Therapeutic high affinity T cell receptor targeting a KRASG12D cancer neoantigen

Poole, Andrew; Karuppiah, V.; Hartt, Annabelle; Haidar, Jaafar N.; Moureau, Sylvie; Dobrzycki, Tomasz; Hayes, Conor; Rowley, Christopher N.; Dias, Jorge S.; Harper, Stephen; Barnbrook, Keir; Hock, M. Benjamin; Coles, C.H.; Yang, Wei; Aleksic, Milos; Lin, Aimee Bence; Robinson, R.A.; Dukes, Joe D; Liddy, Nathaniel; Kamp, Marc W. van der; Vuidepot, Annelise; Cole, D.K.; Whale, Andrew; Chillakuri, Chandramouli

doi:10.1038/s41467-022-32811-1

Cited by 45 publications

(43 citation statements)

References 67 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In contrast, adoptive T cell transfer therapy, another promising anti‐tumour strategy, requires tumour‐reactive TCRs with highly effective tumour‐killing activity [4] . JDI is a type of TCR clone that can specifically bind to the tumour peptide KRAS‐G12D rather than 9V‐MHC [44] . As shown in Figure 4, the binding of JDI TCR to 9V‐MHC was significantly weaker than that of 1G4 TCR to 9V‐MHC.…”

Section: Resultsmentioning

confidence: 99%

T Cell Antigen Recognition and Discrimination by Electrochemiluminescence Imaging

Yan,

Zhou,

Ding

et al. 2023

Angew Chem Int Ed

View full text Add to dashboard Cite

Adoptive T lymphocyte (T cell) transfer and tumour‐specific peptide vaccines are innovative cancer therapies. An accurate assessment of the specific reactivity of T cell receptors (TCRs) to tumour antigens is required because of the high heterogeneity of tumour cells and the immunosuppressive tumour microenvironment. In this study, we report a label‐free electrochemiluminescence (ECL) imaging approach for recognising and discriminating between TCRs and tumour‐specific antigens by imaging the immune synapses of T cells. Various T cell stimuli, including agonistic antibodies, auxiliary molecules, and tumour‐specific antigens, were modified on the electrode's surface to allow for their interaction with T cells bearing different TCRs. The formation of immune synapses activated by specific stimuli produced a negative (shadow) ECL image, from which T cell antigen recognition and discrimination were evaluated by analysing the spreading area and the recognition intensity of T cells. This approach provides an easy way to assess TCR‐antigen specificity and screen both of them for immunotherapies.

show abstract

Section: Resultsmentioning

confidence: 99%

T Cell Antigen Recognition and Discrimination by Electrochemiluminescence Imaging

Yan,

Zhou,

Ding

et al. 2023

Angew Chem Int Ed

View full text Add to dashboard Cite

show abstract

“…These SNVs were found at allele frequencies ranging from 25% to 34% representing potential future actionable mutations. [29][30][31][32][33] The SNV analysis also uncovered other SNVs, including multiple in the PDE4DIP gene in the one Ph + and the four KMT2Ar patient samples, with two or three different PDE4DIP SNVs detected in each sample (Figures 1D and Figure S2D). The biological significance of these is not known, but recurrent mutations in the PDE4DIP gene have been reported in different cancers, including leukemia.…”

Section: Rna-seq Reveals Nonsynonymous Variants Not Identified By Dia...mentioning

confidence: 86%

Transcriptome analysis of primary adult B‐cell lineage acute lymphoblastic leukemia identifies pathogenic variants and gene fusions, and predicts subtypes for in depth molecular diagnosis

Podgorica,

Drivet,

Viken

et al. 2024

European J of Haematology

View full text Add to dashboard Cite

BackgroundB‐cell acute lymphoblastic leukemia (B‐ALL) is classified into subgroups based on known driver oncogenes and molecular lesions, including translocations and recurrent mutations. However, the current diagnostic tests do not identify subtypes or oncogenic lesions for all B‐ALL samples, creating a heterogeneous B‐ALL group of unknown subtypes.MethodsWe sorted primary adult B‐ALL cells and performed transcriptome analysis by bulk RNA sequencing (RNA‐seq).ResultsTranscriptomic analysis of an adult B‐ALL cohort allowed the classification of four patient samples with subtypes that were not previously revealed by standard gene panels. The leukemia of two patients were of the DUX4 subtype and two were CRLF2+ Ph‐like B‐ALL. Furthermore, single nucleotide variant analysis detected the oncogenic NRAS‐G12D, KRAS‐G12D, and KRAS‐G13D mutations in three of the patient samples, presenting targetable mutations. Additional oncogenic variants and gene fusions were uncovered, as well as multiple variants in the PDE4DIP gene across five of the patient samples.ConclusionWe demonstrate that RNA‐seq is an effective tool for precision medicine in B‐ALL by providing comprehensive molecular profiling of leukemia cells, identifying subtype and oncogenic lesions, and stratifying patients for appropriate therapy.

show abstract

“…In contrast to TCR engineering approaches ( 49 ), PC-CAR development can yield nanomolar-range peptide-specific scFv binding without the need for further affinity enhancement. Thus, our binding mechanism is well-poised for future development of bispecific T cell engager constructs (BiTEs) ( 50 , 51 ).…”

Section: Discussionmentioning

confidence: 99%

Structural principles of peptide-centric chimeric antigen receptor recognition guide therapeutic expansion

Sun,

Florio,

Gupta

et al. 2023

Sci. Immunol.

View full text Add to dashboard Cite

Peptide-centric chimeric antigen receptors (PC-CARs) recognize oncoprotein epitopes displayed by cell-surface human leukocyte antigens (HLAs) and offer a promising strategy for targeted cancer therapy. We have previously developed a PC-CAR targeting a neuroblastoma-associated PHOX2B peptide, leading to robust tumor cell lysis restricted by two common HLA allotypes. Here, we determine the 2.1-angstrom crystal structure of the PC-CAR–PHOX2B–HLA-A*24:02–β 2 m complex, which reveals the basis for antigen-specific recognition through interactions with CAR complementarity-determining regions (CDRs). This PC-CAR adopts a diagonal docking mode, where interactions with both conserved and polymorphic HLA framework residues permit recognition of multiple HLA allotypes from the A9 serological cross-reactive group, covering a combined global population frequency of up to 46.7%. Biochemical binding assays, molecular dynamics simulations, and structural and functional analyses demonstrate that high-affinity PC-CAR recognition of cross-reactive pHLAs necessitates the presentation of a specific peptide backbone, where subtle structural adaptations of the peptide are critical for high-affinity complex formation, and CAR T cell killing. Our results provide a molecular blueprint for engineering CARs with optimal recognition of tumor-associated antigens in the context of different HLAs, while minimizing cross-reactivity with self-epitopes.

show abstract

Therapeutic high affinity T cell receptor targeting a KRASG12D cancer neoantigen

Cited by 45 publications

References 67 publications

T Cell Antigen Recognition and Discrimination by Electrochemiluminescence Imaging

T Cell Antigen Recognition and Discrimination by Electrochemiluminescence Imaging

Transcriptome analysis of primary adult B‐cell lineage acute lymphoblastic leukemia identifies pathogenic variants and gene fusions, and predicts subtypes for in depth molecular diagnosis

Structural principles of peptide-centric chimeric antigen receptor recognition guide therapeutic expansion

Contact Info

Product

Resources

About