CD40 ligand-modified chimeric antigen receptor T cells enhance antitumor function by eliciting an endogenous antitumor response Journal Article

   

Authors:	Kuhn, N. F.; Purdon, T. J.; van Leeuwen, D. G.; Lopez, A. V.; Curran, K. J.; Daniyan, A. F.; Brentjens, R. J.
Article Title:	CD40 ligand-modified chimeric antigen receptor T cells enhance antitumor function by eliciting an endogenous antitumor response
Abstract:	Chimeric antigen receptor (CAR) T cells provide great efficacy in B cell malignancies. However, improved CAR T cell therapies are still needed. Here, we engineered tumor-targeted CAR T cells to constitutively express the immune-stimulatory molecule CD40 ligand (CD40L) and explored efficacy in different mouse leukemia/lymphoma models. We observed that CD40L + CAR T cells circumvent tumor immune escape via antigen loss through CD40/CD40L-mediated cytotoxicity and induction of a sustained, endogenous immune response. After adoptive cell transfer, the CD40L + CAR T cells displayed superior antitumor efficacy, licensed antigen-presenting cells, enhanced recruitment of immune effectors, and mobilized endogenous tumor-recognizing T cells. These effects were absent in Cd40 −/− mice and provide a rationale for the use of CD40L + CAR T cells in cancer treatment. © 2019 Elsevier Inc. Kuhn et al. engineer tumor-targeted CAR T cells to constitutively express CD40L. Through direct CD40/CD40L-mediated cytotoxicity and indirect induction of an immune response by enhancing recruitment and activation of immune effectors, the CD40L + CAR T cells overcome tumor immune escape via antigen loss. © 2019 Elsevier Inc.
Keywords:	controlled study; leukemia; nonhuman; t lymphocyte; animal cell; mouse; animal tissue; spleen; dendritic cell; cd40 ligand; animal experiment; animal model; in vivo study; cytotoxicity; b lymphocyte; immunotherapy; gamma interferon; lymphoma cell; lymphoma; chimeric antigen receptor; natural killer cell; adoptive transfer; tumor immunity; cytokine production; upregulation; ligand binding; antigen presenting cell; cell expansion; antigen-presenting cells; t lymphocyte activation; cell transfer; tumor necrosis factor; chemical modification; immobilized cell; cd40 antigen; cd40; priority journal; article; car t cells; chimeric antigen receptor t-cell immunotherapy; endogenous t cells
Journal Title:	Cancer Cell
Volume:	35
Issue:	3
ISSN:	1535-6108
Publisher:	Cell Press
Date Published:	2019-03-18
Start Page:	473
End Page:	488.e6
Language:	English
DOI:	10.1016/j.ccell.2019.02.006
PUBMED:	30889381
PROVIDER:	scopus
PMCID:	PMC6428219
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85062341688&doi=10.1016%2fj.ccell.2019.02.006&partnerID=40&md5=dbc1efa4007d1267c1578afb0f76a47a
Notes:	Source: Scopus

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