Combined CD28 and 4-1BB costimulation potentiates affinity-tuned chimeric antigen receptor-engineered T cells Journal Article


Authors: Drent, E.; Poels, R.; Ruiter, R.; van de Donk, N. W. C. J.; Zweegman, S.; Yuan, H.; de Bruijn, J.; Sadelain, M.; Lokhorst, H. M.; Groen, R. W. J.; Mutis, T.; Themeli, M.
Article Title: Combined CD28 and 4-1BB costimulation potentiates affinity-tuned chimeric antigen receptor-engineered T cells
Abstract: Purpose: Targeting nonspecific, tumor-associated antigens (TAA) with chimeric antigen receptors (CAR) requires specific attention to restrict possible detrimental on-target/off-tumor effects. A reduced affinity may direct CAR-engineered T (CART) cells to tumor cells expressing high TAA levels while sparing low expressing normal tissues. However, decreasing the affinity of the CAR-target binding may compromise the overall antitumor effects. Here, we demonstrate the prime importance of the type of intracellular signaling on the function of lowaffinity CAR-T cells. Experimental Design: We used a series of single-chain variable fragments (scFv) with five different affinities targeting the same epitope of the multiple myeloma-associated CD38 antigen. The scFvs were incorporated in three different CAR costimulation designs and we evaluated the antitumor functionality and off-tumor toxicity of the generated CAR-T cells in vitro and in vivo. Results: We show that the inferior cytotoxicity and cytokine secretion mediated by CD38 CARs of very low-affinity (Kd < 1.9 × 10-6 mol/L) bearing a 4-1BB intracellular domain can be significantly improved when a CD28 costimulatory domain is used. Additional 4-1BB signaling mediated by the coexpression of 4-1BBL provided the CD28-based CD38 CAR-T cells with superior proliferative capacity, preservation of a central memory phenotype, and significantly improved in vivo antitumor function, while preserving their ability to discriminate target antigen density. Conclusions: A combinatorial costimulatory design allows the use of very low-affinity binding domains (Kd < 1 mmol/L) for the construction of safe but also optimally effective CAR-T cells. Thus, very-low-affinity scFvs empowered by selected costimulatory elements can enhance the clinical potential of TAA-targeting CARs. © 2019 American Association for Cancer Research.
Journal Title: Clinical Cancer Research
Volume: 25
Issue: 13
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2019-07-01
Start Page: 4014
End Page: 4025
Language: English
DOI: 10.1158/1078-0432.Ccr-18-2559
PUBMED: 30979735
PROVIDER: scopus
DOI/URL:
Notes: Source: Scopus
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  1. Michel W J Sadelain
    489 Sadelain