scholarly journals TCR-like CARs and TCR-CARs targeting neoepitopes: an emerging potential

2021 ◽  
Author(s):  
Mansour Poorebrahim ◽  
Niloufar Mohammadkhani ◽  
Reza Mahmoudi ◽  
Monireh Gholizadeh ◽  
Elham Fakhr ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Great Promise ◽  
Antigen Receptors ◽  
Chimeric Antigen Receptors ◽  
Antitumor Therapy ◽  
Know How ◽  
Normal Tissues ◽  
Tumor Eradication

AbstractNeoepitopes or neoantigens are a spectrum of unique mutations presented in a particular patient’s tumor. Neoepitope-based adoptive therapies have the potential of tumor eradication without undue damaging effect on normal tissues. In this context, methods based on the T cell receptor (TCR) engineering or chimeric antigen receptors (CARs) have shown great promise. This review focuses on the TCR-like CARs and TCR-CARs directed against tumor-derived epitopes, with a concerted view on neoepitopes. We also address the current limitations of the field to know how to harness the full benefits of this approach and thereby design a sustained and specific antitumor therapy.

Abstract 1425: Chimeric antigen receptors based on T cell receptor-like antibodies

2019 ◽  
Author(s):  
Ling Wu ◽  
Joanna Brzostek ◽  
Shvetha Sankaran ◽  
Triscilla Tan ◽  
Conrad Chan ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Antigen Receptors ◽  
Chimeric Antigen Receptors

Abstract 1425: Chimeric antigen receptors based on T cell receptor-like antibodies

2019 ◽  
Author(s):  
Ling Wu ◽  
Joanna Brzostek ◽  
Shvetha Sankaran ◽  
Triscilla Tan ◽  
Conrad Chan ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Antigen Receptors ◽  
Chimeric Antigen Receptors

scholarly journals A novel method to generate T-cell receptor–deficient chimeric antigen receptor T cells

2018 ◽  
Vol 2 (5) ◽  
pp. 517-528 ◽  
Author(s):  
Takahiro Kamiya ◽  
Desmond Wong ◽  
Yi Tian Png ◽  
Dario Campana
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Chimeric Antigen Receptor ◽  
Cell Receptor ◽  
Surface Expression ◽  
Antigen Receptors ◽  
Chimeric Antigen Receptors ◽  
Key Points ◽  
Novel Method

Key Points Newly designed PEBLs prevent surface expression of T-cell receptor in T cells without affecting their function. Combined with chimeric antigen receptors, PEBLs can rapidly generate powerful antileukemic T cells without alloreactivity.

Ig alpha and Ig beta are functionally homologous to the signaling proteins of the T-cell receptor

1994 ◽  
Vol 14 (2) ◽  
pp. 1095-1103
Author(s):  
A L Burkhardt ◽  
T Costa ◽  
Z Misulovin ◽  
B Stealy ◽  
J B Bolen ◽  
...  
Keyword(s):  
Signal Transduction ◽  
T Cells ◽  
T Cell ◽  
B Cell ◽  
T Cell Receptor ◽  
Interleukin 2 ◽  
Antigen Receptor ◽  
Cell Receptor ◽  
Antigen Receptors ◽  
Cell Antigen

Signal transduction by antigen receptors and some Fc receptors requires the activation of a family of receptor-associated transmembrane accessory proteins. One common feature of the cytoplasmic domains of these accessory molecules is the presence is at least two YXXA repeats that are potential sites for interaction with Src homology 2 domain-containing proteins. However, the degree of similarity between the different receptor-associated proteins varies from that of T-cell receptor (TCR) zeta and Fc receptor RIIIA gamma chains, which are homologous, to the distantly related Ig alpha and Ig beta proteins of the B-cell antigen receptor. To determine whether T- and B-cell antigen receptors are in fact functionally homologous, we have studied signal transduction by chimeric immunoglobulins bearing the Ig alpha or Ig beta cytoplasmic domain. We found that Ig alpha and Ig beta cytoplasmic domains were able to activate Ca2+ flux, interleukin-2 secretion, and phosphorylation of the same group of cellular substrates as the TCR in transfected T cells. Chimeric proteins were then used to examine the minimal requirements for activation of the Fyn, Lck, and ZAP kinases in T cells. Both Ig alpha and Ig beta were able to trigger Fyn, Lck, and ZAP directly without involvement of TCR components. Cytoplasmic tyrosine residues in Ig beta were required for recruitment and activation of ZAP-70, but these amino acids were not essential for the activation of Fyn and Lck. We conclude that Fyn and Lck are able to recognize a clustered nonphosphorylated immune recognition receptor, but activation of these kinases is not sufficient to induce cellular responses such as Ca2+ flux and interleukin-2 secretion. In addition, the molecular structures involved in antigen receptor signaling pathways are conserved between T and B cells.

