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Adoptively transferred T cells and agents designed to block the CD47-SIRPα 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 SIRPα 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., (© 2024. The Author(s).)

Regulatable CAR platforms could circumvent toxicities associated with CAR-T therapy, but existing systems have shortcomings including leakiness and attenuated activity. Here, we present SNIP CARs, a protease-based platform for regulating CAR activity using an FDA-approved small molecule. Design iterations yielded CAR-T cells that manifest full functional capacity with drug and no leaky activity in the absence of drug. In numerous models, SNIP CAR-T cells were more potent than constitutive CAR-T cells and showed diminished T cell exhaustion and greater stemness. In a ROR1-based CAR lethality model, drug cessation following toxicity onset reversed toxicity, thereby credentialing the platform as a safety switch. In the same model, reduced drug dosing opened a therapeutic window that resulted in tumor eradication in the absence of toxicity. SNIP CARs enable remote tuning of CAR activity, which provides solutions to safety and efficacy barriers that are currently limiting progress in using CAR-T cells to treat solid tumors., Competing Interests: Declaration of interests L.L., R.G.M., M.Z.L., and C.L.M. are coinventors on a patent related to this work. C.L.M. is a cofounder of Lyell Immunopharma, Syncopation Life Sciences, and Link Cell Therapies, which are developing CAR-based therapies, and consults for Lyell, NeoImmune Tech, Apricity, Nektar, Immatics, Ensoma, Mammoth, Glaxo Smith Kline, and Bristol Myers Squibb. L.L., R.G.M., E.S., and E.W.W. are consultants for and hold equity in Lyell Immunopharma. L.L. is a cofounder of, consults for, and holds equity in Syncopation Life Sciences. R.G.M. is a cofounder of, consults for, and holds equity in Syncopation Life Sciences and Link Cell Therapies. R.G.M. is a consultant for Illumina Radiopharmaceuticals, NKarta, ImmunAI, Arovella Therapeutics, Zai Lab, and Aptorum Group. R.G.M. serves on the Data and Safety Monitoring Board for Fate Therapeutics. J.T. is a consultant for Dorian Therapeutics. E.W.W. consults for and holds equity in VISTAN Health. A.T.S. is a founder of Immunai and Cartography Biosciences and receives research funding from Arsenal Biosciences, Allogene Therapeutics, and 10x Genomics. K.R.P. is a cofounder and employee of Cartography Biosciences. H.Y.C. is a cofounder of Accent Therapeutics, Boundless Bio, and Cartography Biosciences and is an advisor to 10x Genomics, Arsenal Biosciences, and Spring Discovery. J.R.C. is a cofounder and equity holder of Trapeze Therapeutics, Combangio, and Virsti Therapeutics; he has financial interests in Aravive, Xyence Therapeutics, and Syncopation Life Sciences; and he is a member of the Board of Directors of Ligand Pharmaceuticals and Revel Pharmaceuticals. S.A.Y.-H. is a consultant for Trapeze Therapeutics and Xyence Therapeutics., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Cancer immunotherapies can be classified into agents that amplify natural immune responses (e.g., checkpoint inhibitors) versus synthetic immunotherapies designed to initiate new responses (e.g., monoclonal antibodies [mAbs], chimeric antigen receptors [CARs]). Checkpoint inhibitors mediate unprecedented benefit in some adult cancers, but have not demonstrated significant activity in pediatric cancers, likely due their paucity of neoantigens. In contrast, synthetic immunotherapies such as mAbs and CAR T cells demonstrate impressive effects against childhood cancers. Intense efforts are underway to enhance the effectiveness of pediatric cancer immunotherapies through improved engineering of synthetic immunotherapies and by combining these with agents designed to amplify immune responses., (Copyright © 2017 Elsevier Inc. All rights reserved.)