PMID- 32430031
OWN - NLM
STAT- MEDLINE
DCOM- 20210513
LR  - 20210513
IS  - 1756-994X (Electronic)
IS  - 1756-994X (Linking)
VI  - 12
IP  - 1
DP  - 2020 May 19
TI  - MHC-I genotype and tumor mutational burden predict response to immunotherapy.
PG  - 45
LID - 10.1186/s13073-020-00743-4 [doi]
LID - 45
AB  - BACKGROUND: Immune checkpoint blockade (ICB) with antibodies inhibiting cytotoxic 
      T lymphocyte-associated protein-4 (CTLA-4) and programmed cell death protein-1 
      (PD-1) (or its ligand (PD-L1)) can stimulate immune responses against cancer and 
      have revolutionized the treatment of tumors. The influence of host germline 
      genetics and its interaction with tumor neoantigens remains poorly defined. We 
      sought to determine the interaction between tumor mutational burden (TMB) and the 
      ability of a patient's major histocompatibility complex class I (MHC-I) to 
      efficiently present mutated driver neoantigens in predicting response ICB. 
      METHODS: Comprehensive genomic profiling was performed on 83 patients with 
      diverse cancers treated with ICB to determine TMB and human leukocyte antigen-I 
      (HLA-I) genotype. The ability of a patient's MHC-I to efficiently present mutated 
      driver neoantigens (defined by the Patient Harmonic-mean Best Rank (PHBR) score 
      (with lower PHBR indicating more efficient presentation)) was calculated for each 
      patient. RESULTS: The median progression-free survival (PFS) for PHBR score < 0.5 
      vs. >/= 0.5 was 5.1 vs. 4.4 months (P = 0.04). Using a TMB cutoff of 10 
      mutations/mb, the stable disease > 6 months/partial response/complete response 
      rate, median PFS, and median overall survival (OS) of TMB high/PHBR high vs. TMB 
      high/PHBR low were 43% vs. 78% (P = 0.049), 5.8 vs. 26.8 months (P = 0.03), and 
      17.2 months vs. not reached (P = 0.23), respectively. These findings were 
      confirmed in an independent validation cohort of 32 patients. CONCLUSIONS: Poor 
      presentation of driver mutation neoantigens by MHC-I may explain why some tumors 
      (even with a high TMB) do not respond to ICB.
FAU - Goodman, Aaron M
AU  - Goodman AM
AD  - Division of Blood and Marrow Transplantation, Department of Medicine, University 
      of California San Diego, La Jolla, CA, 92093, USA. a1goodman@ucsd.edu.
AD  - Division of Hematology/Oncology Center for Personalized Cancer Therapy, 
      Department of Medicine, University of California San Diego, La Jolla, CA, 92093, 
      USA. a1goodman@ucsd.edu.
AD  - UC San Diego Moores Cancer Center, 855 Health Sciences Drive, La Jolla, CA, 
      92093-0658, USA. a1goodman@ucsd.edu.
FAU - Castro, Andrea
AU  - Castro A
AD  - Division of Medical Genetics, Department of Medicine, University of California 
      San Diego, La Jolla, CA, 92093, USA.
AD  - Bioinformatics and Systems Biology Program, University of California San Diego, 
      La Jolla, CA, 92093, USA.
AD  - Health Science, Department of Biomedical Informatics, School of Medicine, 
      University of California, San Diego, La Jolla, CA, 92093, USA.
FAU - Pyke, Rachel Marty
AU  - Pyke RM
AD  - Division of Medical Genetics, Department of Medicine, University of California 
      San Diego, La Jolla, CA, 92093, USA.
AD  - Bioinformatics and Systems Biology Program, University of California San Diego, 
      La Jolla, CA, 92093, USA.
FAU - Okamura, Ryosuke
AU  - Okamura R
AD  - Division of Hematology/Oncology Center for Personalized Cancer Therapy, 
      Department of Medicine, University of California San Diego, La Jolla, CA, 92093, 
      USA.
FAU - Kato, Shumei
AU  - Kato S
AD  - Division of Hematology/Oncology Center for Personalized Cancer Therapy, 
      Department of Medicine, University of California San Diego, La Jolla, CA, 92093, 
      USA.
AD  - UC San Diego Moores Cancer Center, 855 Health Sciences Drive, La Jolla, CA, 
      92093-0658, USA.
FAU - Riviere, Paul
AU  - Riviere P
AD  - Division of Hematology/Oncology Center for Personalized Cancer Therapy, 
      Department of Medicine, University of California San Diego, La Jolla, CA, 92093, 
      USA.
