PMID- 38014236
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20240408
DP  - 2023 Nov 15
TI  - Enhancing CAR-T Cell Metabolism to Overcome Hypoxic Conditions in the Brain Tumor 
      Microenvironment.
LID - 2023.11.13.566775 [pii]
LID - 10.1101/2023.11.13.566775 [doi]
AB  - The efficacy of chimeric antigen receptor (CAR)-T therapy has been limited 
      against brain tumors to date. CAR-T cells infiltrating syngeneic intracerebral 
      SB28-EGFRvIII glioma revealed impaired mitochondrial ATP production and a 
      markedly hypoxic status compared to ones migrating to subcutaneous tumors. Drug 
      screenings to improve metabolic states of T cells under hypoxic conditions led us 
      to evaluate the combination of AMPK activator Metformin and the mTOR inhibitor 
      Rapamycin (Met+Rap). Met+Rap-pretreated mouse CAR-T cells showed activated 
      PPAR-gamma coactivator 1alpha (PGC-1alpha) through mTOR inhibition and AMPK activation, 
      and a higher level of mitochondrial spare respiratory capacity than those 
      pretreated with individual drugs or without pretreatment. Moreover, 
      Met+Rap-pretreated CAR-T cells demonstrated persistent and effective anti-glioma 
      cytotoxic activities in the hypoxic condition. Furthermore, a single intravenous 
      infusion of Met+Rap-pretreated CAR-T cells significantly extended the survival of 
      mice bearing intracerebral SB28-EGFRvIII gliomas. Mass cytometric analyses 
      highlighted increased glioma-infiltrating CAR-T cells in the Met+Rap group with 
      fewer Ly6c+ CD11b+ monocytic myeloid-derived suppressor cells in the tumors. 
      Finally, human CAR-T cells pretreated with Met+Rap recapitulated the observations 
      with murine CAR-T cells, demonstrating improved functions in vitro hypoxic 
      conditions. These findings advocate for translational and clinical exploration of 
      Met+Rap-pretreated CAR-T cells in human trials.
FAU - Hatae, Ryusuke
AU  - Hatae R
AUID- ORCID: 0000-0001-5636-8064
FAU - Kyewalabye, Keith
AU  - Kyewalabye K
FAU - Yamamichi, Akane
AU  - Yamamichi A
FAU - Chen, Tiffany
AU  - Chen T
FAU - Phyu, Su
AU  - Phyu S
FAU - Chuntova, Pavlina
AU  - Chuntova P
FAU - Nejo, Takahide
AU  - Nejo T
AUID- ORCID: 0000-0002-9191-8823
FAU - Levine, Lauren S
AU  - Levine LS
FAU - Spitzer, Matthew H
AU  - Spitzer MH
FAU - Okada, Hideho
AU  - Okada H
AUID- ORCID: 0000-0003-0076-9920
LA  - eng
PT  - Preprint
DEP - 20231115
PL  - United States
TA  - bioRxiv
JT  - bioRxiv : the preprint server for biology
JID - 101680187
UIN - JCI Insight. 2024 Feb 22;:. PMID: 38386420
PMC - PMC10680638
EDAT- 2023/11/28 06:42
MHDA- 2023/11/28 06:43
PMCR- 2023/11/27
CRDT- 2023/11/28 04:04
PHST- 2023/11/28 06:43 [medline]
PHST- 2023/11/28 06:42 [pubmed]
PHST- 2023/11/28 04:04 [entrez]
PHST- 2023/11/27 00:00 [pmc-release]
AID - 2023.11.13.566775 [pii]
AID - 10.1101/2023.11.13.566775 [doi]
PST - epublish
SO  - bioRxiv [Preprint]. 2023 Nov 15:2023.11.13.566775. doi: 
      10.1101/2023.11.13.566775.