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: | |
Notes: | Source: Scopus |