Restricting CAR T Cell Trafficking Expands Targetable Antigen Space

Morales, E. A.; Dietze, K. A.; Baker, J. M.; Wang, A.; Avila, S. V.; Iglesias, F.; Radhakrishnan, S. V.; Vander Mause, E.; Olson, M. L.; Sun, W.; Rosati, E.; Chidester, S. L.; Iraguha, T.; Fan, X.; Atanackovic, D.; Luetkens, T.

doi:10.1101/2024.02.08.579002

bioRxiv · 10.1101/2024.02.08.579002

Restricting CAR T Cell Trafficking Expands Targetable Antigen Space

Morales, E. A.·Dietze, K. A.·Baker, J. M.·Wang, A.·Avila, S. V.·Iglesias, F.·Radhakrishnan, S. V.·Vander Mause, E.·Olson, M. L.·Sun, W.·Rosati, E.·Chidester, S. L.·Iraguha, T.·Fan, X.·Atanackovic, D.·Luetkens, T.

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Abstract

Chimeric antigen receptor (CAR) T cells are an effective treatment for some blood cancers. However, the lack of tumor-specific surface antigens limits their wider use. We identified a set of surface antigens that are limited in their expression to cancer and the central nervous system (CNS). We developed CAR T cells against one of these antigens, LINGO1, which is widely expressed in Ewing sarcoma (ES). To prevent CNS targeting, we engineered LINGO1 CAR T cells lacking integrin 4 (A4ko), an adhesion molecule essential for migration across the blood-brain barrier. A4ko LINGO1 CAR T cells were efficiently excluded from the CNS but retained efficacy against ES. We show that altering adhesion behavior expands the set of surface antigens targetable by CAR T cells. One sentence summaryAltering integrin-mediated adhesion provides tumor selectivity to CAR T cells by preventing homing to defined normal tissues but retaining tumor trafficking and anti-tumor activity. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=114 SRC="FIGDIR/small/579002v1_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@256b53org.highwire.dtl.DTLVardef@a94775org.highwire.dtl.DTLVardef@1926f62org.highwire.dtl.DTLVardef@cec52e_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Morales, E. A., Dietze, K. A., Baker, J. M., Wang, A., Avila, S. V., Iglesias, F., Radhakrishnan, S. V., Vander Mause, E., Olson, M. L., Sun, W., Rosati, E., Chidester, S. L., Iraguha, T., Fan, X., Atanackovic, D., Luetkens, T.. 2024-02-11. Restricting CAR T Cell Trafficking Expands Targetable Antigen Space. https://doi.org/10.1101/2024.02.08.579002

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