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Abstract Details

T-cell Therapy for Progressive Multifocal Leukoencephalopathy
Infectious Disease
S25 - Diagnostics and Therapeutics in Infectious Disease (4:30 PM-4:42 PM)
006

PML is a fatal disease of the central nervous system caused by JCV. Survival is dependent on early diagnosis and ability to establish T cell immunity. Adoptive transfer of polyomavirus-specific T cells is possible; however, current delays in creating HLA-matched anti-viral T cells can be fatal.

Create an “off-the-shelf” JC virus (JCV)-specific T cell therapy for progressive multifocal leukoencephalopathy (PML) patients who are immunocompromised and unable to adequately immune reconstitute.

PBMCs from healthy donors with specific HLA class I subtypes were stimulated with peptide libraries tiled across the JCV VP1 protein. Multiple rounds of stimulation were performed to identify the peptides that induced the largest CD8+ T cell activation (i.e., INFg, TNFa, CD137, and CD69 expression). For the immunogenic peptides antigens were narrowed and high-affinity antigen-specific CD8+ T cells were isolated using tetramers. Single-cell T cell receptor (TCR) sequencing identified high-affinity, VP1-specific TCR-a/b chain pairs. Candidate TCRs were then precisely introduced into the genome of T cells via CRISPR-Cas9 for further characterization.

A highly conserved region of the JCV VP1 protein (VP1100-108) was identified as an antigen for HLA-A2 CD8+ T cells with little potential for inducing autoimmunity. Fourteen high avidity TCRs specific for VP1100-108 were isolated, and ten demonstrated specific binding to VP1100-108 HLA-A2 tetramers. The top candidates have been integrated into T cells via CRISPR-Cas9 and are being further characterized. Other immunogenic regions of VP1 have been similarly identified for HLA-A1 and A3 alleles.   

We identified immunogenic epitopes from the JCV VP1 protein that bind HLA-A1, A2, and A3 and isolated HLA-A2-restricted TCRs that demonstrated recognition and activation to the epitope of interest. While additional in vitro and in vivo validation is in progress, we believe these cells will offer a rapid, “off-the-shelf”, allogeneic anti-JCV T cell therapy for PML patients who are unable to immune reconstitute.

Authors/Disclosures
Sasha Gupta (University of California, San Francisco)
PRESENTER
Dr. Gupta has nothing to disclose.
No disclosure on file
No disclosure on file
No disclosure on file
No disclosure on file
No disclosure on file
No disclosure on file
No disclosure on file
No disclosure on file
Michael Wilson (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 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 UCSF Weill Institute for Neurosciences. 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. 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.