PMID- 31266784
OWN - NLM
STAT- MEDLINE
DCOM- 20200907
LR  - 20240220
IS  - 2326-6074 (Electronic)
IS  - 2326-6066 (Print)
IS  - 2326-6066 (Linking)
VI  - 7
IP  - 9
DP  - 2019 Sep
TI  - An Anticancer Drug Cocktail of Three Kinase Inhibitors Improved Response to a 
      Dendritic Cell-Based Cancer Vaccine.
PG  - 1523-1534
LID - 10.1158/2326-6066.CIR-18-0684 [doi]
AB  - Monocyte-derived dendritic cell (moDC)-based cancer therapies intended to elicit 
      antitumor T-cell responses have limited efficacy in most clinical trials. 
      However, potent and sustained antitumor activity in a limited number of patients 
      highlights the therapeutic potential of moDCs. In vitro culture conditions used 
      to generate moDCs can be inconsistent, and moDCs generated in vitro are less 
      effective than natural DCs. On the basis of our study highlighting the ability 
      for certain kinase inhibitors to enhance tumor antigenicity, we therefore 
      screened kinase inhibitors for their ability to improve DC immunogenicity. We 
      identified AKT inhibitor MK2206, DNA-PK inhibitor NU7441, and MEK inhibitor 
      trametinib as the compounds most effective at modulating moDC immunogenicity. The 
      combination of these drugs, referred to as MKNUTRA, enhanced moDC activity over 
      treatment with individual drugs while exhibiting minimal toxicity. An evaluation 
      of 335 activation and T-cell-suppressive surface proteins on moDCs revealed that 
      MKNUTRA treatment more effectively matured cells and reduced the expression of 
      tolerogenic proteins as compared with control moDCs. MKNUTRA treatment imparted 
      to ICT107, a glioblastoma (GBM) DC-based vaccine that has completed phase II 
      trials, an increased ability to stimulate patient-derived autologous CD8(+) T 
      cells against the brain tumor antigens IL13Ralpha2((345-354)) and TRP2((180-188)) In 
      vivo, treating ICT107 with MKNUTRA, prior to injection into mice with an 
      established GBM tumor, reduced tumor growth kinetics. This response was 
      associated with an increased frequency of tumor-reactive lymphocytes within 
      tumors and in peripheral tissues. These studies broaden the application of 
      targeted anticancer drugs and highlight their ability to increase moDC 
      immunogenicity.
CI  - (c)2019 American Association for Cancer Research.
FAU - Guo, Jitao
AU  - Guo J
AD  - Division of Medical Oncology, Department of Medicine, University of Colorado, 
      Anschutz Medical Campus, Aurora, Colorado.
FAU - Muse, Elena
AU  - Muse E
AD  - Division of Medical Oncology, Department of Medicine, University of Colorado, 
      Anschutz Medical Campus, Aurora, Colorado.
FAU - Christians, Allison J
AU  - Christians AJ
AUID- ORCID: 0000-0001-5881-3184
AD  - Division of Medical Oncology, Department of Medicine, University of Colorado, 
      Anschutz Medical Campus, Aurora, Colorado.
FAU - Swanson, Steven J
AU  - Swanson SJ
AD  - ImmunoCellular Therapeutics, Ltd., Westlake Village, California.
FAU - Davila, Eduardo
AU  - Davila E
AD  - Division of Medical Oncology, Department of Medicine, University of Colorado, 
      Anschutz Medical Campus, Aurora, Colorado. eduardo.davila@ucdenver.edu.
AD  - Human Immunology and Immunotherapy Initiative, University of Colorado, Anschutz 
      Medical Campus, Aurora, Colorado.
AD  - University of Colorado Comprehensive Cancer Center, Aurora, Colorado.
LA  - eng
GR  - I01 BX004935/BX/BLRD VA/United States
GR  - P30 CA134274/CA/NCI NIH HHS/United States
GR  - R01 CA207913/CA/NCI NIH HHS/United States
GR  - P30 CA046934/CA/NCI NIH HHS/United States
GR  - I01 BX002142/BX/BLRD VA/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20190702
PL  - United States
TA  - Cancer Immunol Res
JT  - Cancer immunology research
JID - 101614637
RN  - 0 (8-dibenzothiophen-4-yl-2-morpholin-4-yl-chromen-4-one)
RN  - 0 (Cancer Vaccines)
RN  - 0 (Chromones)
RN  - 0 (Heterocyclic Compounds, 3-Ring)
RN  - 0 (MK 2206)
RN  - 0 (Morpholines)
RN  - 0 (Protein Kinase Inhibitors)
SB  - IM
MH  - Animals
MH  - Antineoplastic Combined Chemotherapy Protocols/adverse effects/therapeutic use
MH  - Cancer Vaccines/*immunology/therapeutic use
MH  - Cell Communication
MH  - Chromones/pharmacology
MH  - Dendritic Cells/*immunology/metabolism
MH  - Heterocyclic Compounds, 3-Ring/pharmacology
MH  - Humans
MH  - Lymphocyte Activation/drug effects/immunology
MH  - Male
MH  - Mice
MH  - Morpholines/pharmacology
MH  - Neoplasms/*immunology/metabolism/pathology/therapy
MH  - Protein Kinase Inhibitors/*pharmacology
MH  - T-Lymphocyte Subsets/immunology/metabolism
PMC - PMC6726569
MID - NIHMS1533704
EDAT- 2019/07/04 06:00
MHDA- 2020/09/08 06:00
PMCR- 2020/03/01
CRDT- 2019/07/04 06:00
PHST- 2019/03/14 00:00 [received]
PHST- 2019/03/22 00:00 [revised]
PHST- 2019/06/28 00:00 [accepted]
PHST- 2019/07/04 06:00 [pubmed]
PHST- 2020/09/08 06:00 [medline]
PHST- 2019/07/04 06:00 [entrez]
PHST- 2020/03/01 00:00 [pmc-release]
AID - 2326-6066.CIR-18-0684 [pii]
AID - 10.1158/2326-6066.CIR-18-0684 [doi]
PST - ppublish
SO  - Cancer Immunol Res. 2019 Sep;7(9):1523-1534. doi: 10.1158/2326-6066.CIR-18-0684. 
      Epub 2019 Jul 2.