Page 40 - SDIR5 Abstract book 21 12 2021.

IMAGING IN CANCER

Sox2-targeted T cell therapy for treating multiple myeloma

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Tijana Martinov , Shwetha Mureli , Clara McCurdy , Angie Vazquez , Melissa Comstock , Rachel Perret ,
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Thomas Schmitt , Damian Green , Anthony Rongvaux , Philip Greenberg
1 Program in Immunology, Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview
Avenue North, Seattle, WA 98109, United States of America
2 Current affiliation: Freemasons CAR T-cell Research Programme, Malaghan Institute of Medical Research, Kelburn,
Wellington 6012, New Zealand

Background: Multiple myeloma (MM) results from the uncontrolled growth of clonal antibody-producing
plasma cells in the bone marrow, and it remains incurable. Adoptive cell therapy (ACT) is emerging as a
promising treatment for MM, but it requires further improvement and mechanistic understanding prior to
becoming a reproducibly effective standard of care. Recent studies suggest that the transcription factor
Sox2 regulates cell proliferation and self-renewal in MM and other cancers. Spontaneous T cell immunity
to Sox2 has been associated with slower MM progression, and with a prolonged response to therapy. We
hypothesize that adoptively transferred T cells targeting Sox2 will have a clinical benefit in MM. Materials
and Methods: We used in silico epitope prediction algorithms and in vitro CD8+ T cell stimulation assays to
identify Sox2 epitopes that are immunogenic in the context of the HLA-A*02:01 allele. We generated Sox2-
specific CD8+ T cell lines from healthy HLA-A*02:01+ donors, and tested their cytotoxicity using flow
cytometry and real-time imaging assays. We sequenced T cell receptors (TCRs) from the responding T cell
lines, and selected 12 TCRs with a high affinity for further analysis. Results: We confirmed that Sox2-TCR-
transduced T cells can respond to low doses of Sox2 peptide, as well as kill Sox2+ cancer cells in vitro. We
are now poised to test the safety and efficacy of our lead Sox2-TCR candidate in a humanized mouse model
of MM. Conclusion: Collectively, this work will reveal whether Sox2 is a safe and effective T cell target for
treating MM.
Keywords: adoptive cellular immunotherapy, T-cell therapy, multiple myeloma

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