scholarly journals 173 Expression of a membrane-tethered IL-15/IL-15 receptor fusion protein enhances the persistence of MSLN-targeted TRuC-T cells

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A185-A185
Author(s):  
Michelle Fleury ◽  
Derrick McCarthy ◽  
Holly Horton ◽  
Courtney Anderson ◽  
Amy Watt ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Fusion Protein ◽  
T Cell Receptor ◽  
Cytokine Production ◽  
Cell Receptor ◽  
Great Promise ◽  
And Function

BackgroundAdoptive cell therapies have shown great promise in hematological malignancies but have yielded little progress in the context of solid tumors. We have developed T cell receptor fusion construct (TRuC®) T cells, which are equipped with an engineered T cell receptor that utilizes the full complement of TCR signaling subunits and recognizes tumor-associated antigens independent of HLA. In clinical trials, mesothelin (MSLN)-targeting TRuC-T cells (TC-210 or gavo-cel) have shown unprecedented results in patients suffering from advanced mesothelioma and ovarian cancer. To potentially increase the depth of response, we evaluated strategies that can promote intra-tumoral T cell persistence and function. Among the common ??-chain cytokines, IL-15 uniquely supports the differentiation and maintenance of memory T cell subsets by limiting terminal differentiation and conferring resistance to IL-2 mediated activation-induced cell death (AICD). In the studies described here, we evaluated the potential of IL-15 as an enhancement to TRuC-T cell phenotype, persistence and function against MSLN+ targets.MethodsPrimary human T cells were activated and transduced with a lentiviral vector encoding an anti-MSLN binder fused to CD3ε alone or co-expressed with a membrane-tethered IL-15rα/IL-15 fusion protein (IL-15fu). Transduced T cells were expanded for 9 days and characterized for expression of the TRuC, IL-15rα and memory phenotype before subjecting them to in vitro functional assays to evaluate cytotoxicity, cytokine production, and persistence. In vivo efficacy was evaluated in MHC class I/II deficient NSG mice bearing human mesothelioma xenografts.ResultsIn vitro, co-expression of the IL-15fu led to similar cytotoxicity and cytokine production as TC-210, but notably enhanced T-cell expansion and persistence upon repeated stimulation with MSLN+ cell lines. Furthermore, the IL-15fu-enhanced TRuC-T cells sustained a significantly higher TCF-1+ population and retained a stem-like phenotype following activation. Moreover, the IL-15fu-enhanced TRuCs demonstrated robust in vivo expansion and intra-tumoral accumulation as measured by ex vivo analysis of TRuC+ cells in the tumor and blood, with a preferential expansion of CD8+ T cells. Finally, IL-15fu-enhanced TRuC-T cells could be observed in the blood long after the tumors were cleared.ConclusionsThese pre-clinical studies suggest that the IL-15fu can synergize with TC-210 to increase the potency and durability of response in patients with MSLN+ tumors.Ethics ApprovalAll animal studies were approved by the respective Institutional Animal Care and Use Committees.

scholarly journals The gamma and epsilon subunits of the CD3 complex inhibit pre-Golgi degradation of newly synthesized T cell antigen receptors.

