Antitumor effector functions of T cells are dependent on in vivo priming and restricted T-cell receptor expression

2008 ◽  
Vol 122 (10) ◽  
pp. 2280-2285 ◽  
Author(s):  
Carolin Lüking ◽  
Konrad Kronenberger ◽  
Bernhard Frankenberger ◽  
Elfriede Nößner ◽  
Martin Röcken ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Receptor Expression ◽  
Effector Functions ◽  
Antitumor Effector

scholarly journals 161 Development of a CD8 co-receptor independent T cell receptor specific for tumor-associated antigen MAGE-A4 for next generation T cell-based immunotherapy

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A175-A175
Author(s):  
Kathrin Davari ◽  
Tristan Holland ◽  
Laura Prassmayer ◽  
Giulia Longinotti ◽  
Kenneth Ganley ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Cells ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Receptor Expression ◽  
T Cell Subsets ◽  
High Avidity

BackgroundThe cancer-testis antigen MAGE-A4 is an attractive target for T cell-based immunotherapy, especially for indications with unmet clinical need like non-small-cell lung carcinoma or triple-negative breast cancer. Overcoming high tumor burden using adoptive transfer of T cells modified to express a transgenic T cell receptor (TCR) demands optimal recognition of the corresponding target on tumor cells by the TCR-modified T cells (TCR-Ts). Here we describe the isolation and pre-clinical characterization of high avidity TCR-Ts expressing a human leucocyte antigen (HLA)-A*02:01-restricted MAGE-A4-specific TCR that is fully functional in T cells irrespective of CD4 or CD8 co-receptor expression.MethodsAn unbiased CD137-based sorting approach was first used to identify an immunogenic MAGE-A4-derived candidate epitope that was properly processed and presented on HLA-A2 molecules encoded by the HLA-A*02:01 allele. To isolate high avidity T cells via subsequent multimer sorting, an in vitro priming approach using HLA-A2-negative donors (allogeneic-HLA-restricted priming approach) was conducted to bypass central tolerance to this self-antigen. Pre-clinical parameters of safety and activity were assessed in a comprehensive set of in vitro and in vivo studies of the lead TCR candidate derived from a selected T cell clone.ResultsA TCR recognizing the MAGE-A4-derived decapeptide GVYDGREHTV was isolated from primed T cells of a non-tolerant HLA-A2-negative donor. The respective TCR-T cell product bbT485, expressing the lead TCR in T cells from healthy donors, was demonstrated pre-clinically to have a favorable safety profile and superior in vivo potency compared to TCR-Ts made using a TCR derived from an HLA-A2-positive donor bearing a tolerized T cell repertoire to self-antigens. The natural high avidity allogeneic (allo)-derived TCR was found to be CD8 co-receptor-independent, allowing effector functions to be elicited in transgenic CD4+ T helper cells. These CD4+ TCR-T cells not only supported an anti-tumor response by direct killing of MAGE-A4-positive tumor cells, but also upregulated hallmarks associated with helper function, such as CD154 expression and release of key cytokines upon tumor-specific stimulation.ConclusionsThe extensive pre-clinical assessment of safety and in vivo potency of this non-mutated high avidity, CD8 co-receptor-independent, MAGE-A4-specific HLA-A2 restricted TCR provide the basis for its use in clinical TCR-T immunotherapy studies. The ability of this co-receptor-independent TCR to activate all transduced T cells (irrespective of CD4 or CD8 expression) could potentially provide enhanced cellular responses in the clinical setting through the induction of functionally diverse T cell subsets that goes beyond what is currently tested in the clinic.

scholarly journals Antigen and Checkpoint Receptor Recalibration of T Cell Receptor Signal Strength

2021 ◽  
Author(s):  
Thomas A.E. Elliot ◽  
Emma K. Jennings ◽  
David A.J. Lecky ◽  
Natasha Thawait ◽  
Adriana Flores-Langarica ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
T Cell Activation ◽  
Cell Activation ◽  
Signal Strength ◽  
Cell Receptor ◽  
Receptor Expression ◽  
List Type

