Autocrine-based selection of ligands for personalized CAR-T therapy of lymphoma

Stepanov, Alexey V.; Markov, Oleg V.; Chernikov, Ivan V.; Gladkikh, Daniil V.; Zhang, Hongkai; Jones, Teresa M.; Sen’kova, Alexandra V.; Chernolovskaya, E. L.; Zenkova, Marina A.; Kalinin, R. S.; Rubtsova, Maria P.; Meleshko, Alexander; Genkin, Dmitry; Belogurov, Alexey A.; Xie, Jia; Gabibov, Alexander; Lerner, Richard A.

doi:10.1126/sciadv.aau4580

Cited by 24 publications

(24 citation statements)

References 15 publications

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“…Stepanov et al showed it is feasible to isolate from peptide libraries ligands that bind to BCRs presented by lymphoma cells and to use these as targeting moieties in CARs [183].…”

Section: Non Scfv-based Carsmentioning

confidence: 99%

T-cells “à la CAR-T(e)” – Genetically engineering T-cell response against cancer

Eisenberg

Hoogi

Shamul

et al. 2019

Advanced Drug Delivery Reviews

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“…Stepanov et al showed it is feasible to isolate from peptide libraries ligands that bind to BCRs presented by lymphoma cells and to use these as targeting moieties in CARs [183].…”

Section: Non Scfv-based Carsmentioning

confidence: 99%

T-cells “à la CAR-T(e)” – Genetically engineering T-cell response against cancer

Eisenberg

Hoogi

Shamul

et al. 2019

Advanced Drug Delivery Reviews

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“…We assembled fADL-1e-flag-linker-p3 (Addgene ID: 139441) and fADL-1e-HA-linker-p3 (Addgene ID: 139440) vectors that contain p3-N-terminally fused cluster encoding the 3xFLAG or HA (hemagglutinin) epitopes for detection, serine-glycine linkers for the conformational flexibility, and Nco I and Nhe I restriction sites for the subsequent cloning of the oligonucleotides coding for the custom peptide ligands ( Figure 1 A). As a model for the ligand–receptor interaction, we used transgenic Raji-FL cells that express membrane-tethered BCR (B-cell receptor) in a single-chain format, derived from a patient with follicular lymphoma cells, and its peptide ligand P#1 (CILDLPKFC) [ 30 , 32 ] cloned into the phage vector (P#1-HA-p3-fADL-1e or P#1-flag-p3-fADL-1e). Our data suggest that the fADL-1e-based phage vector increased bacteriophage yield by an order of magnitude in comparison with the pHen2-based phagemid vector and hyperphage infection ( Figure 1 B).…”

Section: Resultsmentioning

confidence: 99%

“…The Raji-FL cell line with membrane-tethered BCR in a single-chain format, that specifically binds the P#1 peptide (CILDLPKFC), was obtained earlier by stable transduction of Raji cells [ 32 ]. Raji and Raji-FL cells were cultured in RPMI medium (Gibco, OK, USA) supplemented with 10% ( v / v ) fetal bovine serum (Cytiva, MA, USA) and L-glutamine (Gibco, OK, USA) at 37 °C, 5% CO 2 .…”

Section: Methodsmentioning

confidence: 99%

Exhaustive Search of the Receptor Ligands by the CyCLOPS (Cytometry Cell-Labeling Operable Phage Screening) Technique

Ishina

Filimonova

Захарова

et al. 2020

IJMS

Self Cite

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Effective and versatile screening of the peptide ligands capable of selectively binding to diverse receptors is in high demand for the state-of-the-art technologies in life sciences, including probing of specificity of the cell surface receptors and drug development. Complex microenvironment and structure of the surface receptors significantly reduce the possibility to determine their specificity, especially when in vitro conditions are utilized. Previously, we designed a publicly available platform for the ultra-high-throughput screening (uHTS) of the specificity of surface-exposed receptors of the living eukaryotic cells, which was done by consolidating the phage display and flow cytometry techniques. Here, we significantly improved this methodology and designed the fADL-1e-based phage vectors that do not require a helper hyperphage for the virion assembly. The enhanced screening procedure was tested on soluble human leukocyte antigen (HLA) class II molecules and transgenic antigen-specific B cells that express recombinant lymphoid B-cell receptor (BCR). Our data suggest that the improved vector system may be successfully used for the comprehensive search of the receptor ligands in either cell-based or surface-immobilized assays.

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“…For one tumor immunoglobulin, the self-antigen was identified as myoferlin, a protein associated with cell and nuclear membranes. Interestingly, reactivity with myoferlin was also observed in another study that used a combinatorial peptide library to identify ligands for three FL immunoglobulins [ 122 ]. The myoferlin peptide sequence that was recognized by one of these antibodies was found to be identical to a sequence in a surface protein from Streptococcus mitis and Pneumocystis jirovecii , suggesting crossreactivity with foreign antigens.…”

Section: Bcr Signaling In Follicular Lymphomamentioning

confidence: 85%

Mechanisms of B Cell Receptor Activation and Responses to B Cell Receptor Inhibitors in B Cell Malignancies

Efremov

Turkalj

Laurenti

2020

Cancers

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The B cell receptor (BCR) pathway has been identified as a potential therapeutic target in a number of common B cell malignancies, including chronic lymphocytic leukemia, diffuse large B cell lymphoma, Burkitt lymphoma, follicular lymphoma, mantle cell lymphoma, marginal zone B cell lymphoma, and Waldenstrom’s macroglobulinemia. This finding has resulted in the development of numerous drugs that target this pathway, including various inhibitors of the kinases BTK, PI3K, and SYK. Several of these drugs have been approved in recent years for clinical use, resulting in a profound change in the way these diseases are currently being treated. However, the response rates and durability of responses vary largely across the different disease entities, suggesting a different proportion of patients with an activated BCR pathway and different mechanisms of BCR pathway activation. Indeed, several antigen-dependent and antigen-independent mechanisms have recently been described and shown to result in the activation of distinct downstream signaling pathways. The purpose of this review is to provide an overview of the mechanisms responsible for the activation of the BCR pathway in different B cell malignancies and to correlate these mechanisms with clinical responses to treatment with BCR inhibitors.

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Autocrine-based selection of ligands for personalized CAR-T therapy of lymphoma

Abstract: After decades of nonspecific lymphoma therapy, personalized approaches such as described here are on the horizon.

Cited by 24 publications

References 15 publications

T-cells “à la CAR-T(e)” – Genetically engineering T-cell response against cancer

T-cells “à la CAR-T(e)” – Genetically engineering T-cell response against cancer

Exhaustive Search of the Receptor Ligands by the CyCLOPS (Cytometry Cell-Labeling Operable Phage Screening) Technique

Mechanisms of B Cell Receptor Activation and Responses to B Cell Receptor Inhibitors in B Cell Malignancies

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