PMID- 34235003
OWN - NLM
STAT- MEDLINE
DCOM- 20210802
LR  - 20210802
IS  - 2162-402X (Electronic)
IS  - 2162-4011 (Print)
IS  - 2162-4011 (Linking)
VI  - 10
IP  - 1
DP  - 2021
TI  - Targeting KRAS mutations with HLA class II-restricted TCRs for the treatment of 
      solid tumors.
PG  - 1936757
LID - 10.1080/2162402X.2021.1936757 [doi]
LID - 1936757
AB  - T-cell receptor (TCR) redirected T cells are considered as the next generation of 
      care for the treatment of numerous solid tumors. KRAS mutations are driver 
      neoantigens that are expressed in over 25% of all cancers and are thus regarded 
      as ideal targets for Adoptive Cell Therapy (ACT). We have isolated four 
      KRAS-specific TCRs from a long-term surviving pancreatic cancer patient 
      vaccinated with a mix of mutated KRAS peptides. The sequence of these TCRs could 
      be identified and expressed in primary cells. We demonstrated stable expression 
      of all TCRs as well as target-specific functionality when expressing T cells were 
      co-incubated with target cells presenting KRAS peptides. In addition, these TCRs 
      were all partially co-receptor independent since they were functional in both CD4 
      and CD8 T cells, thus indicating high affinity. Interestingly, we observed that 
      certain TCRs were able to recognize several KRAS mutations in complex with their 
      cognate Human leukocyte antigen (HLA), suggesting that, here, the point mutations 
      were less important for the HLA binding and TCR recognition, whereas others were 
      single-mutation restricted. Finally, we demonstrated that these peptides were 
      indeed processed and presented, since HLA-matched antigen presenting cells 
      exogenously loaded with KRAS proteins were recognized by TCR-transduced T cells. 
      Taken together, our data demonstrate that KRAS mutations are immunogenic for CD4 
      T cells and are interesting targets for TCR-based cancer immunotherapy.
CI  - (c) 2021 The Author(s). Published with license by Taylor & Francis Group, LLC.
FAU - Dillard, Pierre
AU  - Dillard P
AUID- ORCID: 0000-0002-4812-9159
AD  - Translational Research Unit, Department of Cellular Therapy, Oslo University 
      Hospital, Oslo, Norway.
FAU - Casey, Nicholas
AU  - Casey N
AUID- ORCID: 0000-0001-6706-8710
AD  - Translational Research Unit, Department of Cellular Therapy, Oslo University 
      Hospital, Oslo, Norway.
FAU - Pollmann, Sylvie
AU  - Pollmann S
AD  - Translational Research Unit, Department of Cellular Therapy, Oslo University 
      Hospital, Oslo, Norway.
FAU - Vernhoff, Patrik
AU  - Vernhoff P
AD  - Translational Research Unit, Department of Cellular Therapy, Oslo University 
      Hospital, Oslo, Norway.
FAU - Gaudernack, Gustav
AU  - Gaudernack G
AUID- ORCID: 0000-0002-9678-7447
AD  - Department of Cancer Immunology, Institute for Cancer Research, Oslo University 
      Hospital, Oslo, Norway.
FAU - Kvalheim, Gunnar
AU  - Kvalheim G
AD  - Translational Research Unit, Department of Cellular Therapy, Oslo University 
      Hospital, Oslo, Norway.
FAU - Walchli, Sebastien
AU  - Walchli S
AD  - Translational Research Unit, Department of Cellular Therapy, Oslo University 
      Hospital, Oslo, Norway.
FAU - Inderberg, Else Marit
AU  - Inderberg EM
AUID- ORCID: 0000-0002-6147-3536
AD  - Translational Research Unit, Department of Cellular Therapy, Oslo University 
      Hospital, Oslo, Norway.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210617
PL  - United States
TA  - Oncoimmunology
JT  - Oncoimmunology
JID - 101570526
RN  - 0 (Antigens, Neoplasm)
RN  - 0 (HLA Antigens)
RN  - 0 (KRAS protein, human)
RN  - 0 (Receptors, Antigen, T-Cell)
RN  - EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras))
SB  - IM
MH  - Antigens, Neoplasm
MH  - HLA Antigens
MH  - Humans
MH  - Mutation
MH  - *Pancreatic Neoplasms
MH  - *Proto-Oncogene Proteins p21(ras)/genetics
MH  - Receptors, Antigen, T-Cell/genetics
PMC - PMC8216182
OTO - NOTNLM
OT  - Adoptive Cell Therapy
OT  - Immunotherapy
OT  - KRAS
OT  - TCR
EDAT- 2021/07/09 06:00
MHDA- 2021/08/03 06:00
PMCR- 2021/06/17
CRDT- 2021/07/08 06:43
PHST- 2021/07/08 06:43 [entrez]
PHST- 2021/07/09 06:00 [pubmed]
PHST- 2021/08/03 06:00 [medline]
PHST- 2021/06/17 00:00 [pmc-release]
AID - 1936757 [pii]
AID - 10.1080/2162402X.2021.1936757 [doi]
PST - epublish
SO  - Oncoimmunology. 2021 Jun 17;10(1):1936757. doi: 10.1080/2162402X.2021.1936757. 
      eCollection 2021.