PMID- 35484264
OWN - NLM
STAT- MEDLINE
DCOM- 20220520
LR  - 20240507
IS  - 1546-170X (Electronic)
IS  - 1078-8956 (Print)
IS  - 1078-8956 (Linking)
VI  - 28
IP  - 5
DP  - 2022 May
TI  - Immunogenicity and therapeutic targeting of a public neoantigen derived from 
      mutated PIK3CA.
PG  - 946-957
LID - 10.1038/s41591-022-01786-3 [doi]
AB  - Public neoantigens (NeoAgs) represent an elite class of shared cancer-specific 
      epitopes derived from recurrently mutated driver genes. Here we describe a 
      high-throughput platform combining single-cell transcriptomic and T cell receptor 
      (TCR) sequencing to establish whether mutant PIK3CA, among the most frequently 
      genomically altered driver oncogenes, generates an immunogenic public NeoAg. 
      Using this strategy, we developed a panel of TCRs that recognize an endogenously 
      processed neopeptide encompassing a common PIK3CA hotspot mutation restricted by 
      the prevalent human leukocyte antigen (HLA)-A*03:01 allele. Mechanistically, 
      immunogenicity to this public NeoAg arises from enhanced neopeptide/HLA complex 
      stability caused by a preferred HLA anchor substitution. Structural studies 
      indicated that the HLA-bound neopeptide presents a comparatively 'featureless' 
      surface dominated by the peptide's backbone. To bind this epitope with high 
      specificity and affinity, we discovered that a lead TCR clinical candidate 
      engages the neopeptide through an extended interface facilitated by an unusually 
      long CDR3beta loop. In patients with diverse malignancies, we observed NeoAg clonal 
      conservation and spontaneous immunogenicity to the neoepitope. Finally, adoptive 
      transfer of TCR-engineered T cells led to tumor regression in vivo in mice 
      bearing PIK3CA-mutant tumors but not wild-type PIK3CA tumors. Together, these 
      findings establish the immunogenicity and therapeutic potential of a mutant 
      PIK3CA-derived public NeoAg.
CI  - (c) 2022. The Author(s).
FAU - Chandran, Smita S
AU  - Chandran SS
AUID- ORCID: 0000-0001-9266-6878
AD  - Human Oncology and Pathogenesis Program (HOPP), Immuno-Oncology Service, Memorial 
      Sloan Kettering Cancer Center, New York, NY, USA. chandrs1@mskcc.org.
AD  - Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, 
      NY, USA. chandrs1@mskcc.org.
AD  - Parker Institute for Cancer Immunotherapy, New York, NY, USA. chandrs1@mskcc.org.
FAU - Ma, Jiaqi
AU  - Ma J
AUID- ORCID: 0000-0002-6298-0193
AD  - Department of Chemistry and Biochemistry, University of Notre Dame, South Bend, 
      IN, USA.
AD  - Harper Cancer Research Institute, University of Notre Dame, South Bend, IN, USA.
FAU - Klatt, Martin G
AU  - Klatt MG
AUID- ORCID: 0000-0001-8703-7305
AD  - Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan 
      Kettering Cancer Center, New York, NY, USA.
FAU - Dundar, Friederike
AU  - Dundar F
AUID- ORCID: 0000-0002-2301-112X
AD  - Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, 
      USA.
AD  - Applied Bioinformatics Core, Weill Cornell Medicine, New York, NY, USA.
FAU - Bandlamudi, Chaitanya
AU  - Bandlamudi C
AD  - Marie-Josee and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan 
      Kettering Cancer Center, New York, NY, USA.
FAU - Razavi, Pedram
AU  - Razavi P
AUID- ORCID: 0000-0003-4236-0576
AD  - Human Oncology and Pathogenesis Program (HOPP), Immuno-Oncology Service, Memorial 
      Sloan Kettering Cancer Center, New York, NY, USA.
AD  - Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, 
      USA.
AD  - Department of Medicine, Division of Hematology and Medical Oncology, Weill 
      Cornell Medicine, New York, NY, USA.
FAU - Wen, Hannah Y
AU  - Wen HY
AD  - Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, 
      USA.
FAU - Weigelt, Britta
AU  - Weigelt B
AUID- ORCID: 0000-0001-9927-1270
AD  - Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, 
      USA.
FAU - Zumbo, Paul
AU  - Zumbo P
AD  - Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, 
      USA.
AD  - Applied Bioinformatics Core, Weill Cornell Medicine, New York, NY, USA.
