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Targeted delivery of interferon-gamma by synNotch T cells sensitizes neuroblastoma cells to T cell-mediated killing

Fiorella Iglesias, Siani Weston, Stephanie V. Avila, Holly Zhou, Sara Yousef, Mark Fluchel, Erin Morales, Michael L. Olsen, Sabarinath V. Radhakrishnan, Djordje Atanackovic, Tim Luetkens
doi: https://doi.org/10.1101/2022.06.21.496901
Fiorella Iglesias
1Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York City, NY, USA
2Pediatric Oncology and Hematology, University of Utah, Salt Lake City, UT, USA
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Siani Weston
3Division of Hematology and Hematologic Malignancies, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA
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Stephanie V. Avila
3Division of Hematology and Hematologic Malignancies, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA
4Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, MD
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Holly Zhou
5Department of Pathology, University of Utah, Salt Lake City, UT, USA
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Sara Yousef
3Division of Hematology and Hematologic Malignancies, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA
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Mark Fluchel
2Pediatric Oncology and Hematology, University of Utah, Salt Lake City, UT, USA
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Erin Morales
2Pediatric Oncology and Hematology, University of Utah, Salt Lake City, UT, USA
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Michael L. Olsen
3Division of Hematology and Hematologic Malignancies, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA
6Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
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Sabarinath V. Radhakrishnan
3Division of Hematology and Hematologic Malignancies, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA
7Medical College of Wisconsin, Milwaukee, WI, USA
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Djordje Atanackovic
3Division of Hematology and Hematologic Malignancies, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA
4Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, MD
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Tim Luetkens
3Division of Hematology and Hematologic Malignancies, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA
4Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, MD
8Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, USA
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  • For correspondence: tluetkens@som.umaryland.edu
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ABSTRACT

Downregulation of HLA is one of the most common tumor escape mechanisms by enabling tumors to persist in the presence of tumor-reactive T cells. HLA loss is particularly common in children with high-risk neuroblastoma, who have a 50% long-term survival despite dose-intensive regimens. We have now developed an approach for the targeted induction of HLA to restore sensitivity of neuroblastoma cells to T cell-mediated killing. Using synNotch technology, we have generated T cells that, upon binding of the neuroblastoma surface antigen GD2, secrete IFN-γ without conferring direct cytotoxic activity (snGD2i). Treatment with snGD2i cells induces high and durable expression of HLA on neuroblastoma cells in vitro and in vivo and restores sensitivity to TCR-transgenic T cells targeting neuroblastoma-specific antigens. In contrast, treatment does not lead to upregulation of immune checkpoints or systemically increased levels of IFN-γ. Targeted delivery of IFN-γ using snGD2i cells is a promising new strategy to address immune escape in neuroblastoma.

STATEMENT OF SIGNIFICANCE HLA loss remains one of the most common and unsolved immune escape mechanisms in cancer cells. We have now developed a cell-based approach for the targeted upregulation of HLA on tumor cells, which efficiently sensitizes the malignant cells to killing by tumor-reactive T cells.

Competing Interest Statement

F.I., D.A., and T.L. are inventors on U.S. patent application 62/940689 'Upregulating HLA class I on tumor cells' describing the snGD2i-based approach for the targeted upregulation of HLA on cancer cells.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted June 21, 2022.
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Targeted delivery of interferon-gamma by synNotch T cells sensitizes neuroblastoma cells to T cell-mediated killing
Fiorella Iglesias, Siani Weston, Stephanie V. Avila, Holly Zhou, Sara Yousef, Mark Fluchel, Erin Morales, Michael L. Olsen, Sabarinath V. Radhakrishnan, Djordje Atanackovic, Tim Luetkens
bioRxiv 2022.06.21.496901; doi: https://doi.org/10.1101/2022.06.21.496901
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Targeted delivery of interferon-gamma by synNotch T cells sensitizes neuroblastoma cells to T cell-mediated killing
Fiorella Iglesias, Siani Weston, Stephanie V. Avila, Holly Zhou, Sara Yousef, Mark Fluchel, Erin Morales, Michael L. Olsen, Sabarinath V. Radhakrishnan, Djordje Atanackovic, Tim Luetkens
bioRxiv 2022.06.21.496901; doi: https://doi.org/10.1101/2022.06.21.496901

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