CD8 T cell activation after intravenous administration of CD3�CD19 bispecific antibody in patients with non-Hodgkin lymphoma

1995 ◽  
Vol 40 (6) ◽  
pp. 390-396 ◽  
Author(s):  
Gijsbert C. de Gast ◽  
Inez-Anne Haagen ◽  
Anja A. van Houten ◽  
Sigrid C. Klein ◽  
Ashley J. Duits ◽  
...  
Keyword(s):  
T Cell ◽  
Hodgkin Lymphoma ◽  
T Cell Activation ◽  
Intravenous Administration ◽  
Cell Activation ◽  
Bispecific Antibody ◽  
Cd8 T Cell ◽  
Non Hodgkin Lymphoma

CD8 T cell activation after intravenous administration of CD3×CD19 bispecific antibody in patients with non-Hodgkin lymphoma

1995 ◽  
Vol 40 (6) ◽  
pp. 390-396 ◽  
Author(s):  
Gijsbert C. de Gast ◽  
Inez-Anne Haagen ◽  
Anja A. van Houten ◽  
Sigrid C. Klein ◽  
Ashley J. Duits ◽  
...  
Keyword(s):  
T Cell ◽  
Hodgkin Lymphoma ◽  
T Cell Activation ◽  
Intravenous Administration ◽  
Cell Activation ◽  
Bispecific Antibody ◽  
Cd8 T Cell ◽  
Non Hodgkin Lymphoma

NVG-111, a novel ROR1xCD3 bispecific antibody for non-Hodgkin lymphoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 7549-7549
Author(s):  
David Granger ◽  
Satyen Gohil ◽  
Alessandro Barbarulo ◽  
Annalisa Baccaro ◽  
Vincent Muczynski ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Bispecific Antibody ◽  
Phase 1 ◽  
Human Study ◽  
Phase 2 ◽  
Cytokine Release ◽  
Non Hodgkin Lymphoma

7549 Background: Receptor tyrosine kinase-like Orphan Receptor 1 (ROR1) is a type I transmembrane protein is highly expressed on an array of haematological and solid tumours. NVG-111 is a humanised, tandem scFv ROR1xCD3 bispecific antibody previously shown to elicit potent killing of tumour cells in vitro and in vivo by engaging a membrane-proximal epitope in the Wnt5a-binding Frizzled domain of ROR1 and redirecting T cell activity. The in vitro potency and pharmacodynamic responses to NVG-111 were assessed to support progression to a first-in-human study. Methods: The potency of NVG-111 in vitro was determined by evaluating the concentration response for cytotoxicity, T cell activation, and cytokine release in co-cultured Jeko-1 and unstimulated human T cells. Comparative data were generated for the marketed CD19xCD3 bispecific antibody, blinatumomab. Potency data for NVG-111 were used together with allometric scaling from murine PK studies to inform planned clinical doses. Results: NVG-111 demonstrated T cell-dependent cytotoxicity, T cell activation and levels of cytokine release similar in potency to blinatumomab. Cytotoxic responses of both NVG-111 and blinatumomab were more potent than T cell activation and cytokine release. Dose response curves for NVG-111 showed a decrease in activity beyond the concentration of maximal response (ie “hook effect”). We hypothesise this is due to receptor saturation, inhibiting synapse formation. NVG-111 has progressed to a Phase 1/2 first-in-human study in patients with debulked, relapsed/refractory chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), the drug given as add-on to ≥2nd line therapy with a Bruton’s tyrosine kinase inhibitor, or venetoclax. Phase 1 includes escalating doses of 0.3 to 360 µg/day via continuous infusion over 3 cycles (each 21 days on, 7 days off) to establish safety, PK, pharmacodynamics (PD) and recommended phase 2 dose (RP2D). Predicted exposure at 0.3 µg/day is ̃EC20 for cytotoxicity in vitro and below the lowest EC10 for cytokine release. PD biomarkers in the study include systemic cytokines. Phase 2 will study efficacy and safety of the RP2D in CLL and MCL, with primary endpoint complete response rate; other efficacy endpoints include minimal residual disease and progression free survival. Conclusions: NVG-111 shows potent T-cell mediated lymphoma cell cytotoxicity in vitro at concentrations well below those associated with extensive cytokine release. NVG-111 is in an ongoing Phase 1/2 study and may present a novel option for adoptive immunotherapy in patients with non-Hodgkin lymphoma and potentially other cancers. Clinical trial information: 2020-000820-20. [Table: see text]

T-cell Activation Induces Dynamic Changes in miRNA Expression Patterns in CD4 and CD8 T-cell Subsets

