Identification of cell intrinsic properties that are crucial for long term in vivo persistence and function of gene-modified T cells after adoptive transfer into cancer patients

• Applicant: Dr. Daniel Sommermeyer
• Subject Area: Hematology, Oncology
• Term: from 2012 to 2014
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 220384613

Adoptive transfer of antigen-specific effector T cells (TE) into patients is a promising strategy to fight cancer. To broaden the applicability of adoptive T cell therapies, the modification of T cells with genes encoding specific receptors was developed. The feasibility of using modified TE has been confirmed in the first clinical trials. However, clinical success was so far often limited, which is in part due to poor in vivo persistence and function of transferred T cells. Emerging data demonstrate that the ability of T cells to survive and function long term in vivo can be dictated by cell intrinsic properties determined by the phenotypic subset from which the cells are derived. Although TE cells originating from different subsets had similar expression of surface markers and effector functions before transfer, the cells adopted distinct fates in animal models; suggesting that the origin of the cells was decisive. These findings imply that studies to define the molecular pathways that are essential for the survival of transferred TE cells in vivo will be important for the development of more effective immunotherapies for cancer. We will examine gene-modified human TE that will be used in two clinical trials and compare them to T cells that persist after transfer and are re-isolated from the patients. The T cells will be defined by their in vitro function, expression of cell surface markers, mRNA expression profiles, and epigenetic modifications. To facilitate further investigations of T cells with different origins and properties, it is crucial to develop a reliable model system. Thus, we will transfer the human TE used in the clinical trials into immunodeficient mice and determine whether the cells exhibit similar behavior as in the patients. The overall goal of the studies is to define characteristics of T cells that are predictive of cell persistence and function after adoptive T cell transfer.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Stanley Riddell