1990 ◽  
Vol 110 (4) ◽  
pp. 973-986 ◽  
Author(s):  
T Wileman ◽  
G R Carson ◽  
M Concino ◽  
A Ahmed ◽  
C Terhorst
Keyword(s):  
T Cells ◽  
Endoplasmic Reticulum ◽  
Plasma Membrane ◽  
T Cell ◽  
T Cell Receptor ◽  
Intracellular Transport ◽  
Cell Receptor ◽  
Dna Transfection ◽  
Antigen Receptors ◽  
Intracellular Degradation

The T cell receptor for antigen (TCR) is composed of six different transmembrane proteins. T cells carefully control the intracellular transport of the receptor and allow only complete receptors to reach the plasma membrane. In an attempt to understand how T cells regulate this process, we used c-DNA transfection and subunit-specific antibodies to follow the intracellular transport of five subunits (alpha beta gamma delta epsilon) of the receptor. In particular, we assessed the intracellular stability of each chain. Our results showed that the chains were markedly different in their susceptibility to intracellular degradation. TCR alpha and beta and CD3 delta were degraded rapidly, whereas CD3 gamma and epsilon were stable. An analysis of the N-linked oligosaccharides of the glycoprotein subunits suggested that the chains were unable to reach the medial Golgi during the metabolic chase. This was supported by immunofluorescence micrographs that showed both the stable CD3 gamma and unstable CD3 delta chain localized in the endoplasmic reticulum. To study the effects of subunit associations on intracellular transport we used cotransfection to reconstitute precise combinations of subunits. Associations between stable and unstable subunits expressed in the same cell led to the formation of stable complexes. These complexes were retained in or close to the endoplasmic reticulum. The results suggested that the intracellular transport of the T cell receptor could be regulated by two mechanisms. The TCR alpha and beta and CD3 delta subunits were degraded rapidly and as a consequence failed to reach the plasma membrane. CD3 gamma or epsilon were stable but were retained inside the cell. The results also demonstrated that there was an interplay between the two pathways such that the CD3 gamma and epsilon subunits were able to protect labile chains from rapid intracellular degradation. In this way, they could seed subunit assembly in or close to the endoplasmic reticulum and allow a stable receptor to form before its transport to the plasma membrane.

scholarly journals Breast cancer is marked by specific, Public T-cell receptor CDR3 regions shared by mice and humans

2021 ◽  
Vol 17 (1) ◽  
pp. e1008486
Author(s):  
Miri Gordin ◽  
Hagit Philip ◽  
Alona Zilberberg ◽  
Moriah Gidoni ◽  
Raanan Margalit ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Sequence Data ◽  
Breast Tumors ◽  
Cell Receptor ◽  
Beta Chain ◽  
Antigen Receptors ◽  
Partial Success

The partial success of tumor immunotherapy induced by checkpoint blockade, which is not antigen-specific, suggests that the immune system of some patients contain antigen receptors able to specifically identify tumor cells. Here we focused on T-cell receptor (TCR) repertoires associated with spontaneous breast cancer. We studied the alpha and beta chain CDR3 domains of TCR repertoires of CD4 T cells using deep sequencing of cell populations in mice and applied the results to published TCR sequence data obtained from human patients. We screened peripheral blood T cells obtained monthly from individual mice spontaneously developing breast tumors by 5 months. We then looked at identical TCR sequences in published human studies; we used TCGA data from tumors and healthy tissues of 1,256 breast cancer resections and from 4 focused studies including sequences from tumors, lymph nodes, blood and healthy tissues, and from single cell dataset of 3 breast cancer subjects. We now report that mice spontaneously developing breast cancer manifest shared, Public CDR3 regions in both their alpha and beta and that a significant number of women with early breast cancer manifest identical CDR3 sequences. These findings suggest that the development of breast cancer is associated, across species, with biomarker, exclusive TCR repertoires.

scholarly journals Somatic hypermutation of T cell receptor α chain contributes to selection in nurse shark thymus

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Jeannine A Ott ◽  
Caitlin D Castro ◽  
Thaddeus C Deiss ◽  
Yuko Ohta ◽  
Martin F Flajnik ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Somatic Hypermutation ◽  
Cytidine Deaminase ◽  
Cell Receptor ◽  
Antigen Receptors ◽  
Cell Repertoire ◽  
Nurse Shark ◽  
Α Chain ◽  
Complementarity Determining Regions

Since the discovery of the T cell receptor (TcR), immunologists have assigned somatic hypermutation (SHM) as a mechanism employed solely by B cells to diversify their antigen receptors. Remarkably, we found SHM acting in the thymus on α chain locus of shark TcR. SHM in developing shark T cells likely is catalyzed by activation-induced cytidine deaminase (AID) and results in both point and tandem mutations that accumulate non-conservative amino acid replacements within complementarity-determining regions (CDRs). Mutation frequency at TcRα was as high as that seen at B cell receptor loci (BcR) in sharks and mammals, and the mechanism of SHM shares unique characteristics first detected at shark BcR loci. Additionally, fluorescence in situ hybridization showed the strongest AID expression in thymic corticomedullary junction and medulla. We suggest that TcRα utilizes SHM to broaden diversification of the primary αβ T cell repertoire in sharks, the first reported use in vertebrates.

