Antigen-dependent CD28 signaling selectively enhances survival and proliferation in genetically modified activated human primary T lymphocytes

• Published in: The Journal of experimental medicine Vol. 188; no. 4; pp. 619 - 626
• Main Authors: Krause, A, Guo, H F, Latouche, J B, Tan, C, Cheung, N K, Sadelain, M
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 17.08.1998; The Rockefeller University Press
• Subjects: adoptive cell therapy; Animals; Antibodies, Anti-Idiotypic - immunology; Apoptosis; BASIC BIOLOGICAL SCIENCES; CD28 Antigens - genetics; CD28 Antigens - immunology; CD28 Antigens - metabolism; CD3 Complex - immunology; Cell Division; Cell Survival; Cells, Cultured; chimeric receptors; costimulation; ganglioside; Gangliosides - immunology; Gangliosides - pharmacology; gene transfer; Histocompatibility Antigens Class II - immunology; Humans; immunology; Interleukin-2 - biosynthesis; Interleukin-2 - metabolism; Lymphocyte Activation; Mice; Peptides - immunology; Receptors, Interleukin-2 - biosynthesis; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - immunology; research and experimental medicine; Signal Transduction; T-Lymphocytes - immunology
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.188.4.619

Most tumor cells function poorly as antigen-presenting cells in part because they do not express costimulatory molecules. To provide costimulation to T lymphocytes that recognize tumor cells, we constructed a CD28-like receptor specific for GD2, a ganglioside overexpressed on the surface of neuroblastoma, small-cell lung carcinoma, melanoma, and other human tumors. Recognition of GD2 was provided by a single-chain antibody derived from the GD2-specific monoclonal antibody 3G6. We demonstrate that the chimeric receptor 3G6-CD28 provides CD28 signaling upon specific recognition of the GD2 antigen on tumor cells. Human primary T lymphocytes retrovirally transduced with 3G6-CD28 secrete interleukin 2, survive proapoptotic culture conditions, and selectively undergo clonal expansion in the presence of an antiidiotypic antibody specific for 3G6-CD28. Polyclonal CD8(+) lymphocytes expressing 3G6-CD28 are selectively expanded when cultured with cells expressing allogeneic major histocompatibility complex class I together with GD2. Primary T cells given such an antigen-dependent survival advantage should be very useful to augment immune responses against tumor cells.