Abstract Details

Title Advancing Antigen-Specific T cell Therapy for Progressive Multifocal Leukoencephalopathy

Topic Infectious Disease

Presentation(s) N4 - Neuroscience in the Clinic: CAR-T Cell Therapy: Neurologic Applications and Neurotoxicity (6:00 PM-6:15 PM)

Poster/Presentation
Number 001

Objective To perform T cell immune repertoire sequencing on donor polyomavirus-specific T cell populations with the goal of identifying T cell receptors (TCRs) that might be used to create a new “off the shelf” designer T cell therapy for progressive multifocal leukoencephalopathy (PML).

Background PML is an often fatal disease caused by polyomavirus JC (JCV) in immunocompromised patients (i.e. HIV/AIDS, transplant, advanced cancer, or multiple sclerosis (MS) patients treated with certain medications). Successful PML treatment is critically dependent on early recognition and immune reconstitution; unfortunately, rapid immune reconstitution is not always achievable. New therapies are being investigated, including a pilot study conducted at NIH exploring ex vivo polyomavirus-specific T cells generated from partially HLA matched first degree relative donors of PML patients (NCT02694783).

Design/Methods T cell products from six donors participating in the NIH pilot study were obtained, including 2 donor sets of T cells pre- and post-polyomavirus antigen stimulation. Using immune repertoire sequencing of both CD4 and CD8 T cells, V(D)J sequences from post- stimulation donor cells were analyzed to identify clonally expanded TCRs relative to the pre-stimulation same donor controls and across donor samples. These repertoires were further analyzed using the VDJdb database to look for matches to TCRs with known antigens.

Results Across 6 donors in post-stimulation samples there were shared TCRs in 95 instances: 93 of the shared TCRs were shared by 2 of the 6 samples, and 2 of the TCRs were found in 3 of the 6 samples. Of these 95 TCRs, 14 were found in the VDJdB database with matched HLA.

Conclusions Stimulation with the polyomavirus peptide libraries leads to a contraction of TCR diversity with a change in dominant TCRs, suggesting a likely polyomavirus-specific expansion. Most shared and/or dominant TCRs after polyomavirus antigen stimulation were not found within the VDJdb database, which does not include polyomavirus antigens.

Authors/Disclosures
Sasha Gupta, MD (University of California, San Francisco) PRESENTER	Dr. Gupta has nothing to disclose.
	No disclosure on file
Irene Cortese, MD	Dr. Cortese has stock in Keires, AG. Dr. Cortese has stock in Nouscom, AG. Dr. Cortese has stock in PDC*line Pharma.
Michael R. Wilson, MD, FAAN (University of California San Francisco)	Dr. Wilson has received personal compensation in the range of $10,000-$49,999 for serving as an officer or member of the Board of Directors for Delve Bio. Dr. Wilson has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for Cambridge Medical Experts. Dr. Wilson has stock in Delve Bio. The institution of Dr. Wilson has received research support from Genentech / Roche. The institution of Dr. Wilson has received research support from NIH. The institution of Dr. Wilson has received research support from Novartis. The institution of Dr. Wilson has received research support from National Multiple Sclerosis Society. The institution of Dr. Wilson has received research support from Fanconi Anemia Research Foundation. The institution of Dr. Wilson has received research support from Department of Defense. The institution of Dr. Wilson has received research support from Chan Zuckerberg Initiative. Dr. Wilson has received intellectual property interests from a discovery or technology relating to health care. Dr. Wilson has received intellectual property interests from a discovery or technology relating to health care. Dr. Wilson has received personal compensation in the range of $10,000-$49,999 for serving as a Expert Witness with US Dept of Justice.

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