Enhancing Cytotoxic T Lymphocytes for Cellular Therapy in Acute Myeloid Leukemia

Project Overview

• Acute myeloid leukemia (AML) patients who experience relapse after allogeneic hematopoietic stem cell transplantation (HSCT) face low survival rates.
• Among the current therapeutic options for relapsed hematological malignancies post-HSCT is donor lymphocyte infusion (DLI), a well-established therapy involving infusion of the original stem cell donor’s peripheral blood lymphocytes into the recipient. The efficacy of DLI is attributed to the graft-versus-leukemia (GvL) effect, where donor immune cells target and destroy residual leukemia cells.
• The precise cellular mechanisms driving GvL efficacy remain elusive, highlighting the need for improved understanding and enhancement of the graft-versus-leukemia (GvL) effect, particularly in AML.
• Dr. Catherine Wu’s team at Dana-Farber to make a significant breakthrough in understanding the cellular dynamics underlying effective GvL responses. They identified a novel population of CD8+ cytotoxic T lymphocytes (CTLs) that are clonally expanded in AML patients who respond to DLI, suggesting their pivotal role in mediating the GvL effect.
• Dana-Farber Cancer Institute is looking for the right partner with an interest in licensing these assets for further development into new therapeutics or vaccines.

Technology

Despite its long-standing use, DLI’s effectiveness varies significantly between AML and chronic myelogenous leukemia (CML), with only 15-20% of AML patients achieving remission, relative to ~75-80% of CML patients.

Recent advancements in single-cell sequencing have enabled Dr. Catherine Wu’s team at Dana-Farber to make a significant breakthrough in understanding the cellular dynamics underlying effective GvL responses. They identified a novel population of CD8+ cytotoxic T lymphocytes (CTLs) that are clonally expanded in AML patients who respond to DLI, suggesting their pivotal role in mediating the GvL effect. The technology involves enriching donor lymphocytes for these specific CTLs through positive and negative selection using cell sorting techniques. These CTLs promote the GvL effect due to their high expression of the activation marker ZNF683, a gene impacting T cell cytotoxicity and activation pathways. Experiments confirmed a two-fold increase in ZNF683 expression in CTLs compared to naive T lymphocytes, indicating a robust GvL response. Moreover, CTLs characterized as CD3+, CD8+, CD62L-, CD45RA+, and CD57+ were more likely to induce a GvL effect in these patients. Overall, Dr. Wu’s work offers a level of granularity not previously achieved, and by leveraging this novel cell population, we can develop next-generation immunotherapies that can improve remission rates and offer new hope for patients with relapsed AML.

Team Members: Catherine J. Wu, MD, Katie Maurer, MD, PhD, Elham Azizi, PhD

Applications

Pre-treatment Enrichment: Use of immunophenotyping to select and enrich CD8+ CTLs before HSCT or DLI.

In vitro Expansion: Culture donor CTLs with patient leukemia cells to expand leukemia-reactive populations.

Vaccination Strategies: Development of vaccines to prime CTLs with leukemia antigens, promoting targeted expansion.

Cell Therapy Products: Development of chimeric antigen receptor (CAR) T cells targeting specific leukemia antigens.

Monoclonal Antibody Therapy: Creation of monoclonal antibodies or small molecule therapeutics to modulate ZNF683 activity and enhance GvL.

Opportunities

Dana-Farber Cancer Institute is looking for the right partner with an interest in licensing these assets for further development into new therapeutics or vaccines.

Team Members

Catherine J. Wu, MD

Chief, Division of Stem Cell Transplantation and Cellular Therapies, Dana-Farber

Professor, Harvard Medical School

Catherine's Bio

Katie Maurer, MD, PhD

Physician-Scientist, Medical Oncology, Dana-Farber

Katie's Bio

Elham Azizi, PhD

Former Postdoctoral Fellow, Memorial Sloan Kettering Cancer Center

Elham's Bio