PMID- 33554868
OWN - NLM
STAT- MEDLINE
DCOM- 20211018
LR  - 20220204
IS  - 1525-0024 (Electronic)
IS  - 1525-0016 (Print)
IS  - 1525-0016 (Linking)
VI  - 29
IP  - 2
DP  - 2021 Feb 3
TI  - Engineering Tolerance toward Allogeneic CAR-T Cells by Regulation of MHC Surface 
      Expression with Human Herpes Virus-8 Proteins.
PG  - 718-733
LID - S1525-0016(20)30553-0 [pii]
LID - 10.1016/j.ymthe.2020.10.019 [doi]
AB  - Allogeneic, off-the-shelf (OTS) chimeric antigen receptor (CAR) cell therapies 
      have the potential to reduce manufacturing costs and variability while providing 
      broader accessibility to cancer patients and those with other diseases. However, 
      host-versus-graft reactivity can limit the durability and efficacy of OTS cell 
      therapies requiring new strategies to evade adaptive and innate-immune responses. 
      Human herpes virus-8 (HHV8) maintains infection, in part, by evading host T and 
      natural killer (NK) cell attack. The viral K3 gene encodes a membrane-tethered E3 
      ubiquitin ligase that discretely targets major histocompatibility complex (MHC) 
      class I components, whereas K5 encodes a similar E3 ligase with broader 
      specificity, including MHC-II and the MHC-like MHC class I polypeptide-related 
      sequence A (MIC-A)- and sequence B (MIC-B)-activating ligands of NK cells. We 
      created gamma-retroviruses encoding K3 and/or K5 transgenes that efficiently 
      transduce primary human T cells. Expression of K3 or K5 resulted in dramatic 
      downregulation of MHC-IA (human leukocyte antigen [HLA]-A, -B, and -C) and MHC 
      class II (HLA-DR) cell-surface expression. K3 expression was sufficient for 
      T cells to resist exogenously loaded peptide-MHC-specific cytotoxicity, as well 
      as recognition in one-way allogeneic mixed lymphocyte reactions. Further, in 
      immunodeficient mice engrafted with allogeneic T cells, K3-transduced T cells 
      selectively expanded in vivo. Ectopic K5 expression in MHC class I(-), 
      MIC-A(+)/B(+) K562 cells also reduced targeting by primary NK cells. Coexpression 
      of K3 in prostate stem cell antigen (PSCA)-directed, inducible MyD88/CD40 
      (iMC)-enhanced CAR-T cells did not impact cytotoxicity, T cell growth, or 
      cytokine production against HPAC pancreatic tumor target cells, whereas 
      K5-expressing cells showed a modest reduction in interleukin (IL)-2 production 
      without effect on cytotoxicity. Together, these results support application of 
      these E3 ligases to advance development of OTS CAR-T cell products.
CI  - Copyright (c) 2020. Published by Elsevier Inc.
FAU - Wang, Xiaomei
AU  - Wang X
AD  - Research and Development, Bellicum Pharmaceuticals, 2710 Reed Road, Suite 160, 
      Houston, TX 77030, USA.
FAU - Cabrera, Fabricio G
AU  - Cabrera FG
AD  - Research and Development, Bellicum Pharmaceuticals, 2710 Reed Road, Suite 160, 
      Houston, TX 77030, USA.
FAU - Sharp, Kelly L
AU  - Sharp KL
AD  - Research and Development, Bellicum Pharmaceuticals, 2710 Reed Road, Suite 160, 
      Houston, TX 77030, USA.
FAU - Spencer, David M
AU  - Spencer DM
AD  - Research and Development, Bellicum Pharmaceuticals, 2710 Reed Road, Suite 160, 
      Houston, TX 77030, USA.
FAU - Foster, Aaron E
AU  - Foster AE
AD  - Research and Development, Bellicum Pharmaceuticals, 2710 Reed Road, Suite 160, 
      Houston, TX 77030, USA. Electronic address: afoster@bellicum.com.
FAU - Bayle, J Henri
AU  - Bayle JH
AD  - Research and Development, Bellicum Pharmaceuticals, 2710 Reed Road, Suite 160, 
      Houston, TX 77030, USA. Electronic address: jhbayle@bellicum.com.
LA  - eng
PT  - Journal Article
DEP - 20201022
PL  - United States
TA  - Mol Ther
JT  - Molecular therapy : the journal of the American Society of Gene Therapy
JID - 100890581
RN  - 0 (Histocompatibility Antigens)
RN  - 0 (Viral Proteins)
SB  - IM
MH  - Animals
MH  - *Cell- and Tissue-Based Therapy/methods
MH  - Disease Models, Animal
MH  - *Genetic Engineering
MH  - Herpesvirus 8, Human/*immunology
MH  - Histocompatibility Antigens/*immunology
MH  - Humans
MH  - *Immunotherapy, Adoptive/methods
MH  - Mice
MH  - Neoplasms/immunology/therapy
MH  - Viral Proteins/*immunology
MH  - Xenograft Model Antitumor Assays
PMC - PMC7854355
OTO - NOTNLM
OT  - CAR-T cell
OT  - HHV8
OT  - MARCH proteins
OT  - OTS
OT  - allogeneic cell therapy
OT  - iMC
OT  - immune evasion
OT  - off-the-shelf cell therapy
EDAT- 2021/02/09 06:00
MHDA- 2021/10/21 06:00
PMCR- 2022/02/03
CRDT- 2021/02/08 08:43
PHST- 2020/04/27 00:00 [received]
PHST- 2020/09/09 00:00 [revised]
PHST- 2020/10/19 00:00 [accepted]
PHST- 2021/02/08 08:43 [entrez]
PHST- 2021/02/09 06:00 [pubmed]
PHST- 2021/10/21 06:00 [medline]
PHST- 2022/02/03 00:00 [pmc-release]
AID - S1525-0016(20)30553-0 [pii]
AID - 10.1016/j.ymthe.2020.10.019 [doi]
PST - ppublish
SO  - Mol Ther. 2021 Feb 3;29(2):718-733. doi: 10.1016/j.ymthe.2020.10.019. Epub 2020 
      Oct 22.