SummaryHow T cell receptor (TCR) signal strength modulates T cell function and to what extent this is modified by immune checkpoint blockade (ICB) are key questions in immunology. Using Nr4a3-Tocky mice as a digital read-out of NFAT pathway activity, we identify the rapid quantitative and qualitative changes that occur in CD4+ T cells in response to a range of TCR signalling strengths. We demonstrate that the time and dose dependent programming of distinct co-inhibitory receptors rapidly re-calibrates T cell activation thresholds. By developing a new in vivo model, we analyse the immediate effects of ICB on T cell re-activation. Our findings reveal that anti-PD1 but not anti-Lag3 immunotherapy leads to an increased TCR signal strength. We define a strong TCR signal metric of five genes specifically upregulated by anti-PD1 in T cells (TCR.strong), which can stratify clinical outcomes during anti-PD1 monotherapy in melanoma patients. Our study therefore reveals how analysis of TCR signal strength – and its manipulation – can provide powerful metrics for monitoring outcomes to immunotherapy.Key PointsTCR signal strength-dependent programming of CD4+ T cells revealed over time in vivoInhibitory receptor expression is dynamic, TCR signal strength dependent, and rapidly re-calibrates T cell activation thresholdsPD1 but not Lag3 blockade leads to a unique and increased TCR signal strength signature (coined TCR.strong)TCR.strong metric stratifies melanoma patient survival in response to Nivolumab (anti-PD1) therapy

scholarly journals In Vivo Selection of T-Cell Receptor Junctional Region Sequences by HLA-A2 Human T-Cell Lymphotropic Virus Type 1 Tax11-19 Peptide Complexes

2001 ◽  
Vol 75 (2) ◽  
pp. 1065-1071 ◽  
Author(s):  
Mineki Saito ◽  
Graham P. Taylor ◽  
Akiko Saito ◽  
Yoshitaka Furukawa ◽  
Koichiro Usuku ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Virus Type ◽  
Cell Receptor ◽  
Antigen Specificity ◽  
Human T Cell ◽  
Cdr3 Region

ABSTRACT Using HLA-peptide tetrameric complexes, we isolated human T-cell lymphotrophic virus type 1 Tax peptide-specific CD8+ T cells ex vivo. Antigen-specific amino acid motifs were identified in the T-cell receptor Vβ CDR3 region of clonally expanded CD8+ T cells. This result directly confirms the importance of the CDR3 region in determining the antigen specificity in vivo.

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 A Human ErbB2-Specific T-Cell Receptor Confers Potent Antitumor Effector Functions in Genetically Engineered Primary Cytotoxic Lymphocytes

2014 ◽  
Vol 25 (8) ◽  
pp. 730-739 ◽  
Author(s):  
Evripidis Lanitis ◽  
Jenessa B. Smith ◽  
Denarda Dangaj ◽  
Seleeke Flingai ◽  
Mathilde Poussin ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Genetically Engineered ◽  
Cytotoxic Lymphocytes ◽  
Effector Functions ◽  
Antitumor Effector

scholarly journals A Kinetic Threshold between Negative and Positive Selection Based on the Longevity of the T Cell Receptor–Ligand Complex

1999 ◽  
Vol 189 (10) ◽  
pp. 1531-1544 ◽  
Author(s):  
Calvin B. Williams ◽  
Deborah L. Engle ◽  
Gilbert J. Kersh ◽  
J. Michael White ◽  
Paul M. Allen
Keyword(s):  
T Cells ◽  
T Cell ◽  
Positive Selection ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Ligand Complex ◽  
Altered Peptide Ligands ◽  
Self Peptides ◽  
Selection Of

We have developed a unique in vivo system to determine the relationship between endogenous altered peptide ligands and the development of major histocompatibility complex class II– restricted T cells. Our studies use the 3.L2 T cell receptor (TCR) transgenic mouse, in which T cells are specific for Hb(64–76)/I-Ek and positively selected on I-Ek plus self-peptides. To this endogenous peptide repertoire, we have individually added one of six well-characterized 3.L2 ligands. This transgenic approach expands rather than constrains the repertoire of self-peptides. We find that a broad range of ligands produce negative selection of thymocytes in vivo. When compared with the in vitro TCR–ligand binding kinetics, we find that these negatively selecting ligands all have a half-life of 2 s or greater. Additionally, one of two ligands examined with no detectable binding to the 3.L2 TCR and no activity on mature 3.L2 T cells (Q72) enhances the positive selection of transgenic thymocytes in vivo. Together, these data establish a kinetic threshold between negative and positive selection based on the longevity of TCR–ligand complexes.

