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. Multiparametric 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 December 3, 2020.
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