Engineered CD47 protects T cells for enhanced antitumour immunity

Sean A. Yamada-Hunter, Johanna Theruvath, Brianna J. McIntosh, Katherine A. Freitas, Frank Lin, Molly T. Radosevich, Amaury Leruste, Shaurya Dhingra, Naiara Martinez-Velez, Peng Xu, Jing Huang, Alberto Delaidelli, Moksha H. Desai, Zinaida Good, Roel Polak, Audre May, Louai Labanieh, Jeremy Bjelajac, Tara Murty, Zach Ehlinger, Christopher W. Mount, Yiyun Chen, Sabine Heitzeneder, Kristopher D. Marjon, Allison Banuelos, Omair Khan, Savannah L. Wasserman, Jay Y. Spiegel, Sebastian Fernandez-Pol, Calvin J. Kuo, Poul H. Sorensen, Michelle Monje, Robbie G. Majzner, Irving L. Weissman, Bita Sahaf, Elena Sotillo, Jennifer R. Cochran and Crystal L. Mackall ()
Additional contact information
Sean A. Yamada-Hunter: Stanford University School of Medicine
Johanna Theruvath: Stanford University School of Medicine
Brianna J. McIntosh: Stanford University School of Medicine
Katherine A. Freitas: Stanford University School of Medicine
Frank Lin: Stanford University School of Medicine
Molly T. Radosevich: Stanford University School of Medicine
Amaury Leruste: Stanford University School of Medicine
Shaurya Dhingra: Stanford University School of Medicine
Naiara Martinez-Velez: Stanford University School of Medicine
Peng Xu: Stanford University School of Medicine
Jing Huang: Stanford University School of Medicine
Alberto Delaidelli: British Columbia Cancer Agency
Moksha H. Desai: Stanford University School of Medicine
Zinaida Good: Stanford University School of Medicine
Roel Polak: Stanford University School of Medicine
Audre May: Stanford University School of Medicine
Louai Labanieh: Stanford University School of Medicine
Jeremy Bjelajac: Stanford University School of Medicine
Tara Murty: Stanford University School of Medicine
Zach Ehlinger: Stanford University School of Medicine
Christopher W. Mount: Stanford University
Yiyun Chen: Stanford University School of Medicine
Sabine Heitzeneder: Stanford University School of Medicine
Kristopher D. Marjon: Institute for Stem Cell Biology and Regenerative Medicine
Allison Banuelos: Institute for Stem Cell Biology and Regenerative Medicine
Omair Khan: Institute for Stem Cell Biology and Regenerative Medicine
Savannah L. Wasserman: Stanford University School of Medicine
Jay Y. Spiegel: University of Miami
Sebastian Fernandez-Pol: Stanford University School of Medicine
Calvin J. Kuo: Stanford University School of Medicine
Poul H. Sorensen: British Columbia Cancer Agency
Michelle Monje: Stanford University
Robbie G. Majzner: Stanford University School of Medicine
Irving L. Weissman: Institute for Stem Cell Biology and Regenerative Medicine
Bita Sahaf: Stanford University School of Medicine
Elena Sotillo: Stanford University School of Medicine
Jennifer R. Cochran: Stanford University School of Medicine
Crystal L. Mackall: Stanford University School of Medicine

Nature, 2024, vol. 630, issue 8016, 457-465

Abstract: Abstract Adoptively transferred T cells and agents designed to block the CD47–SIRPα axis are promising cancer therapeutics that activate distinct arms of the immune system1,2. Here we administered anti-CD47 antibodies in combination with adoptively transferred T cells with the goal of enhancing antitumour efficacy but observed abrogated therapeutic benefit due to rapid macrophage-mediated clearance of T cells expressing chimeric antigen receptors (CARs) or engineered T cell receptors. Anti-CD47-antibody-mediated CAR T cell clearance was potent and rapid enough to serve as an effective safety switch. To overcome this challenge, we engineered the CD47 variant CD47(Q31P) (47E), which engages SIRPα and provides a ‘don’t eat me’ signal that is not blocked by anti-CD47 antibodies. TCR or CAR T cells expressing 47E are resistant to clearance by macrophages after treatment with anti-CD47 antibodies, and mediate substantial, sustained macrophage recruitment to the tumour microenvironment. Although many of the recruited macrophages manifested an M2-like profile3, the combined therapy synergistically enhanced antitumour efficacy. Our study identifies macrophages as major regulators of T cell persistence and illustrates the fundamental challenge of combining T-cell-directed therapeutics with those designed to activate macrophages. It delivers a therapeutic approach that is capable of simultaneously harnessing the antitumour effects of T cells and macrophages, offering enhanced potency against solid tumours.

Date: 2024
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DOI: 10.1038/s41586-024-07443-8

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