Dose Escalating Anti-αβ-TCR (TOL101) Monoclonal Therapy, Induces Robust Naive and Memory T Inhibition Whilst Promoting Post Dosing Regulatory T Cell Induction
Tolera Therapeutics, Kalamazoo
Northwestern University, Chicago
Barnabas Health, West Orange
Dallas Nephrology Associates, Dallas
University of Kentucky, Lexington
University of Michigan, Ann Arbor
University of Utah, Salt Lake City
University of Colorado, Denver
Cleveland Clinic Foundation, Cleveland
Meeting: 2013 American Transplant Congress
Abstract number: 184
Purpose: Induction therapy success hinges on the ability to robustly inhibit alloreactive T cells. The purpose of this study was to further examine the impact of TOL101 induction on specific T cell subsets, including Memory, Naive and regulatory T cells, in a phase 2 clinical study.
Methods: Eight cohorts (ranging from 0.28, 1.4, 7, 14, 28, 42 mg and an escalating cohort of 14-21-28-42-42 on a daily schedule) with one other receiving 6 daily doses of TOL-101 at successively higher administered doses. Multi–parametric flow cytometry was performed on blood samples daily and at day 7 and 14. CD2+CD4+, CD2+CD8+, Naive (CD45+CD2+CD3+/-CD45RA+), Memory (CD45+CD2+CD3+/-CD45RO+) and regulatory (CD45+CD4+CD25+FOXP3+CD127lo) T cell subsets were examined.
Results: Contrary to CD3 expression, baseline patient samples showed that NaÏve and Memory T cells were observed to express similar ΑΒ TCR levels. Therapeutic doses of TOL101 (28mg, 32mg, 42mg and the dose escalating regimen) were observed to equally impact CD3+ Memory and Naive T cells, with the numbers of these cells reduced below 25 cells/mm3 throughout dosing. Notwithstanding, the number of CD3-CD2+ memory an naive cells returned to baseline by day 3-4 post transplant. In vitro studies show TOL101 induces non-responsiveness in both Memory and NaÏve T cells. The most striking finding was the expansion of function Tregs only in the dose escalating cohort. This finding was further confirmed using in-vitro Treg expansion studies. These TOL101 derived Tregs have been tested in MLR and have shown to have immune regulatory abilities.
Conclusions: Clinically relevant daily infusions of TOL-101 are capable of both inhibiting T cell subsets known to drive early allograft rejection, whilst promoting regulatory T cells, which may provide long term immune regulation and graft support.
Getts, D.: Employee, Tolera.
To cite this abstract in AMA style:
Getts D, Mulgaonkar S, Melton L, Waid T, Sung R, Shihab F, Chastain E, Terry R, Miller S, Wiseman A, Flechner S. Dose Escalating Anti-αβ-TCR (TOL101) Monoclonal Therapy, Induces Robust Naive and Memory T Inhibition Whilst Promoting Post Dosing Regulatory T Cell Induction [abstract]. Am J Transplant. 2013; 13 (suppl 5). https://atcmeetingabstracts.com/abstract/dose-escalating-anti-tcr-tol101-monoclonal-therapy-induces-robust-naive-and-memory-t-inhibition-whilst-promoting-post-dosing-regulatory-t-cell-induction/. Accessed November 22, 2024.« Back to 2013 American Transplant Congress