3 min readTeam Develops New Universal Platform for Cancer Immunotherapy
Philadelphia, PA – Researchers from the Perelman School of Medicine at the University of Pennsylvania report this month in Cancer Research a universal approach to personalized cancer therapy based on T cells. It is the first time a system for making an adaptable, engineered T-cell to attack specific tumour types has been proposed, depending on which abnormal proteins, called antigens, are expressed by individual patients’ tumour cells.
For now, the system is being refined in experiments using healthy donor T cells and animal models of human cancer, with the aim to introduce the personalized cells into patients in the future, explains senior author Dr. Daniel J. Powell Jr., a research assistant professor of Pathology and Laboratory Medicine with Penn’s Ovarian Cancer Research Center.
Tumour antigens are potential targets of an immune response, and identifying which antigens a patient’s tumour cells express would be helpful in designing cancer therapy for that individual. Any mutated protein produced in a tumour cell can act as a tumour antigen. Many tumour cells have surface proteins that are inappropriately expressed for the cell type, or are only normally present during embryonic development. Still other tumour cells display cell surface proteins that are rare or absent on the surfaces of healthy cells and are responsible for activating molecular pathways that cause uncontrolled replication of cells. In most cancers, not all patients have tumour cells that express the exact same antigen, and sometimes tumour cells from a single patient can express different antigens. Because of this complexity, it is important to properly choose which antigen to target with cancer therapy.
T cells engineered to express an engineered antigen, called a chimeric antigen receptor (CAR), offer an attractive strategy for targeting antigens and treating cancer, says Powell. CARs are engineered receptors that graft, for example, the portion of a tumour-specific antibody onto an immune cell. This allows the patients’ T cells to recognize tumour antigens and kill their tumour cells.
For therapy, a large number of tumour-specific, cancer-fighting CAR T cells can be generated in a specialized lab using patients’ own T cells, which are then infused back into them. This approach has shown promising results in patients whose tumours all express the same antigen.
Despite these encouraging findings, currently made CARs have a fixed antigen specificity, which means only one type of tumour antigen can be targeted at a time. Tumour cells that lack that selected antigen can then escape recognition by immune cells and replicate, limiting what might otherwise have been an effective therapy if multiple tumour antigens had been targeted. For this reason, the team sought to make a more generalized receptor framework that is able to produce T cells capable of targeting large panels of known tumour antigens.
To that end, the team developed a new platform from which they could eventually target a variety of tumor antigens, either simultaneously or sequentially. So far, they have engineered T cells against the antigens mesothelin, present on several tumor cell types; epCAM, present on epithelial cell cancers; alpha folate, present on ovarian cancer cells; and, more recently, CD19 on lymphoma cells.
The universal immune receptor recognizes molecules attached to tumour antigens on the surface of tumour cells. When this happens, the T cells produce inflammatory response proteins called cytokines and pore-forming proteins. Those proteins cause the release of enzymes through those pores into tumour cells, thereby killing them.
The new engineered T cells described in the Cancer Research paper recognize and bind exclusively to cancer cells pre-targeted with biotin-labelled molecules, such as antibodies. Biotin is a B complex vitamin necessary for cell growth that can be bound by a molecule called avidin, which is contained in the universal immune receptor. Since nearly any molecule can be biotin labelled, the number of antigens that can be targeted by T cells carrying the biotin-binding immune receptor is nearly infinite. The versatility afforded by this biotin-binding receptor permitted the targeting of a combination of distinct antigens all at once, and even one after another, notes Powell.
The findings demonstrate that a universal T cell can significantly extend conventional CAR approaches, allowing the team to generate T cells of unlimited antigen specificity. This process is geared to make T cell therapy more available to patients and to improve the effectiveness of T-cell immunotherapies for cancer.
First author post-doctoral fellow Dr. Katarzyna Urbanska continues optimization of the universal receptor approach by looking for different ways to improve the interaction of T cells with tumour cells, and how to better direct the T cells and the biotin-labelled molecules to tumour cells in the body.
In the future, Powell and colleagues predict a highly personalized platform for cancer therapy that begins when patient tumors are analyzed for their expression of specific antigens at the Department Pathology and Laboratory Medicine’s new Center for Personalized Diagnostics. When the antigens expressed by a patient’s tumour cells are determined, their T cells will be engineered to express the universal immune receptor, which will be given back to them in combination with biotin-labelled molecules to attach to patients’ tumour antigens for an individualized tumour attack.