scholarly journals Loss of tonic T-cell receptor signals alters the generation but not the persistence of CD8+ memory T cells

Blood ◽  
2010 ◽  
Vol 116 (25) ◽  
pp. 5560-5570 ◽  
Author(s):  
Karla R. Wiehagen ◽  
Evann Corbo ◽  
Michelle Schmidt ◽  
Haina Shin ◽  
E. John Wherry ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Lymphocytic Choriomeningitis ◽  
Sh2 Domain ◽  
Normal Numbers ◽  
Tcr Signaling ◽  
Tcr Signals

Abstract The requirements for tonic T-cell receptor (TCR) signaling in CD8+ memory T-cell generation and homeostasis are poorly defined. The SRC homology 2 (SH2)-domain–containing leukocyte protein of 76 kDa (SLP-76) is critical for proximal TCR-generated signaling. We used temporally mediated deletion of SLP-76 to interrupt tonic and activating TCR signals after clearance of the lymphocytic choriomeningitis virus (LCMV). SLP-76–dependent signals are required during the contraction phase of the immune response for the normal generation of CD8 memory precursor cells. Conversely, LCMV-specific memory CD8 T cells generated in the presence of SLP-76 and then acutely deprived of TCR-mediated signals persist in vivo in normal numbers for more than 40 weeks. Tonic TCR signals are not required for the transition of the memory pool toward a central memory phenotype, but the absence of SLP-76 during memory homeostasis substantially alters the kinetics. Our data are consistent with a model in which tonic TCR signals are required at multiple stages of differentiation, but are dispensable for memory CD8 T-cell persistence.

Flow Cytometric Detection of Neoplastic T Cells in Patients with Mycosis Fungoides Based on Levels of T-Cell Receptor Expression

1994 ◽  
Vol 102 (6) ◽  
pp. 856-860 ◽  
Author(s):  
Miroslaw Kuchnio ◽  
Edward A. Sausville ◽  
Elaine S. Jaffe ◽  
Timothy Greiner ◽  
Francine M. Foss ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mycosis Fungoides ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Receptor Expression ◽  
Flow Cytometric

T-Cell Receptor (TCR)-Mediated Upregulation of BLT1 (LTB4 Receptor) Expression and Activation of Human T Cells by LTB4

2007 ◽  
Vol 119 (1) ◽  
pp. S43
Author(s):  
A. Ahuja ◽  
A. Dakhama ◽  
H. Ohnishi ◽  
J.J. Lucas ◽  
E.W. Gelfand
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Receptor Expression ◽  
Human T Cells ◽  
Ltb4 Receptor

scholarly journals A Novel Approach for the Treatment of T Cell Malignancies: Targeting T Cell Receptor Vβ Families

Vaccines ◽  
2020 ◽  
Vol 8 (4) ◽  
pp. 631
Author(s):  
Jie Wang ◽  
Katarzyna Urbanska ◽  
Prannda Sharma ◽  
Reza Nejati ◽  
Lauren Shaw ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
T Cell Lymphomas ◽  
Novel Approach ◽  
T Cell Malignancies

Peripheral T cell lymphomas (PTCLs) are generally chemotherapy resistant and have a poor prognosis. The lack of targeted immunotherapeutic approaches for T cell malignancies results in part from potential risks associated with targeting broadly expressed T cell markers, namely T cell depletion and clinically significant immune compromise. The knowledge that the T cell receptor (TCR) β chain in human α/β TCRs are grouped into Vβ families that can each be targeted by a monoclonal antibody can therefore be exploited for therapeutic purposes. Here, we develop a flexible approach for targeting TCR Vβ families by engineering T cells to express a chimeric CD64 protein that acts as a high affinity immune receptor (IR). We found that CD64 IR-modified T cells can be redirected with precision to T cell targets expressing selected Vβ families by combining CD64 IR-modified T cells with a monoclonal antibody directed toward a specific TCR Vβ family in vitro and in vivo. These findings provide proof of concept that TCR Vβ-family-specific T cell lysis can be achieved using this novel combination cell–antibody platform and illuminates a path toward high precision targeting of T cell malignancies without substantial immune compromise.

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