Description

Adoptive T Cell Therapy with TCR-Engineered T Cells

Philip D. Greenberg, Kristin G. Anderson, Dan Egan, Sunil R. Hingorani, Shannon K. Oda, Rachel Perret, Leah Schmidt, Tom M. Schmitt, Ingunn M. Stromnes, and Aude G. Chapuis

Fred Hutchinson Cancer Research Center and University of Washington, Seattle, WA, USA

We have been exploring in preclinical models and clinical trials methods to reproducibly provide therapeutic T cell responses by transfer of genetically engineered T cells. Our search for targets in human Acute Myelogenous Leukemia (AML) revealed that WT1, a gene associated with promoting leukemic transformation, is over-expressed in human leukemic stem cells. Extensive screening of normal human repertoires permitted identification of a high affinity TCR specific for WT1 that could reproducibly produce after transduction into CD8 cells high avidity T cells that recognized leukemic cells. Preclinical studies performed in a mouse model demonstrated that CD8 T cells expressing a high affinity TCR specific for this oncogene can be safely administered, with no toxicity to normal tissues known to express low but detectable levels of WT1. We have advanced this approach targeting WT1 to clinical trials, including leukemia patients at high risk of relapse after hematopoietic cell transplant (HCT). Preliminary results of this trial have provided evidence that such T cells can prevent leukemic relapse and sustain long-term remissions. This therapy is being pursued in AML patients who are not HCT candidates. We have also initiated trials with this TCR for treatment of patients with non-small cell lung cancer (NSCLC) or mesothelioma, as WT1 is commonly over-expressed in these as well as many other malignancies.

Unfortunately, providing a high avidity T cell response does not necessarily result in tumor eradication, as substantive obstacles can preclude even a T cell expressing a high affinity TCR from being effective. We are using genetically engineered mouse models to elucidate the cellular and molecular pathways that need to be modulated to achieve meaningful therapeutic benefit in a variety of hematologic and solid tumor settings, including pancreatic and ovarian cancer. Genetic engineering employing synthetic biology technologies is providing means to overcome these obstacles, such as by converting inhibitory pathways that can facilitate tumor evasion and promote T cell exhaustion into activating pathways.