FAU - Fu, Si Ning
AU  - Fu SN
AD  - Human Oncology and Pathogenesis Program (HOPP), Immuno-Oncology Service, Memorial 
      Sloan Kettering Cancer Center, New York, NY, USA.
AD  - Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, 
      NY, USA.
FAU - Banks, Lauren B
AU  - Banks LB
AD  - Human Oncology and Pathogenesis Program (HOPP), Immuno-Oncology Service, Memorial 
      Sloan Kettering Cancer Center, New York, NY, USA.
AD  - Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, 
      NY, USA.
AD  - Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, 
      USA.
FAU - Yi, Fei
AU  - Yi F
AD  - Human Oncology and Pathogenesis Program (HOPP), Immuno-Oncology Service, Memorial 
      Sloan Kettering Cancer Center, New York, NY, USA.
AD  - Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, 
      NY, USA.
FAU - Vercher, Enric
AU  - Vercher E
AD  - Human Oncology and Pathogenesis Program (HOPP), Immuno-Oncology Service, Memorial 
      Sloan Kettering Cancer Center, New York, NY, USA.
FAU - Etxeberria, Inaki
AU  - Etxeberria I
AUID- ORCID: 0000-0003-2713-0836
AD  - Human Oncology and Pathogenesis Program (HOPP), Immuno-Oncology Service, Memorial 
      Sloan Kettering Cancer Center, New York, NY, USA.
FAU - Bestman, Watchain D
AU  - Bestman WD
AD  - Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, 
      USA.
AD  - Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
FAU - Da Cruz Paula, Arnaud
AU  - Da Cruz Paula A
AD  - Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
FAU - Aricescu, Ilinca S
AU  - Aricescu IS
AD  - Human Oncology and Pathogenesis Program (HOPP), Immuno-Oncology Service, Memorial 
      Sloan Kettering Cancer Center, New York, NY, USA.
FAU - Drilon, Alexander
AU  - Drilon A
AUID- ORCID: 0000-0001-6806-9061
AD  - Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, 
      USA.
AD  - Department of Medicine, Division of Hematology and Medical Oncology, Weill 
      Cornell Medicine, New York, NY, USA.
AD  - Early Drug Development Service, Memorial Sloan Kettering Cancer Center, New York, 
      NY, USA.
FAU - Betel, Doron
AU  - Betel D
AUID- ORCID: 0000-0002-8006-7752
AD  - Applied Bioinformatics Core, Weill Cornell Medicine, New York, NY, USA.
AD  - Department of Medicine, Division of Hematology and Medical Oncology, Weill 
      Cornell Medicine, New York, NY, USA.
AD  - Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY, 
      USA.
FAU - Scheinberg, David A
AU  - Scheinberg DA
AD  - Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan 
      Kettering Cancer Center, New York, NY, USA.
AD  - Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, 
      USA.
FAU - Baker, Brian M
AU  - Baker BM
AD  - Department of Chemistry and Biochemistry, University of Notre Dame, South Bend, 
      IN, USA.
AD  - Harper Cancer Research Institute, University of Notre Dame, South Bend, IN, USA.
FAU - Klebanoff, Christopher A
AU  - Klebanoff CA
AUID- ORCID: 0000-0001-9645-3896
AD  - Human Oncology and Pathogenesis Program (HOPP), Immuno-Oncology Service, Memorial 
      Sloan Kettering Cancer Center, New York, NY, USA. klebanoc@mskcc.org.
AD  - Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, 
      NY, USA. klebanoc@mskcc.org.
AD  - Parker Institute for Cancer Immunotherapy, New York, NY, USA. klebanoc@mskcc.org.
AD  - Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, 
      USA. klebanoc@mskcc.org.
AD  - Department of Medicine, Division of Hematology and Medical Oncology, Weill 
      Cornell Medicine, New York, NY, USA. klebanoc@mskcc.org.
AD  - Early Drug Development Service, Memorial Sloan Kettering Cancer Center, New York, 
      NY, USA. klebanoc@mskcc.org.
AD  - Cell Therapy Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 
      klebanoc@mskcc.org.
LA  - eng
GR  - S10 RR028976/RR/NCRR NIH HHS/United States
GR  - S10 RR025528/RR/NCRR NIH HHS/United States
GR  - R01 AI129543/AI/NIAID NIH HHS/United States
GR  - R37 CA259177/CA/NCI NIH HHS/United States
GR  - P30 CA008748/CA/NCI NIH HHS/United States
GR  - S10 OD021527/OD/NIH HHS/United States
GR  - P50 CA217694/CA/NCI NIH HHS/United States
GR  - P30 GM124165/GM/NIGMS 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.
