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Cited by 190CAR-T cell therapy researchImmunotherapy and Immune ResponsesT-cell and B-cell Immunology

HLA-independent T cell receptors for targeting tumors with low antigen density

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Mansilla-Soto, Jorge, Eyquem, Justin, Haubner, Sascha, Hamieh, Mohamad, Feucht, Judith, Paillon, Noémie, Zucchetti, Andrés Ernesto, Li, Zhuoning +17 more·2022·Nature Medicine
DOI 10.1038/s41591-021-01621-1PMC PMC9469647
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Abstract

Chimeric antigen receptors (CARs) are receptors for antigen that direct potent immune responses. Tumor escape associated with low target antigen expression is emerging as one potential limitation of their efficacy. Here we edit the TRAC locus in human peripheral blood T cells to engage cell-surface targets through their T cell receptor-CD3 complex reconfigured to utilize the same immunoglobulin heavy and light chains as a matched CAR. We demonstrate that these HLA-independent T cell receptors (HIT receptors) consistently afford high antigen sensitivity and mediate tumor recognition beyond what CD28-based CARs, the most sensitive design to date, can provide. We demonstrate that the functional persistence of HIT T cells can be augmented by constitutive coexpression of CD80 and 4-1BBL. Finally, we validate the increased antigen sensitivity afforded by HIT receptors in xenograft mouse models of B cell leukemia and acute myeloid leukemia, targeting CD19 and CD70, respectively. Overall, HIT receptors are well suited for targeting cell surface antigens of low abundance.

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  • Efforts to improve functional CAR T cell performance have spawned CAR T cell products co-expressing additional costimulatory receptors.

    “Efforts to improve functional CAR T cell performance has spawned CAR T cell products co-expressing additional costimulatory receptors [3,4,5,6], including CD80/CD86-CD28 [3,5], 41BBL-CD137 [6], CD70-CD27 [7], and CD40-CD40L [8], or the constitutive active CD40/TLR4 [9].”

    From Ectopic PU.1 Expression Provides Chimeric Antigen Receptor (CAR) T Cells with Innate Cell Capacities Including IFN-β Release (2024) · cites this paper as [5]

    The Results section (page not specified) says that co-expressing ligands for CD28 and 4-1BB had previously enhanced the persistence of CAR T cells. This supports the broader point about adding costimulatory support, but the co-expressed molecules described are ligands, not additional costimulatory receptors; this paper's own co-expression experiments used HIT T cells rather than CAR T cells. (LLM, conf=0.86)

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Authors
Mansilla-Soto, J., Eyquem, J., Haubner, S., Hamieh, M., Feucht, J., Paillon, N., Zucchetti, A. E., Li, Z., Sjöstrand, M., Lindenbergh, P. L., Saetersmoen, M., Dobrin, A., Maurin, M., Iyer, A., Garcia Angus, A., Miele, M. M., Zhao, Z., Giavridis, T., van der Stegen, S. J. C., Tamzalit, F., Rivière, I., Huse, M., Hendrickson, R. C., Hivroz, C., & Sadelain, M.
Affiliations
  • Memorial Sloan Kettering Cancer Center (US)
  • Inserm (FR)
Corresponding author
Sadelain, Michel
ORCID
Venue
Nature Medicine
Publisher
Springer Science and Business Media LLC
Published
2022-01-13
Volume
28
Issue
2
Pages
345-352
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
DOI
10.1038/s41591-021-01621-1
PMC
PMC9469647
OpenAlex
W4205786643
Cited by
190
References
5
Citations by year
2026: 32 · 2025: 48 · 2024: 45 · 2023: 44 · 2022: 21
FWCI
16.53
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • Agence Nationale de la Recherche (ANR-17-EURE-0012)
  • National Institutes of Health (1s10od010598-01)
  • National Cancer Institute (P30CA008748)
Topics
  • Health Sciences › Medicine › Oncology › CAR-T cell therapy research
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Keywords
chimeric antigen receptor, tumor escape, T cell receptor/CD3 complex, B-cell leukemia, acute myeloid leukemia, CD19, CD70, xenograft models
MeSH terms
Receptors, Chimeric Antigen, Animals, Histocompatibility Antigens, Humans, Receptors, Antigen, T-Cell, Leukemia, Myeloid, Acute, Immunotherapy, Adoptive, Antigens, CD19, Xenograft Model Antitumor Assays, Mice

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