PMID- 37938771
OWN - NLM
STAT- MEDLINE
DCOM- 20231128
LR  - 20240210
IS  - 1476-4687 (Electronic)
IS  - 0028-0836 (Print)
IS  - 0028-0836 (Linking)
VI  - 623
IP  - 7988
DP  - 2023 Nov
TI  - Targeting of intracellular oncoproteins with peptide-centric CARs.
PG  - 820-827
LID - 10.1038/s41586-023-06706-0 [doi]
AB  - The majority of oncogenic drivers are intracellular proteins, 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 for generating 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 essential for tumorigenesis. We 
      focused 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 (PC-CARs) through a counter panning 
      strategy using predicted potentially cross-reactive peptides. We further proposed 
      that PC-CARs can recognize peptides on additional HLA allotypes when presenting a 
      similar overall molecular surface. Informed by our computational modelling 
      results, we show that PHOX2B PC-CARs also recognize QYNPIRTTF presented by 
      HLA-A*23:01, the most common non-A2 allele in people with African ancestry. 
      Finally, we demonstrate potent and specific killing of neuroblastoma cells 
      expressing these HLAs in vitro and complete tumour regression in mice. These data 
      suggest that PC-CARs have the potential to expand the pool of immunotherapeutic 
      targets to include non-immunogenic intracellular oncoproteins and allow targeting 
      through additional HLA allotypes in a clinical setting.
CI  - (c) 2023. The Author(s).
FAU - Yarmarkovich, Mark
AU  - Yarmarkovich M
AD  - Perlmutter Cancer Center, New York University Grossman School of Medicine, New 
      York, NY, USA. mark.yarmarkovich@nyulangone.org.
AD  - Division of Oncology and Center for Childhood Cancer Research, Children's 
      Hospital of Philadelphia, Philadelphia, PA, USA. 
      mark.yarmarkovich@nyulangone.org.
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
AUID- ORCID: 0000-0001-6066-5491
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
AUID- ORCID: 0000-0003-1087-9840
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
AUID- ORCID: 0000-0001-6897-2656
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  - Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 
      USA.
AD  - Department of Pathology and Lab Medicine, 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  - Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 
      USA.
AD  - Department of Pathology and Lab Medicine, 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  - R01 AI143997/AI/NIAID NIH HHS/United States
GR  - R35 CA220500/CA/NCI NIH HHS/United States
GR  - R35 GM125034/GM/NIGMS NIH HHS/United States
GR  - U54 CA232568/CA/NCI NIH HHS/United States
PT  - Journal Article
DEP - 20231108
PL  - England
TA  - Nature
JT  - Nature
JID - 0410462
RN  - 0 (Antigens, Neoplasm)
RN  - 0 (HLA-A Antigens)
RN  - 0 (NBPhox protein)
RN  - 0 (Oncogene Proteins)
RN  - 0 (Peptides)
RN  - 0 (Receptors, Chimeric Antigen)
SB  - IM
MH  - Animals
MH  - Humans
MH  - Mice
MH  - Africa/ethnology
MH  - Alleles
MH  - Amino Acid Sequence
MH  - *Antigens, Neoplasm
MH  - Carcinogenesis
MH  - Cross Reactions
MH  - HLA-A Antigens/chemistry/immunology
MH  - *Neuroblastoma/genetics/immunology/therapy
MH  - *Oncogene Proteins/antagonists & inhibitors/immunology
MH  - *Peptides/antagonists & inhibitors/chemistry/immunology
MH  - *Receptors, Chimeric Antigen/immunology/therapeutic use
PMC - PMC10665195
COIS- J.M.M. and M.Y. have equity stake in Tantigen Bio 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., N.G.S. and B.R.K. are 
      co-inventors on a patent filed regarding the PHOX2B PC-CAR.
EDAT- 2023/11/08 12:43
MHDA- 2023/11/24 06:42
PMCR- 2023/11/08
CRDT- 2023/11/08 11:59
PHST- 2023/03/23 00:00 [received]
PHST- 2023/10/03 00:00 [accepted]
PHST- 2023/11/24 06:42 [medline]
PHST- 2023/11/08 12:43 [pubmed]
PHST- 2023/11/08 11:59 [entrez]
PHST- 2023/11/08 00:00 [pmc-release]
AID - 10.1038/s41586-023-06706-0 [pii]
AID - 6706 [pii]
AID - 10.1038/s41586-023-06706-0 [doi]
PST - ppublish
SO  - Nature. 2023 Nov;623(7988):820-827. doi: 10.1038/s41586-023-06706-0. Epub 2023 
      Nov 8.