DEP - 20220428
PL  - United States
TA  - Nat Med
JT  - Nature medicine
JID - 9502015
RN  - 0 (Antigens, Neoplasm)
RN  - 0 (Receptors, Antigen, T-Cell)
RN  - EC 2.7.1.137 (Class I Phosphatidylinositol 3-Kinases)
RN  - EC 2.7.1.137 (PIK3CA protein, human)
SB  - IM
MH  - Animals
MH  - *Antigens, Neoplasm/genetics
MH  - Class I Phosphatidylinositol 3-Kinases/genetics
MH  - Humans
MH  - Mice
MH  - Mutation/genetics
MH  - *Neoplasms/genetics
MH  - Receptors, Antigen, T-Cell
PMC - PMC9117146
COIS- S.S.C. and C.A.K. are inventors of the TCR discovery platform and the PIK3CA 
      public NeoAg TCRs described in this manuscript, which were licensed to Intima 
      Bioscience in December 2021. Licensing revenue is shared with S.S.C. and C.A.K. 
      according to MSKCC institutional policies. MSKCC has filed for patent protection 
      for D.A.S. and M.G.K. for work related to mass spectrometry. C.A.K. has consulted 
      for, or is on the scientific and/or clinical advisory boards for Achilles 
      Therapeutics, Aleta BioTherapeutics, Bellicum Pharmaceuticals, Bristol Myers 
      Squibb, Catamaran Bio, Cell Design Labs, Decheng Capital, G1 Therapeutics, Klus 
      Pharma, Obsidian Therapeutics, PACT Pharma, Roche/Genentech and T-knife. B.M.B. 
      has previously consulted for Eurkea Therapuetics and is on the scientific 
      advisory board of T-Cure Bioscience. D.A.S. has an equity interest in, consults 
      for or is on the board of Sellas Life Sciences, Pfizer, Oncopep, Actinium, 
      Co-Immune, Eureka, Repertoire, Sapience, Iovance and Arvinas. B.W. reports ad hoc 
      membership of the scientific advisory board of Repare Therapeutics. A.D.C.P. has 
      received honoraria or has served on advisory boards for Ignyta/Genentech/Roche, 
      Loxo/Bayer/Lilly, Takeda/Ariad/Millenium, TP Therapeutics, AstraZeneca, Pfizer, 
      Blueprint Medicines, Helsinn, Beigene, BergenBio, Hengrui Therapeutics, Exelixis, 
      Tyra Biosciences, Verastem, MORE Health, Abbvie, 14ner/Elevation Oncology, 
      ArcherDX, Monopteros, Novartis, EMD Serono, Medendi, Repare RX, Nuvalent, Merus, 
      Chugai Pharmaceutical, Remedica, mBrace, AXIS, EPG Health, Harborside Nexus, 
      Liberum, RV More, Ology, Amgen, TouchIME and Janssen; Associated Research Paid to 
      Institution from Pfizer, Exelixis, GlaxoSmithKlein, Teva, Taiho and PharmaMar; 
      Research support from Foundation Medicine; Royalties from Wolters Kluwer; Other 
      from Merck, Puma, Merus and Boehringer Ingelheim; and CME Honoraria from 
      Medscape, OncLive, PeerVoice, Physicians Education Resources, Targeted Oncology, 
      Research to Practice, Axis, Peerview Institute, Paradigm Medical Communications, 
      WebMD, MJH Life Sciences, Med Learning, Imedex, Answers in CME, Clinical Care 
      Options, EPG Health, JNCC/Harborside, Liberum and Remedica. All other authors 
      declare no competing interests.
EDAT- 2022/04/29 06:00
MHDA- 2022/05/21 06:00
PMCR- 2022/04/28
CRDT- 2022/04/28 23:22
PHST- 2021/04/02 00:00 [received]
PHST- 2022/03/16 00:00 [accepted]
PHST- 2022/04/29 06:00 [pubmed]
PHST- 2022/05/21 06:00 [medline]
PHST- 2022/04/28 23:22 [entrez]
PHST- 2022/04/28 00:00 [pmc-release]
AID - 10.1038/s41591-022-01786-3 [pii]
AID - 1786 [pii]
AID - 10.1038/s41591-022-01786-3 [doi]
PST - ppublish
SO  - Nat Med. 2022 May;28(5):946-957. doi: 10.1038/s41591-022-01786-3. Epub 2022 Apr 
      28.