PMID- 21546571
OWN - NLM
STAT- MEDLINE
DCOM- 20110929
LR  - 20171116
IS  - 1538-7445 (Electronic)
IS  - 0008-5472 (Linking)
VI  - 71
IP  - 13
DP  - 2011 Jul 1
TI  - In vivo persistence, tumor localization, and antitumor activity of CAR-engineered
      T cells is enhanced by costimulatory signaling through CD137 (4-1BB).
PG  - 4617-27
LID - 10.1158/0008-5472.CAN-11-0422 [doi]
AB  - Human T cells engineered to express a chimeric antigen receptor (CAR) specific
      for folate receptor-alpha (FRalpha) have shown robust antitumor activity against 
      epithelial cancers in vitro but not in the clinic because of their inability to
      persist and home to tumor in vivo. In this study, CARs were constructed
      containing a FRalpha-specific scFv (MOv19) coupled to the T-cell receptor CD3zeta
      chain signaling module alone (MOv19-zeta) or in combination with the CD137
      (4-1BB) costimulatory motif in tandem (MOv19-BBzeta). Primary human T cells
      transduced to express conventional MOv19-zeta or costimulated MOv19-BBzeta CARs
      secreted various proinflammatory cytokines, and exerted cytotoxic function when
      cocultured with FRalpha(+) tumor cells in vitro. However, only transfer of human 
      T cells expressing the costimulated MOv19-BBzeta CAR mediated tumor regression in
      immunodeficient mice bearing large, established FRalpha(+) human cancer.
      MOv19-BBzeta CAR T-cell infusion mediated tumor regression in models of
      metastatic intraperitoneal, subcutaneous, and lung-involved human ovarian cancer.
      Importantly, tumor response was associated with the selective survival and tumor 
      localization of human T cells in vivo and was only observed in mice receiving
      costimulated MOv19-BBzeta CAR T cells. T-cell persistence and antitumor activity 
      were primarily antigen-driven; however, antigen-independent CD137 signaling by
      CAR improved T-cell persistence but not antitumor activity in vivo. Our results
      show that anti-FRalpha CAR outfitted with CD137 costimulatory signaling in tandem
      overcome issues of T-cell persistence and tumor localization that limit the
      conventional FRalpha T-cell targeting strategy to provide potent antitumor
      activity in vivo.
CI  - (c)2011 AACR.
FAU - Song, De-Gang
AU  - Song DG
AD  - Ovarian Cancer Research Center, Department of Obstetrics and Gynecology and
      Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania
      19104, USA.
FAU - Ye, Qunrui
AU  - Ye Q
FAU - Carpenito, Carmine
AU  - Carpenito C
FAU - Poussin, Mathilde
AU  - Poussin M
FAU - Wang, Li-Ping
AU  - Wang LP
FAU - Ji, Chunyan
AU  - Ji C
FAU - Figini, Mariangela
AU  - Figini M
FAU - June, Carl H
AU  - June CH
FAU - Coukos, George
AU  - Coukos G
FAU - Powell, Daniel J Jr
AU  - Powell DJ Jr
LA  - eng
GR  - P50 CA083638/CA/NCI NIH HHS/United States
GR  - R21 CA152540/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20110505
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Folate Receptor 1)
RN  - 0 (Immunoglobulin Fragments)
RN  - 0 (Receptors, Antigen, T-Cell)
RN  - 0 (Tumor Necrosis Factor Receptor Superfamily, Member 9)
SB  - IM
MH  - Animals
MH  - Female
MH  - Folate Receptor 1/*immunology
MH  - Humans
MH  - Immunoglobulin Fragments/genetics/immunology
MH  - Immunotherapy, Adoptive/*methods
MH  - Mice
MH  - Ovarian Neoplasms/immunology/therapy
MH  - Protein Engineering
MH  - Receptors, Antigen, T-Cell/genetics/*immunology
MH  - T-Lymphocytes/*immunology
MH  - Tumor Necrosis Factor Receptor Superfamily, Member
      9/biosynthesis/genetics/*immunology
MH  - Xenograft Model Antitumor Assays
PMC - PMC4140173
MID - NIHMS596690
EDAT- 2011/05/07 06:00
MHDA- 2011/10/01 06:00
CRDT- 2011/05/07 06:00
PHST- 2011/05/07 06:00 [entrez]
PHST- 2011/05/07 06:00 [pubmed]
PHST- 2011/10/01 06:00 [medline]
AID - 0008-5472.CAN-11-0422 [pii]
AID - 10.1158/0008-5472.CAN-11-0422 [doi]
PST - ppublish
SO  - Cancer Res. 2011 Jul 1;71(13):4617-27. doi: 10.1158/0008-5472.CAN-11-0422. Epub
      2011 May 5.