Oncotarget

Research Papers:

Targeted lymphodepletion with a CD45-directed antibody radioconjugate as a novel conditioning regimen prior to adoptive cell therapy

Wojciech Dawicki, Kevin J.H. Allen, Ravendra Garg, Eileen M. Geoghegan, Mark S. Berger, Dale L. Ludwig _ and Ekaterina Dadachova

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Oncotarget. 2020; 11:3571-3581. https://doi.org/10.18632/oncotarget.27731

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Abstract

Wojciech Dawicki1, Kevin J.H. Allen1, Ravendra Garg1, Eileen M. Geoghegan2, Mark S. Berger2, Dale L. Ludwig2 and Ekaterina Dadachova1

1 College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK, Canada

2 Actinium Pharmaceuticals, New York, NY, USA

Correspondence to:

Dale L. Ludwig,email: dludwig@actiniumpharma.com

Keywords: anti-CD45 targeted lymphodepletion; radioimmunotherapy; adoptive cell therapy; 131Iodine; 177Lutetium

Received: June 13, 2020     Accepted: August 17, 2020     Published: September 29, 2020

ABSTRACT

Chimeric antigen receptor (CAR) T cell therapies, and adoptive cell therapy (ACT) in general, represent one of the most promising anti-cancer strategies. Conditioning has been shown to improve the immune homeostatic environment to enable successful ACT or CAR-T engraftment and expansion in vivo following infusion, and represents potential point of intervention to decrease serious toxicities following CAR-T treatment. In contrast to relatively non-specific chemotherapy-derived lymphodepletion, targeted lymphodepletion with radioimmunotherapy (RIT) directed to CD45 may be a safer and more effective alternative to target and deplete immune cells. Here we describe the results of preclinical studies with an anti-mouse CD45 antibody 30F11, labeled with two different beta-emitters 131Iodine (131I) and 177Lutetium (177Lu), to investigate the effect of anti-CD45 RIT lymphodepletion on immune cell types and on tumor control in a model of adoptive cell therapy. Treatment of mice with 3.7 MBq 131I-30F11 or 1.48 MBq 177Lu-30F11 safely depleted immune cells such as spleen CD4+ and CD8+ T Cells, B and NK cells as well as Tregs in OT I tumor model while sparing RBC and platelets and enabled E. G7 tumor control. Our results support the application of CD45-targeted RIT lymphodepletion with a non-myeloablative dose of 131I-30F11 or 177Lu-30F11 antibody prior to adoptive cell therapy.


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