FAU - Frampton, Garrett
AU  - Frampton G
AD  - Foundation Medicine, Cambridge, MA, 02141, USA.
FAU - Sokol, Ethan
AU  - Sokol E
AD  - Foundation Medicine, Cambridge, MA, 02141, USA.
FAU - Zhang, Xinlian
AU  - Zhang X
AD  - Division of Biostatistics and Bioinformatics, Department of Family Medicine and 
      Public Health, University of California San Diego, La Jolla, CA, 92093, USA.
FAU - Ball, Edward D
AU  - Ball ED
AD  - Division of Blood and Marrow Transplantation, Department of Medicine, University 
      of California San Diego, La Jolla, CA, 92093, USA.
AD  - UC San Diego Moores Cancer Center, 855 Health Sciences Drive, La Jolla, CA, 
      92093-0658, USA.
FAU - Carter, Hannah
AU  - Carter H
AD  - Division of Medical Genetics, Department of Medicine, University of California 
      San Diego, La Jolla, CA, 92093, USA.
AD  - Bioinformatics and Systems Biology Program, University of California San Diego, 
      La Jolla, CA, 92093, USA.
AD  - CIFAR, MaRS Centre, West Tower, 661 University Ave., Suite 505, Toronto, ON, M5G 
      1M1, Canada.
FAU - Kurzrock, Razelle
AU  - Kurzrock R
AD  - Division of Hematology/Oncology Center for Personalized Cancer Therapy, 
      Department of Medicine, University of California San Diego, La Jolla, CA, 92093, 
      USA.
AD  - UC San Diego Moores Cancer Center, 855 Health Sciences Drive, La Jolla, CA, 
      92093-0658, USA.
LA  - eng
GR  - P30 CA023100/CA/NCI NIH HHS/United States
GR  - TL1 TR001443/TR/NCATS NIH HHS/United States
GR  - T15 LM011271/LM/NLM NIH HHS/United States
GR  - DP5 OD017937/OD/NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20200519
PL  - England
TA  - Genome Med
JT  - Genome medicine
JID - 101475844
RN  - 0 (Antigens, Neoplasm)
RN  - 0 (Antineoplastic Agents, Immunological)
RN  - 0 (Histocompatibility Antigens Class I)
SB  - IM
MH  - Antigens, Neoplasm/genetics
MH  - Antineoplastic Agents, Immunological/*therapeutic use
MH  - Female
MH  - Genotype
MH  - Histocompatibility Antigens Class I/*genetics
MH  - Humans
MH  - Immunotherapy
MH  - Male
MH  - Middle Aged
MH  - Mutation
MH  - Neoplasms/*drug therapy/*genetics/mortality
MH  - Survival Analysis
PMC - PMC7236948
OTO - NOTNLM
OT  - Biomarkers
OT  - Checkpoint blockade
OT  - MHC-I
OT  - TMB
COIS- Dr. Goodman receives speaking fees from Seattle Genetics and consulting fees from 
      Jazz Pharmaceuticals, Daiichi Sankyo, EUSA Pharma, and Kyowa Kirin. Dr. Frampton 
      and Dr. Sokol are employees and equity holders of Foundation Medicine. Dr. 
      Kurzrock receives research funding from Genentech, Merck, Serono, Pfizer, 
      Sequenom, Foundation Medicine, Konica Minolta, Grifols, and Guardant, as well as 
      consultant fees from X Biotech, Loxo, Neomed, and Actuate Therapeutics, and 
      speaker fees from Roche, and has an ownership interest in IDbyDNA and CureMatch 
      Inc. Paul Riviere receives funding from Peptide Logic LLC. Dr. Kato serves as a 
      consultant for Foundation Medicine. Dr. Pyke is an employee of Personalis, Inc. 
      The remaining authors declare that they have no competing interests.
EDAT- 2020/05/21 06:00
MHDA- 2021/05/14 06:00
PMCR- 2020/05/19
CRDT- 2020/05/21 06:00
PHST- 2019/09/27 00:00 [received]
PHST- 2020/05/05 00:00 [accepted]
PHST- 2020/05/21 06:00 [entrez]
PHST- 2020/05/21 06:00 [pubmed]
PHST- 2021/05/14 06:00 [medline]
PHST- 2020/05/19 00:00 [pmc-release]
AID - 10.1186/s13073-020-00743-4 [pii]
AID - 743 [pii]
AID - 10.1186/s13073-020-00743-4 [doi]
PST - epublish
SO  - Genome Med. 2020 May 19;12(1):45. doi: 10.1186/s13073-020-00743-4.