Altered T-cell clone diversity is associated with successful response to Acthar Gel treatment in infantile spasm patients
Abstract number :
436
Submission category :
1. Basic Mechanisms / 1D. Mechanisms of Therapeutic Interventions
Year :
2020
Submission ID :
2422778
Source :
www.aesnet.org
Presentation date :
12/6/2020 5:16:48 PM
Published date :
Nov 21, 2020, 02:24 AM
Authors :
Alan Dombkowski, Wayne State University; Daniela Cukovic - Wayne State University; Sheetal Panday - Wayne State University; Senthil Sundaram - Wayne State University; Aimee Luat - Children’s Hospital of Michigan;;
Rationale:
First-line therapy for infantile spasms (IS) includes adrenocorticotropic hormone (Acthar Gel, Mallinckrodt Pharmaceuticals). The underlying mechanism of action is poorly understood, and treatment response is variable. An improved understanding of the mechanism(s) may enable a personalized medicine approach to identify patients likely to respond. The immune suppressive properties of Acthar Gel suggests an immune mechanism contributes to the pathophysiology of IS. To test our hypothesis that an altered immune profile is associated with the likelihood of response to Acthar Gel treatment, we performed a pilot study using immune repertoire profiling of T lymphocytes in IS patients who had been treated with Acthar Gel.
Method:
We performed a retrospective study using archived cortical tissue that was surgically resected to treat intractable seizures in pediatric patients who had previously been treated for IS with Acthar Gel. Tissue was collected and analyzed with IRB approval. T-cell receptor sequencing was performed on 11 tissue specimens using an Ion Torrent sequencer and the TCR-B SR assay (Thermo Fisher). The spectrum of T-cell clones and their abundance was measured in each sample. Clone evenness and diversity were compared between response groups.
Results:
We successfully quantified T-cell receptor profiles in resected cortical tissue. T-cell evenness was lower in patients who had cessation of spasms after Acthar Gel treatment compared to non-responders (P=0.025), indicating clonal expansion of a subset of T-cells. Median evenness of patients with an incomplete response (partial or relapse) was intermediate.
Conclusion:
We demonstrated the feasibility of using immune repertoire profiling to investigate drug treatment response in IS. Our findings suggest that responsiveness to Acthar Gel is related to an altered immune profile reflective of clonal T-cell activation and expansion. These results warrant further investigation with a prospective study of T-cell profiles in blood drawn prior to treatment for IS.
Funding:
:This study was supported by: Mallinckrodt Pharmaceuticals, Children’s Foundation of Michigan R2-2019-31, and NIH NINDS R56 NS079429.
Basic Mechanisms