Combinatorial antigen recognition with balanced signaling promotes selective tumor eradication by engineered T cells

1] Center for Cell Engineering, Memorial Sloan-Kettering Cancer Center (MSKCC), New York, New York, USA. [2] Biochemistry, Cell, and Molecular Biology Program, Weill Cornell Graduate School for Medical Sciences, Cornell University, New York, New York, USA.
Nature Biotechnology (Impact Factor: 41.51). 12/2012; 31(1). DOI: 10.1038/nbt.2459
Source: PubMed


Current T-cell engineering approaches redirect patient T cells to tumors by transducing them with antigen-specific T-cell receptors (TCRs) or chimeric antigen receptors (CARs) that target a single antigen. However, few truly tumor-specific antigens have been identified, and healthy tissues that express the targeted antigen may undergo T cell-mediated damage. Here we present a strategy to render T cells specific for a tumor in the absence of a truly tumor-restricted antigen. T cells are transduced with both a CAR that provides suboptimal activation upon binding of one antigen and a chimeric costimulatory receptor (CCR) that recognizes a second antigen. Using the prostate tumor antigens PSMA and PSCA, we show that co-transduced T cells destroy tumors that express both antigens but do not affect tumors expressing either antigen alone. This 'tumor-sensing' strategy may help broaden the applicability and avoid some of the side effects of targeted T-cell therapies.

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Available from: Michael Bachmann, Apr 01, 2014
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    • "Nevertheless, given the paucity of truly tumor-specific antigens to target, the outstanding target-specific reactivity conferred by our CARs suggests that PSCA deserves further consideration as a clinically relevant antitumor target in pancreatic cancer patients with otherwise no treatment options. Strategies involving the use of complementary CARs (Kloss et al., 2013) or suicide gene safety switches (Di Stasi et al., 2011) may be devised to capitalize on the potent target recognition of this CAR, avoiding the toxicity related to recognition of normal tissues. "
    Dataset: PSCA

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    • "In this regard, PSMA is physiologically expressed in kidney, nervous system glia, and small intestine [18], and the risk to damage these organs and structures cannot be excluded simply based on the fine target specificity demonstrated in an experimental setting by the novel mAb we used to design our CAR [19]. However, in a clinical scenario, this vector containing a bidirectional promoter could be exploited to address this safety issue, namely by driving the simultaneous expression of a CAR molecule and a “safety switch” suicide gene, such as an inducible caspase or the herpes simplex virus thymidine kinase (HSV-TK) [35], [42]; or alternatively a chimeric costimulatory receptor (CCR) for combinatorial antigen recognition [43]. "
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    ABSTRACT: Immunology-based interventions have been proposed as a promising curative chance to effectively attack postoperative minimal residual disease and distant metastatic localizations of prostate tumors. We developed a chimeric antigen receptor (CAR) construct targeting the human prostate-specific membrane antigen (hPSMA), based on a novel and high affinity specific mAb. As a transfer method, we employed last-generation lentiviral vectors (LV) carrying a synthetic bidirectional promoter capable of robust and coordinated expression of the CAR molecule, and a bioluminescent reporter gene to allow the tracking of transgenic T cells after in vivo adoptive transfer. Overall, we demonstrated that CAR-expressing LV efficiently transduced short-term activated PBMC, which in turn were readily stimulated to produce cytokines and to exert a relevant cytotoxic activity by engagement with PSMA+ prostate tumor cells. Upon in vivo transfer in tumor-bearing mice, CAR-transduced T cells were capable to completely eradicate a disseminated neoplasia in the majority of treated animals, thus supporting the translation of such approach in the clinical setting.
    PLoS ONE 10/2014; 9(10):e109427. DOI:10.1371/journal.pone.0109427 · 3.23 Impact Factor
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    • "Alternatively, the generation of target lists, such as we present here may be exploited in the future when a new generation of immunotherapeutic agents where more than one set of antigens is required to fully activate an effector T-cell-can be developed. The creation of a treatment strategy for prostate cancer that requires recognition of both PMSA and PSCA to fully trigger a dual-engineered T-cell population may be one such approach (70). Our next step will be to validate surface expression of the transcripts described here by flow cytometry, and thus complement gene expression data with the demonstrated presence of protein that could be targeted on the surface of pediatric T-ALL. "
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    Frontiers in Oncology 06/2014; 4:134. DOI:10.3389/fonc.2014.00134
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