PMID- 34732890
OWN - NLM
STAT- MEDLINE
DCOM- 20220328
LR  - 20231125
IS  - 1476-4687 (Electronic)
IS  - 0028-0836 (Print)
IS  - 0028-0836 (Linking)
VI  - 599
IP  - 7885
DP  - 2021 Nov
TI  - Cross-HLA targeting of intracellular oncoproteins with peptide-centric CARs.
PG  - 477-484
LID - 10.1038/s41586-021-04061-6 [doi]
AB  - The majority of oncogenic drivers are intracellular proteins, thus constraining 
      their immunotherapeutic targeting to mutated peptides (neoantigens) presented by 
      individual human leukocyte antigen (HLA) allotypes(1). However, most cancers have 
      a modest mutational burden that is insufficient to generate responses using 
      neoantigen-based therapies(2,3). Neuroblastoma is a paediatric cancer that 
      harbours few mutations and is instead driven by epigenetically deregulated 
      transcriptional networks(4). Here we show that the neuroblastoma immunopeptidome 
      is enriched with peptides derived from proteins that are essential for 
      tumourigenesis and focus on targeting the unmutated peptide QYNPIRTTF, discovered 
      on HLA-A*24:02, which is derived from the neuroblastoma dependency gene and 
      master transcriptional regulator PHOX2B. To target QYNPIRTTF, we developed 
      peptide-centric chimeric antigen receptors (CARs) using a counter-panning 
      strategy with predicted potentially cross-reactive peptides. We further 
      hypothesized that peptide-centric CARs could recognize peptides on additional HLA 
      allotypes when presented in a similar manner. Informed by computational 
      modelling, we showed that PHOX2B peptide-centric CARs also recognize QYNPIRTTF 
      presented by HLA-A*23:01 and the highly divergent HLA-B*14:02. Finally, we 
      demonstrated potent and specific killing of neuroblastoma cells expressing these 
      HLAs in vitro and complete tumour regression in mice. These data suggest that 
      peptide-centric CARs have the potential to vastly expand the pool of 
      immunotherapeutic targets to include non-immunogenic intracellular oncoproteins 
      and widen the population of patients who would benefit from such therapy by 
      breaking conventional HLA restriction.
CI  - (c) 2021. The Author(s).
FAU - Yarmarkovich, Mark
AU  - Yarmarkovich M
AD  - Division of Oncology and Center for Childhood Cancer Research, Children's 
      Hospital of Philadelphia, Philadelphia, PA, USA.
FAU - Marshall, Quinlen F
AU  - Marshall QF
AUID- ORCID: 0000-0002-4736-9716
AD  - Division of Oncology and Center for Childhood Cancer Research, Children's 
      Hospital of Philadelphia, Philadelphia, PA, USA.
FAU - Warrington, John M
AU  - Warrington JM
AD  - Division of Oncology and Center for Childhood Cancer Research, Children's 
      Hospital of Philadelphia, Philadelphia, PA, USA.
FAU - Premaratne, Rasika
AU  - Premaratne R
AD  - Myrio Tx, Melbourne, Victoria, Australia.
FAU - Farrel, Alvin
AU  - Farrel A
AD  - Division of Oncology and Center for Childhood Cancer Research, Children's 
      Hospital of Philadelphia, Philadelphia, PA, USA.
AD  - Department of Biomedical and Health Informatics, Children's Hospital of 
      Philadelphia, Philadelphia, PA, USA.
FAU - Groff, David
AU  - Groff D
AD  - Division of Oncology and Center for Childhood Cancer Research, Children's 
      Hospital of Philadelphia, Philadelphia, PA, USA.
FAU - Li, Wei
AU  - Li W
AD  - University of Pittsburgh, Pittsburgh, PA, USA.
FAU - di Marco, Moreno
AU  - di Marco M
AD  - University of Tubingen, Tubingen, Germany.
FAU - Runbeck, Erin
AU  - Runbeck E
AD  - Division of Oncology and Center for Childhood Cancer Research, Children's 
      Hospital of Philadelphia, Philadelphia, PA, USA.
FAU - Truong, Hau
AU  - Truong H
AD  - Division of Oncology and Center for Childhood Cancer Research, Children's 
      Hospital of Philadelphia, Philadelphia, PA, USA.
FAU - Toor, Jugmohit S
AU  - Toor JS
AD  - Department of Chemistry and Biochemistry, University of California Santa Cruz, 
      Santa Cruz, CA, USA.
FAU - Tripathi, Sarvind
AU  - Tripathi S
AUID- ORCID: 0000-0002-6959-0577
AD  - Department of Chemistry and Biochemistry, University of California Santa Cruz, 
      Santa Cruz, CA, USA.
FAU - Nguyen, Son
AU  - Nguyen S
AUID- ORCID: 0000-0002-0475-5158
AD  - Massachusetts Institute of Technology, Cambridge, MA, USA.
FAU - Shen, Helena
AU  - Shen H
AUID- ORCID: 0000-0002-0500-441X
AD  - Division of Oncology and Center for Childhood Cancer Research, Children's 
      Hospital of Philadelphia, Philadelphia, PA, USA.
FAU - Noel, Tiffany
AU  - Noel T
AD  - Division of Oncology and Center for Childhood Cancer Research, Children's 
      Hospital of Philadelphia, Philadelphia, PA, USA.
FAU - Church, Nicole L
AU  - Church NL
AD  - Myrio Tx, Melbourne, Victoria, Australia.
FAU - Weiner, Amber
AU  - Weiner A
AD  - Division of Oncology and Center for Childhood Cancer Research, Children's 
      Hospital of Philadelphia, Philadelphia, PA, USA.
