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; Crystal L Mackall

doi:10.1038/s41586-024-07443-8

Engineered CD47 protects T cells for enhanced antitumour immunity

Nature. 2024 May 15. doi: 10.1038/s41586-024-07443-8. Online ahead of print.

Authors

Sean A Yamada-Hunter^#^{1

2}, Johanna Theruvath^#¹, Brianna J McIntosh³, Katherine A Freitas^{1

4}, Frank Lin^{1

5}, Molly T Radosevich¹, Amaury Leruste¹, Shaurya Dhingra¹, Naiara Martinez-Velez¹, Peng Xu¹, Jing Huang¹, Alberto Delaidelli⁶, Moksha H Desai¹, Zinaida Good^{1

2

7}, Roel Polak^{8

9}, Audre May^{1

4}, Louai Labanieh^{1

2

10}, Jeremy Bjelajac^{1

11}, Tara Murty^{1

12

13}, Zach Ehlinger¹, Christopher W Mount^{13

14

15}, Yiyun Chen¹, Sabine Heitzeneder¹, Kristopher D Marjon^{11

16}, Allison Banuelos^{11

16}, Omair Khan^{11

13

16}, Savannah L Wasserman¹, Jay Y Spiegel¹⁷, Sebastian Fernandez-Pol¹⁸, Calvin J Kuo⁸, Poul H Sorensen⁶, Michelle Monje^{13

14

15

19}, Robbie G Majzner^{16

19}, Irving L Weissman^{11

16

18

20}, Bita Sahaf¹, Elena Sotillo¹, Jennifer R Cochran^{3

4

10

21}, Crystal L Mackall^{22

23

24

25

26

27

28

29}

Affiliations

¹ Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
² Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA.
³ Cancer Biology Program, Stanford University School of Medicine, Stanford, CA, USA.
⁴ Immunology Graduate Program, Stanford University School of Medicine, Stanford, CA, USA.
⁵ Masters in Translational Research and Applied Medicine Program, Stanford University School of Medicine, Stanford, CA, USA.
⁶ British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
⁷ Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA, USA.
⁸ Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
⁹ Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.
¹⁰ Department of Bioengineering, Stanford University, Stanford, CA, USA.
¹¹ Institute for Stem Cell Biology and Regenerative Medicine, Stanford, CA, USA.
¹² Program in Biophysics, Stanford University, Stanford, CA, USA.
¹³ Medical Scientist Training Program, Stanford University, Stanford, CA, USA.
¹⁴ Department of Neurology, Stanford University School of Medicine, Stanford, CA, USA.
¹⁵ Neurosciences Program, Stanford University, Stanford, CA, USA.
¹⁶ Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
¹⁷ Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA.
¹⁸ Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
¹⁹ Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.
²⁰ Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine, Stanford, CA, USA.
²¹ Department of Chemical Engineering, Stanford University, Stanford, CA, USA.
²² Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. cmackall@stanford.edu.
²³ Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. cmackall@stanford.edu.
²⁴ Cancer Biology Program, Stanford University School of Medicine, Stanford, CA, USA. cmackall@stanford.edu.
²⁵ Immunology Graduate Program, Stanford University School of Medicine, Stanford, CA, USA. cmackall@stanford.edu.
²⁶ Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA. cmackall@stanford.edu.
²⁷ Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. cmackall@stanford.edu.
²⁸ Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA. cmackall@stanford.edu.
²⁹ Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine, Stanford, CA, USA. cmackall@stanford.edu.

^# Contributed equally.

PMID: 38750365
DOI: 10.1038/s41586-024-07443-8

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 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 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.