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: 39.08). 12/2012; 31(1). DOI: 10.1038/nbt.2459
Source: PubMed

ABSTRACT 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.

Download full-text


Available from: Michael Bachmann, Apr 01, 2014
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Despite advances in the understanding of its molecular pathophysiology, pancreatic cancer remains largely incurable highlighting the need for novel therapies. We developed a chimeric antigen receptor (CAR) specific for prostate stem cell antigen (PSCA), a glycoprotein that is over-expressed in pancreatic cancer starting at early stages of malignant transformation. To optimize the CAR design, we used antigen-recognition domains derived from mouse or human antibodies, and intracellular signaling domains containing one or two T cell co-stimulatory elements, in addition to CD3zeta. Comparing multiple constructs established that the CAR based on human monoclonal antibody Ha1-4.117 had the greatest reactivity in vitro. To further analyze this CAR, we developed a human pancreatic cancer xenograft model and adoptively transferred CAR engineered T cells into animals with established tumors. CAR-engineered human lymphocytes induced significant antitumor activity and, unlike what has been described for other CARs, a second generation CAR (containing CD28 co-signaling domain) induced a more potent antitumor effect than a third generation CAR (containing CD28 and 41BB co-signaling domains). While our results provide evidence to support PSCA as a target antigen for CAR-based immunotherapy of pancreatic cancer, the expression of PSCA on selected normal tissues could be a source of limiting toxicity.
    Human gene therapy 04/2014; 25(12). DOI:10.1089/hum.2013.209 · 3.62 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Chimeric antigen receptor (CAR) T cells face a unique set of challenges in the context of solid tumors. To induce a favorable clinical outcome, CAR T cells have to surmount a series of increasingly arduous tasks. First, they have to be made specific for an antigen whose expression clearly demarcates tumor from normal tissue. Then, they must be able to home and penetrate the desmoplastic stroma that surrounds the tumor. Once within the tumor, they must expand, persist, and mediate cytotoxicity in a hostile milieu largely composed of immunosuppressive modulators. Whereas a seemingly herculean task, all of the aforementioned requirements can potentially be met effectively through both intrinsic and/or extrinsic modifications of CAR T cells. In this review, we delineate the barriers imposed by solid tumors on CARs and strategies that have and should be undertaken to improve therapeutic response.
    The Cancer Journal 20(2):151-5. DOI:10.1097/PPO.0000000000000032 · 3.61 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The 27th annual meeting of the Society for Immunotherapy of Cancer (SITC) was held on October 26–28, 2012 in North Bethesda, Maryland and the highlights of the meeting are summarized. The topics covered at this meeting included advances in cancer treatment using adoptive cell therapy (ACT), oncolytic viruses, dendritic cells (DCs), immune check point modulators and combination therapies. Advances in immune editing of cancer, immune modulation by cancer and the tumor microenvironment were also discussed as were advances in single cell analysis and the manufacture and potency testing of tumor infiltrating lymphocytes (TIL).
    05/2013; 1(1). DOI:10.1186/2051-1426-1-4
Show more