FAU - Kendsersky, Nathan
AU  - Kendsersky N
AUID- ORCID: 0000-0003-0132-8748
AD  - Division of Oncology and Center for Childhood Cancer Research, Children's 
      Hospital of Philadelphia, Philadelphia, PA, USA.
FAU - Martinez, Dan
AU  - Martinez D
AD  - Department of Pathology and Lab Medicine, Children's Hospital of Philadelphia, 
      Philadelphia, PA, USA.
FAU - Weisberg, Rebecca
AU  - Weisberg R
AD  - Division of Oncology and Center for Childhood Cancer Research, Children's 
      Hospital of Philadelphia, Philadelphia, PA, USA.
FAU - Christie, Molly
AU  - Christie M
AD  - Division of Oncology and Center for Childhood Cancer Research, Children's 
      Hospital of Philadelphia, Philadelphia, PA, USA.
FAU - Eisenlohr, Laurence
AU  - Eisenlohr L
AD  - Department of Pathology and Lab Medicine, Children's Hospital of Philadelphia, 
      Philadelphia, PA, USA.
FAU - Bosse, Kristopher R
AU  - Bosse KR
AD  - Division of Oncology and Center for Childhood Cancer Research, Children's 
      Hospital of Philadelphia, Philadelphia, PA, USA.
AD  - Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 
      USA.
FAU - Dimitrov, Dimiter S
AU  - Dimitrov DS
AUID- ORCID: 0000-0002-2258-1024
AD  - University of Pittsburgh, Pittsburgh, PA, USA.
FAU - Stevanovic, Stefan
AU  - Stevanovic S
AD  - University of Tubingen, Tubingen, Germany.
FAU - Sgourakis, Nikolaos G
AU  - Sgourakis NG
AD  - Division of Oncology and Center for Childhood Cancer Research, Children's 
      Hospital of Philadelphia, Philadelphia, PA, USA.
FAU - Kiefel, Ben R
AU  - Kiefel BR
AD  - Myrio Tx, Melbourne, Victoria, Australia.
FAU - Maris, John M
AU  - Maris JM
AUID- ORCID: 0000-0002-8088-7929
AD  - Division of Oncology and Center for Childhood Cancer Research, Children's 
      Hospital of Philadelphia, Philadelphia, PA, USA. maris@chop.edu.
AD  - Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 
      USA. maris@chop.edu.
LA  - eng
GR  - R35 GM125034/GM/NIGMS NIH HHS/United States
GR  - R35 CA220500/CA/NCI NIH HHS/United States
GR  - T32 CA009140/CA/NCI NIH HHS/United States
GR  - R01 AI143997/AI/NIAID NIH HHS/United States
GR  - P01 CA217959/CA/NCI NIH HHS/United States
GR  - T32 GM132039/GM/NIGMS NIH HHS/United States
GR  - K08 CA230223/CA/NCI NIH HHS/United States
GR  - U54 CA232568/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PT  - Retracted Publication
DEP - 20211103
PL  - England
TA  - Nature
JT  - Nature
JID - 0410462
RN  - 0 (Antigens, Neoplasm)
RN  - 0 (HLA Antigens)
RN  - 0 (Homeodomain Proteins)
RN  - 0 (NBPhox protein)
RN  - 0 (Oncogene Proteins)
RN  - 0 (Receptors, Chimeric Antigen)
RN  - 0 (Transcription Factors)
RN  - 82115-62-6 (Interferon-gamma)
SB  - IM
CIN - Sci Immunol. 2022 Jan 07;7(67):eabn9189. PMID: 34995093
CIN - Cancer Cell. 2022 Jan 10;40(1):20-22. PMID: 35016027
RIN - Nature. 2023 Nov;623(7988):872. PMID: 37938785
MH  - Animals
MH  - Antigens, Neoplasm/*immunology/metabolism
MH  - Cell Line
MH  - Cell Line, Tumor
MH  - Cross Reactions
MH  - Cross-Priming
MH  - Female
MH  - HLA Antigens/*immunology/metabolism
MH  - Homeodomain Proteins/immunology/metabolism
MH  - Humans
MH  - *Immunotherapy
MH  - Interferon-gamma/immunology
MH  - Mice
MH  - Neoplasms/*immunology/metabolism/*therapy
MH  - Oncogene Proteins/antagonists & inhibitors/*immunology/metabolism
MH  - Receptors, Chimeric Antigen/*immunology
MH  - T-Lymphocytes/immunology
MH  - Transcription Factors/immunology/metabolism
PMC - PMC8599005
COIS- J.M.M. and M.Y. have equity stake in Tantigen Bio Inc. and HuLA Therapeutics. 
      Both companies have interest in commercializing technologies described herein. 
      B.R.K. is an employee of and has equity interests in Myrio Therapeutics. R.P. and 
      N.L.C. are employees of Myrio Therapeutics. J.M.M., M.Y. and B.R.K. are 
      co-inventors on a patent filed regarding the PHOX2B PC-CAR.
EDAT- 2021/11/05 06:00
MHDA- 2022/03/29 06:00
PMCR- 2021/11/03
CRDT- 2021/11/04 06:18
PHST- 2021/04/20 00:00 [received]
PHST- 2021/09/23 00:00 [accepted]
PHST- 2021/11/05 06:00 [pubmed]
PHST- 2022/03/29 06:00 [medline]
PHST- 2021/11/04 06:18 [entrez]
PHST- 2021/11/03 00:00 [pmc-release]
AID - 10.1038/s41586-021-04061-6 [pii]
AID - 4061 [pii]
AID - 10.1038/s41586-021-04061-6 [doi]
PST - ppublish
SO  - Nature. 2021 Nov;599(7885):477-484. doi: 10.1038/s41586-021-04061-6. Epub 2021 
      Nov 3.