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Cancer Immunol Res. 2014 Feb;2(2):112-20. doi: 10.1158/2326-6066.CIR-13-0170.

Mesothelin-specific chimeric antigen receptor mRNA-engineered T cells induce anti-tumor activity in solid malignancies.

Author information

  • 1Abramson Cancer Center; University of Pennsylvania, Philadelphia, PA ; Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
  • 2Abramson Cancer Center; University of Pennsylvania, Philadelphia, PA ; Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
  • 3Abramson Cancer Center; University of Pennsylvania, Philadelphia, PA ; Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
  • 4Abramson Cancer Center; University of Pennsylvania, Philadelphia, PA.
  • 5Abramson Cancer Center; University of Pennsylvania, Philadelphia, PA ; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
  • 6Abramson Cancer Center; University of Pennsylvania, Philadelphia, PA ; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA ; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

Abstract

Off-target toxicity due to the expression of target antigens in normal tissue represents a major obstacle to the use of chimeric antigen receptor (CAR)-engineered T cells for treatment of solid malignancies. To circumvent this issue, we established a clinical platform for engineering T cells with transient CAR expression by using in vitro transcribed mRNA encoding a CAR that includes both the CD3-ΞΆ and 4-1BB co-stimulatory domains. We present two case reports from ongoing trials indicating that adoptive transfer of mRNA CAR T cells that target mesothelin (CARTmeso cells) is feasible and safe without overt evidence of off-tumor on-target toxicity against normal tissues. CARTmeso cells persisted transiently within the peripheral blood after intravenous administration and migrated to primary and metastatic tumor sites. Clinical and laboratory evidence of antitumor activity was demonstrated in both patients and the CARTmeso cells elicited an antitumor immune response revealed by the development of novel anti-self antibodies. These data demonstrate the potential of utilizing mRNA engineered T cells to evaluate, in a controlled manner, potential off-tumor on-target toxicities and show that short-lived CAR T cells can induce epitope-spreading and mediate antitumor activity in patients with advanced cancer. Thus, these findings support the development of mRNA CAR-based strategies for carcinoma and other solid tumors.

PMID:
24579088
[PubMed]
PMCID:
PMC3932715
[Available on 2015/2/1]
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