Design of CD40 Agonists and Their Use in Growing B Cells for Cancer Immunotherapy

• Published in: International Reviews of Immunology Vol. 31; no. 4; pp. 279 - 288
• Main Authors: Kornbluth, Richard S., Stempniak, Mariusz, Stone, Geoffrey W.
• Format: Journal Article
• Language: English
• Published: England Informa Healthcare 01.08.2012; Taylor & Francis
• Subjects: Acrp30; adiponectin; Animals; Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal - therapeutic use; antibody therapy; Antigen Presentation; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; B cell; B-Lymphocytes - drug effects; B-Lymphocytes - immunology; B-Lymphocytes - transplantation; cancer; CD154; CD40; CD40 Antigens - agonists; CD40 Antigens - immunology; CD40 Ligand - pharmacology; CD40L; Cell Proliferation - drug effects; Clinical Trials as Topic; dendritic cell; FcgammaR; Humans; Immunotherapy - methods; multimer; Neoplasms - immunology; Neoplasms - therapy; protein engineering; receptor; Receptor Aggregation; Signal Transduction; surfactant protein D; T cell; TNFSF5
• ISSN: 0883-0185; 1937-4364; 1563-5244
• DOI: 10.3109/08830185.2012.703272

CD40 stimulation has produced impressive results in early-stage clinical trials of patients with cancer. Further progress will be facilitated by a better understanding of how the CD40 receptor becomes activated and the subsequent functions of CD40-stimulated immune cells. This review focuses on two aspects of this subject. The first is the recent recognition that signaling by CD40 is initiated when the receptors are induced to cluster within the membrane of responding cells. This requirement for CD40 clustering explains the stimulatory effects of certain anti-CD40 antibodies and the activity of many-trimer, but not one-trimer, forms of CD40 ligand (CD40L, CD154). The second topic is the use of these CD40 activators to expand B cells ("CD40-B cells"). As antigen-presenting cells (APCs), CD40-B cells are as effective as dendritic cells, with the important difference that CD40 B cells can be induced to proliferate in vitro, whereas DCs proliferate poorly if at all. As a result, the use of CD40-B cells as antigen-presenting cells (APCs) promises to streamline the generation of anti-tumor CD8+ T cells for the adoptive cell therapy (ACT) of cancer.