MicroRNA ◽  
2015 ◽  
Vol 4 (2) ◽  
pp. 117-122 ◽  
Author(s):  
Nato Teteloshvili ◽  
Katarzyna Smigielska-Czepiel ◽  
Bart-Jan Kroesen ◽  
Elisabeth Brouwer ◽  
Joost Kluiver ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Mirna Expression ◽  
Cell Activation ◽  
Expression Patterns ◽  
Cd8 T Cell ◽  
T Cell Subsets ◽  
Dynamic Changes

406 CDX527–01, a phase 1 dose-escalation and expansion study of the PD-L1xCD27 bispecific antibody CDX-527 in patients with advanced malignancies

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A431-A431
Author(s):  
Michael Yellin ◽  
Tracey Rawls ◽  
Diane Young ◽  
Philip Golden ◽  
Laura Vitale ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Dose Escalation ◽  
Clinical Studies ◽  
Cell Activation ◽  
Bispecific Antibody ◽  
Phase 1 ◽  
Clinical Activity ◽  
Tumor Types ◽  
Anti Tumor Activity

BackgroundCD27 ligation and PD-1 blockade elicit complementary signals mediating T cell activation and effector function. CD27 is constitutively expressed on most mature T cells and the interaction with its ligand, CD70, plays key roles in T cell costimulation leading to activation, proliferation, enhanced survival, maturation of effector capacity, and memory. The PD-1/PD-L1 pathway plays key roles in inhibiting T cell responses. Pre-clinical studies demonstrate synergy in T cell activation and anti-tumor activity when combining a CD27 agonist antibody with PD-(L)1 blockade, and clinical studies have confirmed the feasibility of this combination by demonstrating safety and biological and clinical activity. CDX-527 is a novel human bispecific antibody containing a neutralizing, high affinity IgG1k PD-L1 mAb (9H9) and the single chain Fv fragment (scFv) of an agonist anti-CD27 mAb (2B3) genetically attached to the C-terminus of each heavy chain, thereby making CDX-527 bivalent for each target. Pre-clinical studies have demonstrated enhanced T cell activation by CDX-527 and anti-tumor activity of a surrogate bispecific compared to individual mAb combinations, and together with the IND-enabling studies support the advancement of CDX-527 into the clinic.MethodsA Phase 1 first-in-human, open-label, non-randomized, multi-center, dose-escalation and expansion study evaluating safety, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity of CDX-527 is ongoing. Eligible patients have advanced solid tumor malignancies and have progressed on standard-of-care therapy. Patients must have no more than one prior anti-PD-1/L1 for tumor types which have anti-PD-1/L1 approved for that indication and no prior anti-PD-1/L1 for tumor types that do not have anti-PD-1/L1 approved for that indication. CDX-527 is administered intravenously once every two weeks with doses ranging from 0.03 mg/kg up to 10.0 mg/kg or until the maximum tolerated dose. The dose-escalation phase initiates with a single patient enrolled in cohort 1. In the absence of a dose limiting toxicity or any ≥ grade 2 treatment related AE, cohort 2 will enroll in a similar manner as cohort 1. Subsequent dose-escalation cohorts will be conducted in 3+3 manner. In the tumor-specific expansion phase, up to 4 individual expansion cohort(s) of patients with specific solid tumors of interest may be enrolled to further characterize the safety, PK, PD, and efficacy of CDX 527. Tumor assessments will be performed every 8-weeks by the investigator in accordance with iRECIST. Biomarker assessments will include characterizing the effects on peripheral blood immune cells and cytokines, and for the expansion cohorts, the impact of CDX-527 on the tumor microenvironment.ResultsN/AConclusionsN/ATrial RegistrationNCT04440943Ethics ApprovalThe study was approved by WIRB for Northside Hospital, approval number 20201542

Alterations in STAT Signaling Dysregulate CD8 T Cell Activation

2021 ◽  
Vol 147 (2) ◽  
pp. AB151
Author(s):  
Jose Campos ◽  
Peyton Conrey ◽  
Samir Sayed ◽  
Tiphanie Vogel ◽  
Jennifer Leiding ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cd8 T Cell ◽  
Stat Signaling

Efficiency and Mechanism of Antigen-specific CD8+ T-cell Activation Using Synthetic Long Peptides

2012 ◽  
Vol 35 (2) ◽  
pp. 142-153 ◽  
Author(s):  
Maarten L. Zandvliet ◽  
Michel G. D. Kester ◽  
Ellis van Liempt ◽  
Arnoud H. de Ru ◽  
Peter A. van Veelen ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cd8 T Cell ◽  
Synthetic Long Peptides
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