Allogeneic Double Negative T cell Therapy as a Novel Treatment for AML Patients

Allogeneic bone marrow transplantation (allo-BMT) is a potentially curative treatment for high-risk leukemia patients. However, a high disease relapse rate caused by residual disease and an associated toxicity such as graft-vs.-host disease (GvHD) remain as major issues that hamper recipients' survival. Many forms of immunosuppressants to control GvHD increase the risk of disease relapse, and therefore, there is an unmet need for a treatment that can target chemotherapy-resistant blasts with low off-tumor toxicity. Approaches to prevent GvHD while maintaining or enhancing graft-versus-leukemia (GvL) are the ‘Holy Grail’ for allo-BMT patients. CD3+ CD4- CD8- double negative T cell (DNT) is an unconventional mature T cell subset found in periphery. In this thesis, I have developed a method to expand therapeutically-relevant numbers of clinical-grade DNTs obtained from healthy donors (HDs) and extensively characterized them. I demonstrated that ex vivo expanded HD-DNTs target an array of leukemic cell lines and primary AML cells including chemotherapy-resistant patient samples in vitro and significantly reduce the leukemia load in patient-derived xenograft (PDX) models. Unlike CD4+ and CD8+ conventional T (Tconv) cells, DNTs do not attack normal allogeneic cells and normal xenogeneic tissues in vitro and in xenograft models. Further, potentials of using allogeneic DNTs as an off-the-shelf adoptive cell therapy have been demonstrated herein, including resistance to host-versus-graft (HvG) rejection and lack of GvHD-inducing activities. Interestingly, allogeneic DNTs effectively suppressed proliferation of Tconv cells and prevented priming of CD8+ T cells against allogeneic antigens, and infusion of DNTs with human peripheral blood mononuclear cells (PBMCs) into mice suppressed xenogeneic GvHD caused by Tconv cells. Notably, co-infusion of DNTs and PBMC into leukemia-bearing recipient eradicated the disease while suppressing tissue damage caused by Tconv cells. Collectively, in this thesis, I have developed a novel form of a cellular therapy for leukemia patients that has potentials to be used as an off-the-shelf treatment as a monotherapy or as a follow-up therapy to allo-BMT.

Department dc:contributor.department

Immunology

Year dc:date.issued

2019

Author dc:creator

• Lee, Jong Bok

Advisor dc:contributor.advisor

• Zhang, Li

• acute myeloid leukemia
• adoptive T cell therapy
• Double negative T cell
• T cell

Handle dc:identifier.uri

http://hdl.handle.net/1807/107960

OAI identifier oai:identifier

oai:utoronto.scholaris.ca:1807/107960