title: Expression of a functional CCR2 receptor enhances tumor localization and tumor eradication by retargeted human T cells expressing a mesothelin-specific chimeric antibody receptor.
abstract: OBJECTIVE
  Adoptive T-cell immunotherapy with tumor infiltrating lymphocytes or genetically-modified T cells has yielded dramatic results in some cancers. However, T cells need to traffic properly into tumors to adequately exert therapeutic effects.
  
  
  METHODS
  The chemokine CCL2 was highly secreted by malignant pleural mesotheliomas (MPM; a planned tumor target), but the corresponding chemokine receptor (CCR2) was minimally expressed on activated human T cells transduced with a chimeric antibody receptor (CAR) directed to the MPM tumor antigen mesothelin (mesoCAR T cells). The chemokine receptor CCR2b was thus transduced into mesoCAR T cells using a lentiviral vector, and the modified T cells were used to treat established mesothelin-expressing tumors.
  
  
  RESULTS
  CCR2b transduction led to CCL2-induced calcium flux and increased transmigration, as well as augmentation of in vitro T-cell killing ability. A single intravenous injection of 20 million mesoCAR + CCR2b T cells into immunodeficient mice bearing large, established tumors (without any adjunct therapy) resulted in a 12.5-fold increase in T-cell tumor infiltration by day 5 compared with mesoCAR T cells. This was associated with significantly increased antitumor activity.
  
  
  CONCLUSIONS
  CAR T cells bearing a functional chemokine receptor can overcome the inadequate tumor localization that limits conventional CAR targeting strategies and can significantly improve antitumor efficacy in vivo.
authors: Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 19104, USA. edmund.moon@uphs.upenn.edu
authors: Edmund K
authors: EK
authors: Moon
authors: Carmine
authors: C
authors: Carpenito
authors: Jing
authors: J
authors: Sun
authors: Liang-Chuan S
authors: LC
authors: Wang
authors: Veena
authors: V
authors: Kapoor
authors: Jarrod
authors: J
authors: Predina
authors: Daniel J
authors: DJ
authors: Powell
authors: James L
authors: JL
authors: Riley
authors: Carl H
authors: CH
authors: June
authors: Steven M
authors: SM
authors: Albelda
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