Identifying highly active anti-CCR4 CAR T cells for the treatment of T-cell lymphoma

Author:

Watanabe Keisuke12,Gomez Angela M.1,Kuramitsu Shunichiro1,Siurala Mikko1,Da Tong1,Agarwal Sangya1ORCID,Song Decheng1,Scholler John1ORCID,Rotolo Antonia3ORCID,Posey Avery D.134ORCID,Rook Alain H.5,Haun Paul L.5,Ruella Marco136,Young Regina M.1,June Carl H.137ORCID

Affiliation:

1. 1Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA

2. 2Division of Cancer Immunology, National Cancer Center Research Institute, Tokyo, Japan

3. 3Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia, PA

4. 4Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA

5. 5Department of Dermatology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA

6. 6Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA

7. 7Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA

Abstract

Abstract A challenge when targeting T-cell lymphoma with chimeric antigen receptor (CAR) T-cell therapy is that target antigens are often shared between T cells and tumor cells, resulting in fratricide between CAR T cells and on-target cytotoxicity on normal T cells. CC chemokine receptor 4 (CCR4) is highly expressed in many mature T-cell malignancies, such as adult T-cell leukemia/lymphoma (ATLL) and cutaneous T-cell lymphoma (CTCL), and has a unique expression profile in normal T cells. CCR4 is predominantly expressed by type-2 and type-17 helper T cells (Th2 and Th17) and regulatory T cells (Treg), but it is rarely expressed by other T helper (Th) subsets and CD8+ cells. Although fratricide in CAR T cells is generally thought to be detrimental to anticancer functions, in this study, we demonstrated that anti-CCR4 CAR T cells specifically depleted Th2 and Tregs, while sparing CD8+ and Th1 T cells. Moreover, fratricide increased the percentage of CAR+ T cells in the final product. CCR4-CAR T cells were characterized by high transduction efficiency, robust T-cell expansion, and rapid fratricidal depletion of CCR4-positive T cells during CAR transduction and expansion. Furthermore, mogamulizumab-based CCR4-CAR T cells induced superior antitumor efficacy and long-term remission in mice engrafted with human T-cell lymphoma cells. In summary, CCR4–depleted anti-CCR4 CAR T cells are enriched in Th1 and CD8+ T cells and exhibit high antitumor efficacy against CCR4–expressing T-cell malignancies.

Publisher

American Society of Hematology

Subject

Hematology

Reference67 articles.

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