Engineered CD47 protects T cells for enhanced antitumour immunity

• 成果类型: Article
• 署名作者: Yamada-Hunter, Sean A.; Theruvath, Johanna; McIntosh, Brianna J.; Freitas, Katherine A.; Lin, Frank; Radosevich, Molly T.; Leruste, Amaury; Dhingra, Shaurya; Martinez-Velez, Naiara; Xu, Peng; Huang, Jing; Delaidelli, Alberto; Desai, Moksha H.; Good, Zinaida; Polak, Roel; May, Audre; Labanieh, Louai; Bjelajac, Jeremy; Murty, Tara; Ehlinger, Zach; Mount, Christopher W.; Chen, Yiyun; Heitzeneder, Sabine; Marjon, Kristopher D.; Banuelos, Allison; Khan, Omair; Wasserman, Savannah L.; Spiegel, Jay Y.; Fernandez-Pol, Sebastian; Kuo, Calvin J.; Sorensen, Poul H.; Monje, Michelle; Majzner, Robbie G.; Weissman, Irving L.; Sahaf, Bita; Sotillo, Elena; Cochran, Jennifer R.; Mackall, Crystal L.
• 署名单位: Stanford University; Stanford Cancer Institute; Stanford University; Stanford University; Stanford University; British Columbia Cancer Agency; Stanford University; Stanford University; Princess Maxima Center; Stanford University; Stanford University; Stanford University; Stanford University; Stanford University; Stanford University; Stanford Cancer Institute; University of Miami; Stanford University; Stanford University; Stanford University; Stanford University
• 刊物名称: Nature
• ISSN/ISSBN: 0028-5265
• DOI: 10.1038/s41586-024-07443-8
• 发表日期: 2024-06-13
• 页码: 457-+
• 关键词: macrophages; clearance; affinity

摘要

Adoptively transferred T cells and agents designed to block the CD47-SIRP alpha axis are promising cancer therapeutics that activate distinct arms of the immune system(1,2). 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) (47(E)), which engages SIRP alpha and provides a 'don't eat me' signal that is not blocked by anti-CD47 antibodies. TCR or CAR T cells expressing 47(E) 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 profile(3), 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.