Journal
MOLECULAR THERAPY
Volume 23, Issue 4, Pages 769-778Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/mt.2015.4
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Funding
- National Institutes of Health [CA095152, CA138738, CA059350, CA008748]
- St. Baldrick's Foundation - AVM Traders Scholar's Award
- William Lawrence and Blanche Hughes Foundation
- Emerald Foundation
- VSB Scholarship
- Dutch Cancer Society
- Damon Runyon Clinical Investigator Award
- Annual Terry Fox Run for Cancer Research (New York, NY)
- Mr. William H. Goodwin and Mrs. Alice Goodwin
- Commonwealth Cancer Foundation for Research
- Experimental Therapeutics Center of Memorial Sloan Kettering Cancer Center
- Geoffrey Beene Cancer Foundation
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Adoptive cell therapy with genetically modified T cells expressing a chimeric antigen receptor (CAR) is a promising therapy for patients with B-cell acute lymphoblastic leukemia. However, CAR-modified T cells (CAR T cells) have mostly failed in patients with solid tumors or low-grade B-cell malignancies including chronic lymphocytic leukemia with bulky lymph node involvement. Herein, we enhance the antitumor efficacy of CAR T cells through the constitutive expression of CD40 ligand (CD40L, CD154). T cells genetically modified to constitutively express CD40L (CD40L-modified T cells) demonstrated increased proliferation and secretion of proinflammatory T(H)1 cytokines. Further, CD40L-modified T cells augmented the immunogenicity of CD40(+) tumor cells by the upregulated surface expression of costimulatory molecules (CD80 and CD86), adhesion molecules (CD54, CD58, and CD70), human leukocyte antigen (HLA) molecules (Class I and HLA-DR), and the Fas-death receptor (CD95). Additionally, CD40L-modified T cells induced maturation and secretion of the proinflammatory cytokine interleukin-12 by monocyte-derived dendritic cells. Finally, tumor-targeted CD19-specific CAR/CD40L T cells exhibited increased cytotoxicity against CD40(+) tumors and extended the survival of tumor-bearing mice in a xenotransplant model of CD19(+) systemic lymphoma. This preclinical data supports the clinical application of CAR T cells additionally modified to constitutively express CD40L with anticipated enhanced antitumor efficacy.
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