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Cited by 10CAR-T cell therapy researchImmunotherapy and Immune ResponsesT-cell and B-cell Immunology

The DOI matches its Crossref record; 7 of the 7 references it cites were found in a registry or an index.

Rational Protein Engineering to Enhance MHC-Independent T-cell Receptors

Open access
Chang, Ju-Fang, Landmann, Jack H., Chang, Tien-Ching, Selli, Mehmet Emrah, Tenzin, Yangdon, Warrington, John M., Ritchey, Julie, Hsu, Yu-Sung, Slade, Michael, Gupta, Deepesh Kumar, DiPersio, John F., Holehouse, Alex S., Singh, Nathan·2024·Cancer Discovery
DOI 10.1158/2159-8290.cd-23-1393PMC PMC11530325

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Abstract

Chimeric antigen receptor (CAR)–based therapies have pioneered synthetic cellular immunity but remain limited in their long-term efficacy. Emerging data suggest that dysregulated CAR-driven T-cell activation causes T-cell dysfunction and therapeutic failure. To re-engage the precision of the endogenous T-cell response, we designed MHC-independent T-cell receptors (miTCR) by linking antibody variable domains to T-cell receptor constant chains. Using predictive modeling, we observed that this standard “cut and paste” approach to synthetic protein design resulted in myriad biochemical conflicts at the hybrid variable–constant domain interface. Through iterative modeling and sequence modifications, we developed structure-enhanced miTCRs which significantly improved receptor-driven T-cell function across multiple tumor models. We found that 41BB costimulation specifically prolonged miTCR T-cell persistence and enabled improved leukemic control in vivo compared with classic CAR T cells. Collectively, we have identified core features of hybrid receptor structure responsible for regulating function. Significance: Improving the durability of engineered T-cell immunotherapies is critical to enhancing efficacy. We used a structure-informed design to evolve improved miTCR function across several models. This work underscores the central role of synthetic receptor structure in T-cell function and provides a framework for improved receptor engineering.

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Research works printed but not linked: 39

