on the surface of the tumor vasculature in a wide range of human cancers, including ovarian, liver, bladder, prostate, breast and kidney, and is therefore of considerable interest for tumor therapy. Here we explore for the first time the feasibility of targeting the tumor vasculature using CLEC14A-specific CARs. Initially we generated CARs from several CLEC14A-specific monoclonal antibodies and then expressed them in T cells. In vitro T cell functional assays demonstrated that these CARs can trigger potent antigen-specific activation including cytotoxicity in engineered T cells. These CARs recognize both human and mouse forms of CLEC14A, so safety/efficacy studies could be conducted using mouse models. Following infusion of escalating doses of engineered T cells into healthy mice, circulating CAR-T cells persisted for at least the next 5 weeks without signs of toxicity. To explore anti-tumor effects, Lewis lung carcinoma cells were subcutaneously implanted into C57BL6 mice and 4 days later mice received a single dose of CLEC14A-specific CAR-T cells. Our recent data demonstrate statistically significant inhibition of tumor growth in mice treated with CAR-T cells compared with mock-transduced T cells. The engineered cells also appeared to expand/accumulate at the tumor site. These data suggest CLEC14A can be safely and effectively targeted with CAR-T cells, potentially offering a potent and widely applicable cancer therapy.
Original languageEnglish
JournalCancer Research
Volume74
Issue number19 Suppl
DOIs
Publication statusPublished - Oct 2014
Event AACR Annual Meeting 2014 - San Diego, United States
Duration: 5 Apr 20149 Apr 2014

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