Challenges of CRISPR-based Gene Editing in Primary T Cells

2022 ◽  
Author(s):  
Alaleh Rezalotfi ◽  
Lea Fritz ◽  
Reinhold Förster ◽  
Berislav Bošnjak
Keyword(s):  
T Cells ◽  
T Cell ◽  
Great Promise ◽  
Antigen Receptors ◽  
Virus Infections ◽  
Chimeric Antigen Receptors ◽  
Effective Treatment Option ◽  
Cell Immunotherapy ◽  
Genetic Modifications ◽  
Immunosuppressed Patients

Adaptive T cell immunotherapy holds great promise for the successful treatment of leukemia as well as other types of cancers. More recently, it was also shown to be an effective treatment option for chronic virus infections in immunosuppressed patients. Autologous or allogeneic T cells used for immunotherapy are usually genetically modified to express novel T cell or chimeric antigen receptors. The production of such cells was significantly simplified with the CRISPR/Cas system allowing deletion or insertion of novel genes at specific locations within the genome. In this review, we describe recent methodological breakthroughs important for the conduction of these genetic modifications, summarize crucial points to be considered when conducting such experiments, and highlight the potential pitfalls of these approaches.

scholarly journals T cell receptor repertoire for a viral epitope in humans is diversified by tolerance to a background major histocompatibility complex antigen.

1995 ◽  
Vol 182 (6) ◽  
pp. 1703-1715 ◽  
Author(s):  
S R Burrows ◽  
S L Silins ◽  
D J Moss ◽  
R Khanna ◽  
I S Misko ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Specific Response ◽  
Major Histocompatibility ◽  
Antigen Receptors ◽  
Barr Virus ◽  
Receptor Repertoire ◽  
Tcr Repertoire ◽  
Epstein Barr

Two unusual characteristics of the memory response to the immunodominant Epstein-Barr virus (EBV) epitope FLRGRAYGL, which associates with HLA B8, have provided an unique opportunity to investigate self tolerance and T cell receptor (TCR) plasticity in humans. First, the response is exceptionally restricted, dominated by cytotoxic T lymphocytes (CTL) with identical TCR protein sequences (Argaet, V. P., C. W. Schmidt, S. R. Burrows, S. L. Silins, M. G. Kurilla, D. L. Doolan, A. Suhrbier, D. J. Moss, E. Kieff, T. B. Sculley, and I. S. Misko. 1994. J. Exp. Med. 180:2335-2340). Second, CTL expressing this receptor are cross-reactive with the alloantigen HLA B* 4402 on uninfected cells (Burrows, S. R., R. Khanna, J. M. Burrows, and D. J. Moss. 1994. J. Exp. Med. 179:1155-1161). No CTL using this conserved public TCR could be reactivated from the peripheral blood of EBV exposed individuals expressing both HLA B8 and B*4402, demonstrating the clonal inactivation of potentially self-reactive T cells in humans. A significant FLRGRAYGL-specific response was still apparent, however, and TCR sequence analysis of multiple CTL clones revealed an oligoclonal TCR repertoire for this determinant within these individuals, using diverse V and J gene segments and CDR3 regions. In addition, a significant public TCR component was identified in which several distinct alpha/beta rearrangements are shared by CTL clones from a number of unrelated HLA B8+, B*4402+ donors. The striking dominance of public TCR in the response to this EBV epitope suggests a strong genetic bias in TCR gene recombination. Fine specificity analysis using peptide analogues showed that, of six different antigen receptors for FLRGRAYGL/HLA B8, none associate closely with the peptide's full array of potential TCR contact residues. Whereas the HLA B*4402-cross-reactive receptor binds amino acids toward the COOH terminus of the peptide, others preferentially favor an NH2-terminal determinant, presumably evading an area that mimics a structure presented on HLA B*4402. Thus, tolerance to a background major histocompatibility antigen can effectively diversify the TCR repertoire for a foreign epitope by deflecting the response away from an immunodominant combination of TCR-binding residues.

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