Abstract
Adoptively transferred T cells and agents designed to block the CD47/SIRPα axis are promising antitumor therapeutics, which activate distinct arms of the immune system. We administered anti-CD47 (αCD47) with adoptively transferred T cells with the goal of enhancing antitumor efficacy but observed rapid macrophage-mediated clearance of T cells expressing chimeric antigen receptors (CARs) or engineered T cell receptors, which blunted therapeutic benefit. αCD47 mediated CAR T clearance was potent and rapid enough to serve as an effective safety switch. To overcome this challenge, we engineered a CD47 variant (47E) that engaged SIRPα and provided a “don’t-eat-me” signal that was not blocked by αCD47 antibodies. TCR or CAR T cells expressing 47E were resistant to clearance by macrophages following αCD47, and mediated significant, sustained macrophage recruitment into the TME. Although many of the recruited macrophages manifested an M2-like profile, the combined therapy resulted in synergistic enhancement in antitumor efficacy. This work 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 further delivers a therapeutic approach capable of simultaneously harnessing the antitumor effects of T cells and macrophages that manifests markedly enhanced potency against solid tumors.
Competing Interest Statement
S.A.Y.-H., J.T., B.J.M., J.R.C., and C.L.M. are coinventors on a patent related to this work. C.L.M. is a cofounder of Lyell Immunopharma, CARGO Therapeutics, and Link Cell Therapies, which are developing CAR-based therapies, and consults for Lyell, CARGO, Link, Nektar, Immatics, Ensoma, Mammoth, Legend, and Bristol Myers Squibb. S.A.Y.-H. is a consultant for Quince Therapeutics. J.T. is a consultant for Dorian Therapeutics. L.L. and E.S. are consultants for and hold equity in Lyell Immunopharma. L.L. is a cofounder of, consults for, and holds equity in CARGO Therapeutics. O.K. is a Senior Fellow with ARTIS Ventures. R.G.M. is a co-founder of and hold equity in Link Cell Therapies. R.G.M. is a consultant for NKarta, Arovella Pharmaceuticals, Innervate Radiopharmaceuticals, GammaDelta Therapeutics, Aptorum Group, Zai Labs, Immunai, Gadeta, FATE Therapeutics (DSMB) and Waypoint Bio. I.L.W. was a director, stockholder and consultant in Forty Seven, but not Gilead, and is a co-founder, director and consultant for Bitterroot Bio and PHeast, and a co-founder of 48. I.L.W. is also on the scientific advisory board of Appia. J.R.C. is a cofounder and equity holder of Trapeze Therapeutics, Combangio, and Virsti Therapeutics, has financial interests in Aravive, Xyence Therapeutics, and Cargo Therapeutics, and is a member of the Board of Directors of Ligand Pharmaceuticals and Revel Pharmaceuticals. The remaining authors declare no competing interests.
Footnotes
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