Our laboratory's research is focused on the following two major areas:

1) Developing novel adoptive T cell therapy for the treatment of leukemia and lung cancer.

Human CD3+CD4-CD8-CD56- T cells, termed double negative (DN) T cells, compose a small population of peripheral T cells, and their function remains largely unclear. Recently, we have developed a novel protocol by which therapeutic quality and quantity of human DN T cells can be obtained from peripheral blood of healthy donors by ex vivo expansion. More importantly, we have demonstrated that these ex vivo propagated human DN T cells have potent anti-tumour function both in vitro and in patient-derived xenograft models. DN T cells effectively target lung cancer and primary leukemic cells, including those that are resistant to chemotherapy while spare normal blood and bone marrow cells. Unlike conventional T cells, infusion of DN T cells does not cause tissue damage or graft-versus-host disease, supporting the safety of clinical use of DN T cells.  Based on these findings, a phase I clinical trial using DN T cells to treat patients with acute myeloid leukemia and are at high risk of disease recurrence has been proved by Health Canada. As cryopreserved DN T cells from one healthy donor can target leukemic cells obtained from different patients in a non-HLA-restricted manner, it is possible to develop DN T cells as “off-the-shelf” living drugs. We are currently investigating the mechanisms by which these DN T cells selectively recognize and kill cancer cells but not normal cells and tissues, and exploring the possibility of using DN T cells either alone or in combination with other therapies to eliminate cancer cells and prevent disease recurrence.

2) Dissecting cellular and molecular mechanisms involved in immunity and tolerance and their relevance in diseases.

The ability to induce unresponsiveness to our own tissue and transplanted organ grafts while retaining immune responses towards viruses and malignant cells has been a dream of immunologists and clinicians for many years. To achieve this goal requires understanding the cellular and molecular mechanisms that control and regulate immune responses. Another research focus of our laboratory is to understand the cellular and molecular mechanisms governing tolerance and immunity and to translate obtained knowledge into novel therapies for immune related diseases. We study the mechanisms by which regulatory T cells, particularly NK-CD3+ CD4 and CD8 double negative (DN Tregs) control immune responses and prevent graft-vs-host disease and transplant rejection.

Study Status: completed

Institute: Toronto General Hospital Research Institute

Study Purpose: Develop a new cell therapy platform for treating diseases.

Background: DNT cells are a rare subset of mature T cells existing in rodents and humans. Extensive preclinical studies have demonstrated that both allogenic mouse and human DNT cells are able to target various cancer cells without observed side effects.

Study Methods: Zhang lab has developed a method to propagate these cells in the laboratory and studied them in animal models and used them to treat patients with blood cancers in clinical trials.

Key Findings: Both preclinical studies and clinical trials showed that double negative T cells are very safe and showed the potential efficacy in treating patients with leukemia. Further clinical trials are needed to determine the effectiveness of DNT cells in treating cancers and autoimmune diseases. If the efficacy is confirmed, DNT cells can be used as a new type of living drug to treat patients with unmet medical needs.

Health Conditions: Cancer, Transplant Program

For a list of Dr. Zhang's publications, please visit PubMed or <a href="https://www.scopus.com/authid/detail.uri?authorId=45861740000

• Inaugural Maria H. Bacardi Chair in Transplantation
• Research Director, University of Toronto Transplantation Institute
• Professor, Department of Laboratory Medicine & Pathobiology, University of Toronto
• Professor, Department of Immunology, University of Toronto
• Professor, Institute of Medical Sciences, Faculty of Medicine, University of Toronto