PMID- 33731480 OWN - NLM STAT- MEDLINE DCOM- 20210906 LR - 20240331 IS - 1091-6490 (Electronic) IS - 0027-8424 (Print) IS - 0027-8424 (Linking) VI - 118 IP - 12 DP - 2021 Mar 23 TI - Targeting loss of heterozygosity for cancer-specific immunotherapy. LID - 10.1073/pnas.2022410118 [doi] LID - e2022410118 AB - Developing therapeutic agents with potent antitumor activity that spare normal tissues remains a significant challenge. Clonal loss of heterozygosity (LOH) is a widespread and irreversible genetic alteration that is exquisitely specific to cancer cells. We hypothesized that LOH events can be therapeutically targeted by "inverting" the loss of an allele in cancer cells into an activating signal. Here we describe a proof-of-concept approach utilizing engineered T cells approximating NOT-gate Boolean logic to target counterexpressed antigens resulting from LOH events in cancer. The NOT gate comprises a chimeric antigen receptor (CAR) targeting the allele of human leukocyte antigen (HLA) that is retained in the cancer cells and an inhibitory CAR (iCAR) targeting the HLA allele that is lost in the cancer cells. We demonstrate that engineered T cells incorporating such NOT-gate logic can be activated in a genetically predictable manner in vitro and in mice to kill relevant cancer cells. This therapeutic approach, termed NASCAR (Neoplasm-targeting Allele-Sensing CAR), could, in theory, be extended to LOH of other polymorphic genes that result in altered cell surface antigens in cancers. CI - Copyright (c) 2021 the Author(s). Published by PNAS. FAU - Hwang, Michael S AU - Hwang MS AD - Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287. AD - HHMI, Chevy Chase, MD 20815. AD - Lustgarten Laboratory for Pancreatic Cancer Research, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287. FAU - Mog, Brian J AU - Mog BJ AD - Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287. AD - HHMI, Chevy Chase, MD 20815. AD - Lustgarten Laboratory for Pancreatic Cancer Research, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287. AD - Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218. FAU - Douglass, Jacqueline AU - Douglass J AD - Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287. AD - HHMI, Chevy Chase, MD 20815. AD - Lustgarten Laboratory for Pancreatic Cancer Research, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287. FAU - Pearlman, Alexander H AU - Pearlman AH AUID- ORCID: 0000-0002-3504-7517 AD - Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287. AD - HHMI, Chevy Chase, MD 20815. AD - Lustgarten Laboratory for Pancreatic Cancer Research, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287. FAU - Hsiue, Emily Han-Chung AU - Hsiue EH AD - Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287. AD - HHMI, Chevy Chase, MD 20815. AD - Lustgarten Laboratory for Pancreatic Cancer Research, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287. FAU - Paul, Suman AU - Paul S AUID- ORCID: 0000-0001-9357-3702 AD - Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287. AD - HHMI, Chevy Chase, MD 20815. AD - Lustgarten Laboratory for Pancreatic Cancer Research, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287. AD - Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287. FAU - DiNapoli, Sarah R AU - DiNapoli SR AUID- ORCID: 0000-0002-3675-9030 AD - Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287. AD - HHMI, Chevy Chase, MD 20815. AD - Lustgarten Laboratory for Pancreatic Cancer Research, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287. FAU - Konig, Maximilian F AU - Konig MF AUID- ORCID: 0000-0001-5045-5255 AD - Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287. AD - HHMI, Chevy Chase, MD 20815. AD - Lustgarten Laboratory for Pancreatic Cancer Research, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287. AD - Division of Rheumatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21224. FAU - Pardoll, Drew M AU - Pardoll DM AD - Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287. AD - Bloomberg approximately Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21287. FAU - Gabelli, Sandra B AU - Gabelli SB AUID- ORCID: 0000-0003-1205-5204 AD - Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287. AD - Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21287. AD - Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205. FAU - Bettegowda, Chetan AU - Bettegowda C AD - Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287. AD - Lustgarten Laboratory for Pancreatic Cancer Research, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287. AD - Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287. AD - Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205. FAU - Papadopoulos, Nickolas AU - Papadopoulos N AD - Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287. AD - Lustgarten Laboratory for Pancreatic Cancer Research, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287. AD - Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287. AD - Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205. AD - Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD 21205. FAU - Vogelstein, Bert AU - Vogelstein B AD - Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287. AD - HHMI, Chevy Chase, MD 20815. AD - Lustgarten Laboratory for Pancreatic Cancer Research, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287. AD - Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287. AD - Bloomberg approximately Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21287. AD - Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205. AD - Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD 21205. FAU - Zhou, Shibin AU - Zhou S AD - Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287; sbzhou@jhmi.edu kinzlke@jhmi.edu. AD - Lustgarten Laboratory for Pancreatic Cancer Research, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287. AD - Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287. AD - Bloomberg approximately Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21287. FAU - Kinzler, Kenneth W AU - Kinzler KW AD - Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287; sbzhou@jhmi.edu kinzlke@jhmi.edu. AD - Lustgarten Laboratory for Pancreatic Cancer Research, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287. AD - Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287. AD - Bloomberg approximately Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21287. AD - Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD 21205. LA - eng GR - T32 GM136577/GM/NIGMS NIH HHS/United States GR - P30 CA006973/CA/NCI NIH HHS/United States GR - T32 CA009071/CA/NCI NIH HHS/United States GR - T32 AR048522/AR/NIAMS NIH HHS/United States GR - U01 CA230691/CA/NCI NIH HHS/United States GR - R37 CA230400/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - United States TA - Proc Natl Acad Sci U S A JT - Proceedings of the National Academy of Sciences of the United States of America JID - 7505876 RN - 0 (Antigens, Neoplasm) RN - 0 (Biomarkers, Tumor) RN - 0 (HLA Antigens) RN - 0 (Single-Chain Antibodies) SB - IM CIN - e2102936118 MH - Alleles MH - Antigens, Neoplasm/immunology MH - *Biomarkers, Tumor MH - Cell- and Tissue-Based Therapy MH - HLA Antigens/genetics/immunology MH - Humans MH - *Immunotherapy/methods MH - Immunotherapy, Adoptive MH - *Loss of Heterozygosity MH - *Molecular Targeted Therapy/adverse effects/methods MH - Neoplasms/*etiology/*therapy MH - Single-Chain Antibodies/pharmacology/therapeutic use PMC - PMC8000272 OTO - NOTNLM OT - cancer immunotherapy OT - cell engineering OT - chimeric antigen receptor OT - human leukocyte antigen OT - loss of heterozygosity COIS- Competing interest statement: B.V., K.W.K., and N.P. are founders of Thrive Earlier Detection. K.W.K. and N.P. are consultants to and were on the Board of Directors of Thrive Earlier Detection. B.V., K.W.K., N.P., and S.Z. own equity in Exact Sciences. B.V., K.W.K., N.P., S.Z., and D.M.P. are founders of, hold or may hold equity in, and serve or may serve as consultants to ManaT Bio. B.V., K.W.K., N.P., and S.Z. are founders of, hold equity in, and serve as consultants to Personal Genome Diagnostics. S.Z. has a research agreement with BioMed Valley Discoveries. K.W.K. and B.V. are consultants to Sysmex, Eisai, and CAGE Pharma and hold equity in CAGE Pharma. B.V. is also a consultant to Catalio. K.W.K., B.V., S.Z., and N.P. are consultants to and hold equity in NeoPhore. N.P. is an advisor to and holds equity in CAGE Pharma. C.B. is a consultant to Depuy-Synthes and Bionaut Pharmaceuticals. S.B.G. is a founder and holds equity in AMS. The terms of all these arrangements are being managed by Johns Hopkins University in accordance with its conflict of interest policies. M.F.K. received personal fees from Bristol Myers Squibb and Celltrion. D.M.P. reports grant and patent royalties through institution from Bristol Myers Squibb, a grant from Compugen, stock from Trieza Therapeutics and Dracen Pharmaceuticals, and founder equity from Potenza; being a consultant for Aduro Biotech, Amgen, AstraZeneca (MedImmune/Amplimmune), Bayer, DNAtrix, Dynavax Technologies Corporation, Ervaxx, FLX Bio, Rock Springs Capital, Janssen, Merck, Tizona, and Immunomic Therapeutics; being on the scientific advisory board of Five Prime Therapeutics, Camden Nexus II, and WindMIL; and being on the board of directors for Dracen Pharmaceuticals. EDAT- 2021/03/19 06:00 MHDA- 2021/09/07 06:00 PMCR- 2021/03/17 CRDT- 2021/03/18 06:12 PHST- 2021/03/18 06:12 [entrez] PHST- 2021/03/19 06:00 [pubmed] PHST- 2021/09/07 06:00 [medline] PHST- 2021/03/17 00:00 [pmc-release] AID - 2022410118 [pii] AID - 202022410 [pii] AID - 10.1073/pnas.2022410118 [doi] PST - ppublish SO - Proc Natl Acad Sci U S A. 2021 Mar 23;118(12):e2022410118. doi: 10.1073/pnas.2022410118.