Targeting B-cell neoplasia with T-cell receptors recognizing a CD20-derived peptide on patient-specific HLA

Mensali, Nadia; Fan, Yuxin; Oei, Vincent Yi Sheng; Yang, Weiwen; Walseng, Even; Kumari, Seema; Fallang, Lars-Egil; Kolstad, Arne; Uckert, Wolfgang; Malmberg, Karl Johan; Wälchli, Sébastien; Olweus, Johanna

doi:10.1080/2162402x.2016.1138199

Cited by 6 publications

(8 citation statements)

References 73 publications

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“…It is possible that the method of isolating T cells from mice based on CD20 tetramer binding might have been biased toward detecting high-affinity TCRs with consequently a high potential for cross-reactivity. Although TCRs against various B cell lineage-restricted antigens, including the same CD20 p188-196 epitope, have been previously reported in preclinical settings (52)(53)(54)(55)(56), systematic cross-reactivity screening data for those TCRs have not been published. Therefore, it is unknown whether clinically translatable TCRs against the CD20 p188-196 epitope exist in nature.…”

Section: Hla Restrictionmentioning

confidence: 99%

Multi-tiered approach to detect autoimmune cross-reactivity of therapeutic T cell receptors

et al. 2023

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T cell receptor (TCR)–engineered T cell therapy using high-affinity TCRs is a promising treatment modality for cancer. Discovery of high-affinity TCRs especially against self-antigens can require approaches that circumvent central tolerance, which may increase the risk of cross-reactivity. Despite the potential for toxicity, no standardized approach to screen cross-reactivity has been established in the context of preclinical safety evaluation. Here, we describe a practical framework to prospectively detect clinically prohibitive cross-reactivity of therapeutic TCR candidates. Cross-reactivity screening consisted of multifaceted series of assays including assessment of p-MHC tetramer binding, cell line recognition, and reactivity against candidate peptide libraries. Peptide libraries were generated using conventional contact residue motif–guided search, amino acid substitution matrix–based search unguided by motif information, and combinatorial peptide library scan–guided search. We demonstrate the additive nature of a layered approach, which efficiently identifies unsafe cross-reactivity including one undetected by conventional motif-guided search. These findings have important implications for the safe development of TCR-based therapies.

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Section: Hla Restrictionmentioning

confidence: 99%

Multi-tiered approach to detect autoimmune cross-reactivity of therapeutic T cell receptors

et al. 2023

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“…This suggests that tumor escape might be reduced if TCRs are used to target the molecules also that are expressed on the cell surface. We developed a CD20-specific TCR efficiently recognizing lymphoma and leukemia cells [70][71][72]. Instead of exploiting genetic engineering to achieve high affinity, we presented peptides from CD20 on foreign HLA to overcome immunological self-tolerance to "normal" proteins.…”

Section: Tcr Targetsmentioning

confidence: 99%

Advances in immune therapies in hematological malignancies

et al. 2021

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Immunotherapy in cancer takes advantage of the exquisite specificity, potency, and flexibility of the immune system to eliminate alien tumor cells. It involves strategies to activate the entire immune defense, by unlocking mechanisms developed by tumor cells to escape from surrounding immune cells, as well as engineered antibody and cellular therapies. What is important to note is that these are therapeutics with curative potential. The earliest example of immune therapy is allogeneic stem cell transplantation, introduced in 1957, which is still an important modality in hematology, most notably in myeloid malignancies. In this review, we discuss developmental trends of immunotherapy in hematological malignancies, focusing on some of the strategies that we believe will have the most impact on future clinical practice in this field. In particular, we delineate novel developments for therapies that have already been introduced into the clinic, such as immune checkpoint inhibition and chimeric antigen receptor T‐cell therapies. Finally, we discuss the therapeutic potential of emerging strategies based on T‐cell receptors and adoptive transfer of allogeneic natural killer cells.

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“…Using this method, human T-cell clones with high affinity for tumor-associated antigens, such as cyclin D1, WT1, and MDM2, were isolated, and these high-affinity TCR genes were cloned into vectors for gene therapy [ 548 – 551 ]. In mouse models, human T cells with allogeneic HLA-A2 antigen-specific TCR gene transduction were shown to clear tumor cells [ 549 , 552 ]. (3) TCR sequences can be modified to improve affinity as follows: Improving affinity by changing the sequence of the TCR is an effective way to improve the effects of TCR-T-cell therapy.…”

Section: Introductionmentioning

confidence: 99%

The screening, identification, design and clinical application of tumor-specific neoantigens for TCR-T cells

Li,

Xiao,

Wang

et al. 2023

Mol Cancer

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Recent advances in neoantigen research have accelerated the development of tumor immunotherapies, including adoptive cell therapies (ACTs), cancer vaccines and antibody-based therapies, particularly for solid tumors. With the development of next-generation sequencing and bioinformatics technology, the rapid identification and prediction of tumor-specific antigens (TSAs) has become possible. Compared with tumor-associated antigens (TAAs), highly immunogenic TSAs provide new targets for personalized tumor immunotherapy and can be used as prospective indicators for predicting tumor patient survival, prognosis, and immune checkpoint blockade response. Here, the identification and characterization of neoantigens and the clinical application of neoantigen-based TCR-T immunotherapy strategies are summarized, and the current status, inherent challenges, and clinical translational potential of these strategies are discussed.

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Targeting B-cell neoplasia with T-cell receptors recognizing a CD20-derived peptide on patient-specific HLA

Cited by 6 publications

References 73 publications

Multi-tiered approach to detect autoimmune cross-reactivity of therapeutic T cell receptors

Multi-tiered approach to detect autoimmune cross-reactivity of therapeutic T cell receptors

Advances in immune therapies in hematological malignancies

The screening, identification, design and clinical application of tumor-specific neoantigens for TCR-T cells

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