  1. Good, 2021, An NK-like CAR T cell transition in CAR T cell dysfunction, Cell, 184, 6081, 10.1016/j.cell.2021.11.016 · DOI
  2. Selli, 2023, Costimulatory domains direct distinct fates of CAR-driven T-cell dysfunction, Blood, 141, 3153
  3. Fraietta, 2018, Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia, Nat Med, 24, 563, 10.1038/s41591-018-0010-1 · DOI · Paper page
  4. Davenport, 2018, Chimeric antigen receptor T cells form nonclassical and potent immune synapses driving rapid cytotoxicity, Proc Natl Acad Sci U S A, 115, E2068, 10.1073/pnas.1716266115 · DOI
  5. Weber, 2021, Transient rest restores functionality in exhausted CAR-T cells through epigenetic remodeling, Science, 372, eaba1786, 10.1126/science.aba1786 · DOI
  6. Chandran, 2022, Immunogenicity and therapeutic targeting of a public neoantigen derived from mutated PIK3CA, Nat Med, 28, 946, 10.1038/s41591-022-01786-3 · DOI
  7. Leidner, 2022, Neoantigen T-cell receptor gene therapy in pancreatic cancer, N Engl J Med, 386, 2112, 10.1056/NEJMoa2119662 · DOI
  8. Helsen, 2018, The chimeric TAC receptor co-opts the T cell receptor yielding robust anti-tumor activity without toxicity, Nat Commun, 9, 3049, 10.1038/s41467-018-05395-y · DOI
  9. Baeuerle, 2019, Synthetic TRuC receptors engaging the complete T cell receptor for potent anti-tumor response, Nat Commun, 10, 2087, 10.1038/s41467-019-10097-0 · DOI
  10. Hassan, 2023, Mesothelin-targeting T cell receptor fusion construct cell therapy in refractory solid tumors: phase 1/2 trial interim results, Nat Med, 29, 2099, 10.1038/s41591-023-02452-y · DOI
  11. Gross, 1989, Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity, Proc Natl Acad Sci U S A, 86, 10024, 10.1073/pnas.86.24.10024 · DOI
  12. Becker, 1989, Expression of a hybrid immunoglobulin-T cell receptor protein in transgenic mice, Cell, 58, 911, 10.1016/0092-8674(89)90943-4 · DOI
  13. Liu, 2021, Chimeric STAR receptors using TCR machinery mediate robust responses against solid tumors, Sci Transl Med, 13, eabb5191, 10.1126/scitranslmed.abb5191 · DOI
  14. Mansilla-Soto, 2022, HLA-independent T cell receptors for targeting tumors with low antigen density, Nat Med, 28, 345, 10.1038/s41591-021-01621-1 · DOI · Paper page
  15. Dong, 2019, Structural basis of assembly of the human T cell receptor-CD3 complex, Nature, 573, 546, 10.1038/s41586-019-1537-0 · DOI
  16. Teplyakov, 2018, Crystal structure of B-cell co-receptor CD19 in complex with antibody B43 reveals an unexpected fold, Proteins, 86, 495, 10.1002/prot.25485 · DOI
  17. Kelley, 2015, The Phyre2 web portal for protein modeling, prediction and analysis, Nat Protoc, 10, 845, 10.1038/nprot.2015.053 · DOI · Paper page
  18. Fry, 2018, CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy, Nat Med, 24, 20, 10.1038/nm.4441 · DOI
  19. Singh, 2021, Antigen-independent activation enhances the efficacy of 4-1BB-costimulated CD22 CAR T cells, Nat Med, 27, 842, 10.1038/s41591-021-01326-5 · DOI
  20. Xiao, 2020, Targeting EphA2 in cancer, J Hematol Oncol, 13, 114, 10.1186/s13045-020-00944-9 · DOI
  21. He, 2023, CD19 CAR antigen engagement mechanisms and affinity tuning, Sci Immunol, 8, eadf1426, 10.1126/sciimmunol.adf1426 · DOI
  22. Ghassemi, 2022, Rapid manufacturing of non-activated potent CAR T cells, Nat Biomed Eng, 6, 118, 10.1038/s41551-021-00842-6 · DOI
  23. Abraham, 2004, Jurkat T cells and development of the T-cell receptor signalling paradigm, Nat Rev Immunol, 4, 301, 10.1038/nri1330 · DOI
  24. Zhao, 2007, High-affinity TCRs generated by phage display provide CD4+ T cells with the ability to recognize and kill tumor cell lines, J Immunol, 179, 5845, 10.4049/jimmunol.179.9.5845 · DOI
  25. Selli, 2023, Inducing T cell dysfunction by chronic stimulation of CAR-engineered T cells targeting cancer cells in suspension cultures, STAR Protoc, 4, 101954, 10.1016/j.xpro.2022.101954 · DOI
  26. Zhao, 2015, Structural design of engineered costimulation determines tumor rejection kinetics and persistence of CAR T cells, Cancer Cell, 28, 415, 10.1016/j.ccell.2015.09.004 · DOI · Paper page
  27. Robbins, 2008, Single and dual amino acid substitutions in TCR CDRs can enhance antigen-specific T cell functions, J Immunol, 180, 6116, 10.4049/jimmunol.180.9.6116 · DOI
  28. Thomas, 2019, Framework engineering to produce dominant T cell receptors with enhanced antigen-specific function, Nat Commun, 10, 4451, 10.1038/s41467-019-12441-w · DOI
  29. Klebanoff, 2017, Inhibition of AKT signaling uncouples T cell differentiation from expansion for receptor-engineered adoptive immunotherapy, JCI Insight, 2, e95103, 10.1172/jci.insight.95103 · DOI
  30. Cappell, 2023, Long-term outcomes following CAR T cell therapy: what we know so far, Nat Rev Clin Oncol, 20, 359, 10.1038/s41571-023-00754-1 · DOI
  31. Singh, 2017, Monocyte lineage-derived IL-6 does not affect chimeric antigen receptor T-cell function, Cytotherapy, 19, 867, 10.1016/j.jcyt.2017.04.001 · DOI · Paper page
  32. Giavridis, 2018, CAR T cell-induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade, Nat Med, 24, 731, 10.1038/s41591-018-0041-7 · DOI · Paper page
  33. Santomasso, 2018, Clinical and biological correlates of neurotoxicity associated with CAR T-cell therapy in patients with B-cell acute lymphoblastic leukemia, Cancer Discov, 8, 958, 10.1158/2159-8290.CD-17-1319 · DOI · Paper page
  34. Van Oekelen, 2021, Neurocognitive and hypokinetic movement disorder with features of parkinsonism after BCMA-targeting CAR-T cell therapy, Nat Med, 27, 2099, 10.1038/s41591-021-01564-7 · DOI
  35. Govers, 2010, T cell receptor gene therapy: strategies for optimizing transgenic TCR pairing, Trends Mol Med, 16, 77, 10.1016/j.molmed.2009.12.004 · DOI
  36. Yang, 2008, Development of optimal bicistronic lentiviral vectors facilitates high-level TCR gene expression and robust tumor cell recognition, Gene Ther, 15, 1411, 10.1038/gt.2008.90 · DOI
  37. Heard, 2022, Antigen glycosylation regulates efficacy of CAR T cells targeting CD19, Nat Commun, 13, 3367, 10.1038/s41467-022-31035-7 · DOI
  38. Pettersen, 2004, UCSF Chimera–a visualization system for exploratory research and analysis, J Comput Chem, 25, 1605, 10.1002/jcc.20084 · DOI
  39. Stadtmauer, 2020, CRISPR-engineered T cells in patients with refractory cancer, Science, 367, eaba7365, 10.1126/science.aba7365 · DOI · Paper page

Metadata

Authors
Chang, J.-F., Landmann, J. H., Chang, T.-C., Selli, M. E., Tenzin, Y., Warrington, J. M., Ritchey, J., Hsu, Y.-S., Slade, M., Gupta, D. K., DiPersio, J. F., Holehouse, A. S., & Singh, N.
Affiliations
Washington University in St. Louis (US)
Corresponding author
Singh, Nathan
ORCID
Venue
Cancer Discovery
Publisher
American Association for Cancer Research (AACR)
Published
2024-07-09
Volume
14
Issue
11
Pages
2109-2121
ISSN
  • 2159-8274 (ISSN-L)
  • 2159-8290
DOI
10.1158/2159-8290.cd-23-1393
PMC
PMC11530325
OpenAlex
W4400451839
Cited by
10
References
7
Citations by year
2026: 3 · 2025: 6 · 2024: 1
FWCI
1.71
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • Cancer Discovery (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • NIH Office of the Director (DP2CA290639)
  • National Institutes of Health (K08CA237740, R37CA285572)
  • Damon Runyon Cancer Research Foundation
  • Be The Match Foundation
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, T cell receptor engineering, antibody variable domains, 4-1BB costimulation, T cell persistence, CAR T-cell dysfunction, leukemia immunotherapy, cancer immunotherapy
MeSH terms
Receptors, Chimeric Antigen, Animals, Humans, Receptors, Antigen, T-Cell, T-Lymphocytes, Protein Engineering, Immunotherapy, Adoptive, Mice

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