Normal cells that have transformed into cancer cells produce and display large amounts of proteins called tumor- and leukemia-associated antigens (TAA). Although immune cells recognize TAAs it has been difficult to develop immunotherapies for humans based on these interactions, in part because many normal cells and tissues produce small amounts of TAAs and the body has a certain amount of self-tolerance that prevents a vigorous immune attack.
Dr. Matthias Theobald from Johannes Gutenburg-University in Mainz, Germany, and colleagues used sophisticated genetic techniques to circumvent this self-tolerance and essentially redirect key human immune cells. Specifically, the researchers focused on the p53 tumor suppressor protein that is mutated in the majority of human cancers. Immune self-tolerance to p53 exists because of low levels of wild-type p53 that are expressed by normal cells.
The researchers used special mice genetically engineered that lack the normal action of CD8 cells required for development of self-tolerance to generate an immune cell receptor (TCR) specific for tumor-associated p53. The gene for this receptor was then transferred to human immune cells and resulted in redirected CD4+ Th and CTL immune cells that aggressively attacked tumor cells.
According to Dr. Theobald, "Our study on the intentional redirection of human CD4+ Th cells and high-avidity CD8 CTL by the delivery of genes encoding a single CD8-independent, high-affinity p53A2.1-specific TCR lays the foundation for the exploitation of this approach for a novel, broad-spectrum immunotherapy of malignant disease."
Jürgen Kuball, Frank W. Schmitz, Ralf-Holger Voss, Edite Antunes Ferreira, Renate Engel, Philippe Guillaume, Susanne Strand, Pedro Romero, Christoph Huber, Linda A. Sherman, and Matthias Theobald: "Cooperation of Human Tumor-Reactive CD4+ and CD8+ T Cells after Redirection of Their Specificity by a High-Affinity p53A2.1-Specific TCR"
The other members of the research team include Jürgen Kuball, Ralf-Holger Voss, Edite Antunes Ferreira, Renate Engel, Christoph Huber, and Susanne Strand of Johannes Gutenberg University in Mainz, Germany; Frank W. Schmitz of Johannes Gutenberg University, presently at the Technical University of Munich; Philippe Guillaume of the Ludwig Institute for Cancer Research in Epalinges, Switzerland; Pedro Romero of the Ludwig Institute for Cancer Research in Lausanne, Switzerland; and Linda A. Sherman of The Scripps Research Institute in La Jolla, California. This work was supported in part by grants from the Deutsche Forschungsgemeinschaft, the Laupitz Foundation, the MAIFOR program, the 6th Framework Programme of the European Commission (on mutant p53 as a target for improved cancer treatment) M.T. is a José Carreras Leukemia Foundation Professor. Ely Lilly provided LY498919.
Publishing in Immunity, Volume 22, Number 1, January 2005, pages 117–129. www.immunity.com
Journal
Immunity