NEW YORK (Reuters Health) - Researchers believe they’ve found a way to circumvent self-tolerance to p53 tumor-associated antigens, laying the groundwork for novel, broad-spectrum cancer immunotherapeutics, they report in the January issue of the journal Immunity.
“Efficient immune attack of malignant disease requires the concerted action of both CD8+ cytotoxic T lymphocytes (CTL) and CD4+ Th cells,” Dr. Matthias Theobald from Johannes Gutenburg-University in Mainz, Germany, along with Swiss and American colleagues, explain in the paper.
The p53 tumor suppressor gene is mutated in most cancers. However, many normal cells express low levels of wild-type p53, preventing a vigorous CD8+ and CD4+ T cell attack on mutated p53.
To try to circumvent this self-tolerance, the scientists used human leukocyte antigen (HLA)-A*0201 (A2.1) transgenic mice to generate a high-affinity, CD8-independent T cell receptor (TCR) specific for tumor-associated p53.
They report that retroviral expression of the gene for this receptor into human T cells “imparted the CD8+ T lymphocytes with broad tumor-specific CTL activity and turned CD4+ T cells into potent tumor-reactive, p53A2.1-specific Th cells.”
Both T cell subsets were “cooperative and interacted synergistically” with dendritic cells and tumor targets, they also report.
“So here we have a T cell receptor, generated by circumventing self-tolerance, that is specific for an almost universal human tumor-associated antigen, that is able to functionally reprogramme human CD8+ T cells and, simultaneously, to reprogramme CD4+ T cells too,” Dr. Theobald told Reuters Health.
“This work is an important contribution to the field of T cell receptor-based gene therapy,” he added.
Trials with this new type of immunotherapy could begin in humans within two years, Dr. Theobald predicted. Those initial studies are likely to involve patients with a subtype of acute myeloid leukemia, which is known to overexpress p53 and does not respond well to standard therapies.
Source: Immunity 2005;22:117-129. [ Google search on this article ]
MeSH Headings:Behavioral Sciences: Communicable Disease Control: Community Psychiatry: Behavioral Disciplines and Activities: DNA-Binding Proteins: Environment and Public Health: Genetic Engineering: Genetic Techniques: Health: Health Occupations: Immunization: Immunologic Techniques: Medicine: Investigative Techniques: Nuclear Proteins: Phosphoproteins: Population Characteristics: Preventive Medicine: Preventive Psychiatry: Primary Prevention: Psychiatry: Public Health: Specialties, Medical: Public Health Practice: Protein p53: T-Lymphocyte Subsets: Immunotherapy, Active: CD8-Positive T-Lymphocytes: Analytical, Diagnostic and Therapeutic Techniques and Equipment: Biological Sciences: Health Care: Psychiatry and PsychologyCopyright © 2002 Reuters Limited. All rights reserved. Republication or redistribution of Reuters content, including by framing or similar means, is expressly prohibited without the prior written consent of Reuters. Reuters shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Reuters and the Reuters sphere logo are registered trademarks and trademarks of the Reuters group of companies around the world.
