PMID- 29464699
OWN - NLM
STAT- MEDLINE
DCOM- 20190101
LR  - 20190101
IS  - 1097-0215 (Electronic)
IS  - 0020-7136 (Linking)
VI  - 143
IP  - 3
DP  - 2018 Aug 1
TI  - Immune checkpoint blockade combined with IL-6 and TGF-beta inhibition improves
      the therapeutic outcome of mRNA-based immunotherapy.
PG  - 686-698
LID - 10.1002/ijc.31331 [doi]
AB  - Improved understanding of cancer immunology has provided insight into the
      phenomenon of frequent tumor recurrence after initially successful immunotherapy.
      A delicate balance exists between the capacity of the immune system to control
      tumor growth and various resistance mechanisms that arise to avoid or even
      counteract the host's immune system. These resistance mechanisms include but are 
      not limited to (i) adaptive expression of inhibitory checkpoint molecules in
      response to the proinflammatory environment and (ii) amplification of cancer stem
      cells, a small fraction of tumor cells possessing the capacity for self-renewal
      and mediating treatment resistance and formation of metastases after long periods
      of clinical remission. Several individual therapeutic agents have so far been
      developed to revert T-cell exhaustion or disrupt the cross-talk between cancer
      stem cells and the tumor-promoting microenvironment. Here, we demonstrate that a 
      three-arm combination therapy-consisting of an mRNA-based vaccine to induce
      antigen-specific T-cell responses, monoclonal antibodies blocking inhibitory
      checkpoint molecules (PD-1, TIM-3, LAG-3), and antibodies targeting IL-6 and
      TGF-beta-improves the therapeutic outcome in subcutaneous TC-1 tumors and
      significantly prolongs survival of treated mice. Our findings point to a need for
      a rational development of multidimensional anticancer therapies, aiming at the
      induction of tumor-specific immunity and simultaneously targeting multiple
      resistance mechanisms.
CI  - (c) 2018 UICC.
FAU - Bialkowski, Lukasz
AU  - Bialkowski L
AUID- ORCID: 0000-0002-9806-404X
AD  - Laboratory of Molecular and Cellular Therapy, Vrije Universiteit Brussel,
      Laarbeeklaan 103E, Brussels, 1090, Belgium.
FAU - Van der Jeught, Kevin
AU  - Van der Jeught K
AD  - Laboratory of Molecular and Cellular Therapy, Vrije Universiteit Brussel,
      Laarbeeklaan 103E, Brussels, 1090, Belgium.
FAU - Bevers, Sanne
AU  - Bevers S
AD  - eTheRNA Immunotherapies, Galileilaan 19, Niel, 2845, Belgium.
FAU - Tjok Joe, Patrick
AU  - Tjok Joe P
AD  - Laboratory of Molecular and Cellular Therapy, Vrije Universiteit Brussel,
      Laarbeeklaan 103E, Brussels, 1090, Belgium.
FAU - Renmans, Dries
AU  - Renmans D
AD  - Laboratory of Molecular and Cellular Therapy, Vrije Universiteit Brussel,
      Laarbeeklaan 103E, Brussels, 1090, Belgium.
FAU - Heirman, Carlo
AU  - Heirman C
AD  - eTheRNA Immunotherapies, Galileilaan 19, Niel, 2845, Belgium.
FAU - Aerts, Joeri L
AU  - Aerts JL
AD  - Laboratory of Molecular and Cellular Therapy, Vrije Universiteit Brussel,
      Laarbeeklaan 103E, Brussels, 1090, Belgium.
FAU - Thielemans, Kris
AU  - Thielemans K
AD  - Laboratory of Molecular and Cellular Therapy, Vrije Universiteit Brussel,
      Laarbeeklaan 103E, Brussels, 1090, Belgium.
AD  - eTheRNA Immunotherapies, Galileilaan 19, Niel, 2845, Belgium.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180313
PL  - United States
TA  - Int J Cancer
JT  - International journal of cancer
JID - 0042124
RN  - 0 (Antineoplastic Agents, Immunological)
RN  - 0 (Interleukin-6)
RN  - 0 (RNA, Messenger)
RN  - 0 (SOXB1 Transcription Factors)
RN  - 0 (Transforming Growth Factor beta)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents, Immunological/*pharmacology/therapeutic use
MH  - Cell Line, Tumor
MH  - Disease Models, Animal
MH  - Gene Expression
MH  - Humans
MH  - Immunotherapy
MH  - Interleukin-6/*antagonists & inhibitors/metabolism
MH  - Melanoma, Experimental
MH  - Mice
MH  - Neoplasms/*genetics/*metabolism/pathology/therapy
MH  - RNA, Messenger/*genetics
MH  - Recurrence
MH  - SOXB1 Transcription Factors/metabolism
MH  - Signal Transduction
MH  - Transforming Growth Factor beta/*antagonists & inhibitors/metabolism
OTO - NOTNLM
OT  - *IL-6
OT  - *TGF-beta
OT  - *immune checkpoint inhibitors
OT  - *mRNA
OT  - *tumor microenvironment
EDAT- 2018/02/22 06:00
MHDA- 2019/01/02 06:00
CRDT- 2018/02/22 06:00
PHST- 2017/08/25 00:00 [received]
PHST- 2018/01/03 00:00 [revised]
PHST- 2018/01/26 00:00 [accepted]
PHST- 2018/02/22 06:00 [pubmed]
PHST- 2019/01/02 06:00 [medline]
PHST- 2018/02/22 06:00 [entrez]
AID - 10.1002/ijc.31331 [doi]
PST - ppublish
SO  - Int J Cancer. 2018 Aug 1;143(3):686-698. doi: 10.1002/ijc.31331. Epub 2018 Mar
      13.