Evidence map›Paper›PMID 37963244›Full record

ArticleProceedings of the National Academy of Sciences of the United States of America2023

Dual-inhibitory domain iCARs improve the efficiency of the AND-NOT gate CAR T strategy.

Nathanael J Bangayan, Liang Wang, Giselle Burton Sojo, Miyako Noguchi, Donghui Cheng, Lisa Ta, Donny Gunn, Zhiyuan Mao, Shiqin Liu, Qingqing Yin and 5 more

Open access · hybridAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Proceedings of the National Academy of Sciences of the United States of America, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.

0numbers the graph read from it
0cells of the map it votes in
43citing papers in PubMed
9.7field-weighted citation impact, top 2% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

43 citing papers in PubMed, 42 citations in OpenAlex.

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  4. Engineering the next generation of cellular therapies for solid tumors: multi-specific armored CARs and TME reprogramming strategies.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2026
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  19. Harnessing chimeric antigen receptor macrophages against solid tumors.Cancer communications (London, England) · 2025
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

15 authors at 2 institutions in 1 country.

Nathanael J BangayanDepartment of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095.
Liang WangDepartment of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA 90095.
Giselle Burton SojoDepartment of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA 90095.
Miyako NoguchiDepartment of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA 90095.
Donghui ChengDepartment of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA 90095.
Lisa TaDepartment of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095.
Donny GunnDepartment of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA 90095.
Zhiyuan MaoDepartment of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095.
Shiqin LiuDepartment of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095.
Qingqing YinDepartment of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095.
Mireille RiedingerDepartment of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA 90095.
Keyu LiDepartment of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095.
Anna M WuDepartment of Immunology and Theranostics, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope, Duarte, CA 91010.ORCID 0000-0001-8487-823X
Tanya StoyanovaDepartment of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095.
Owen N WitteDepartment of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095.ORCID 0000-0003-4461-4533
University of California, Los Angeles · USCity Of Hope National Medical Center · US

Funding

UCLA SPORE IN PROSTATE CANCERP50CA092131 · NCI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI REITER, ROBERT E · 2002 to 2023
$42.6M
TUMOR CELL SURFACES AND CHROMOSOMEST32CA009056 · NCI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI Gay M Crooks, David A. Nathanson · 1985 to 2026
$10.5M
NCI NIH HHS P50 CA092131NCI NIH HHS T32 CA009056
6 · The paper itself

Abstract

CAR (chimeric antigen receptor) T cell therapy has shown clinical success in treating hematological malignancies, but its treatment of solid tumors has been limited. One major challenge is on-target, off-tumor toxicity, where CAR T cells also damage normal tissues that express the targeted antigen. To reduce this detrimental side-effect, Boolean-logic gates like AND-NOT gates have utilized an inhibitory CAR (iCAR) to specifically curb CAR T cell activity at selected nonmalignant tissue sites. However, the strategy seems inefficient, requiring high levels of iCAR and its target antigen for inhibition. Using a TROP2-targeting iCAR with a single PD1 inhibitory domain to inhibit a CEACAM5-targeting CAR (CEACAR), we observed that the inefficiency was due to a kinetic delay in iCAR inhibition of cytotoxicity. To improve iCAR efficiency, we modified three features of the iCAR-the avidity, the affinity, and the intracellular signaling domains. Increasing the avidity but not the affinity of the iCAR led to significant reductions in the delay. iCARs containing twelve different inhibitory signaling domains were screened for improved inhibition, and three domains (BTLA, LAIR-1, and SIGLEC-9) each suppressed CAR T function but did not enhance inhibitory kinetics. When inhibitory domains of LAIR-1 or SIGLEC-9 were combined with PD-1 into a single dual-inhibitory domain iCAR (DiCARs) and tested with the CEACAR, inhibition efficiency improved as evidenced by a significant reduction in the inhibitory delay. These data indicate that a delicate balance between CAR and iCAR signaling strength and kinetics must be achieved to regulate AND-NOT gate CAR T cell selectivity.

Indexed as

NeoplasmsReceptors, Chimeric AntigenHumansImmunotherapy, AdoptiveIron-Dextran ComplexSialic Acid Binding Immunoglobulin-like LectinsT-LymphocytesIron-Dextran ComplexReceptors, Chimeric AntigenSialic Acid Binding Immunoglobulin-like LectinsAND-NOT logic gatechimeric antigen receptorimmunotherapyinhibitory CAR (iCAR)on-target, off-tumor toxicity

Identifiers

PMID37963244
PMCPMC10666036
OpenAlexW4388665568

What OpenQuestion holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.