An "off-the-shelf" CD2 universal CAR-T therapy for T-cell malignancies.
Jingyu Xiang, Jessica M Devenport, Alun J Carter, Karl W Staser, Miriam Y Kim, Julie O' Neal, Julie K Ritchey, Michael P Rettig, Feng Gao, Garrett Rettig, Rolf Turk, Byung Ha Lee, Matthew L Cooper, John F DiPersio
Author Information
Jingyu Xiang: Division of Oncology, Department of Medicine, Washington University in St. Louis, St. Louis, MO, USA. ORCID
Jessica M Devenport: Division of Oncology, Department of Medicine, Washington University in St. Louis, St. Louis, MO, USA.
Alun J Carter: Division of Oncology, Department of Medicine, Washington University in St. Louis, St. Louis, MO, USA.
Karl W Staser: Division of Oncology, Department of Medicine, Washington University in St. Louis, St. Louis, MO, USA.
Miriam Y Kim: Division of Oncology, Department of Medicine, Washington University in St. Louis, St. Louis, MO, USA.
Julie O' Neal: Division of Oncology, Department of Medicine, Washington University in St. Louis, St. Louis, MO, USA. ORCID
Julie K Ritchey: Division of Oncology, Department of Medicine, Washington University in St. Louis, St. Louis, MO, USA.
Michael P Rettig: Division of Oncology, Department of Medicine, Washington University in St. Louis, St. Louis, MO, USA.
Feng Gao: Division of Public Health Sciences, Department of Surgery, Washington University in St. Louis, St. Louis, MO, USA.
Garrett Rettig: Integrated DNA Technologies, Coralville, IA, USA.
Rolf Turk: Integrated DNA Technologies, Coralville, IA, USA. ORCID
Byung Ha Lee: NeoImmuneTech, Inc., Rockville, MD, USA. ORCID
Matthew L Cooper: Division of Oncology, Department of Medicine, Washington University in St. Louis, St. Louis, MO, USA. matthewcooper@wustl.edu. ORCID
John F DiPersio: Division of Oncology, Department of Medicine, Washington University in St. Louis, St. Louis, MO, USA. jdipersi@wustl.edu. ORCID
T-cell malignancies are associated with frequent relapse and high morbidity, which is partly due to the lack of effective or targeted treatment options. To broaden the use of CAR-T cells in pan T-cell malignancies, we developed an allogeneic "universal" CD2-targeting CAR-T cell (UCART2), in which the CD2 antigen is deleted to prevent fratricide, and the T-cell receptor is removed to prevent GvHD. UCART2 demonstrated efficacy against T-ALL and CTCL and prolonged the survival of tumor-engrafted NSG mice in vivo. To evaluate the impact of CD2 on CAR-T function, we generated CD19 CAR-T cells (UCART19) with or without CD2 deletion, single-cell secretome analysis revealed that CD2 deletion in UCART19 reduced frequencies of the effector cytokines (Granzyme-B and IFN-��). We also observed that UCART19��CD2 had reduced anti-tumor efficacy compared to UCART19 in a CD19+NALM6 xenograft model. Of note is that the reduced efficacy resulting from CD2 deletion was reversed when combined with rhIL-7-hyFc, a long-acting recombinant human interleukin-7. Treatment with rhIL-7-hyFc prolonged UCART2 persistence and increased survival in both the tumor re-challenge model and primary patient T-ALL model in vivo. Together, these data suggest that allogeneic fratricide-resistant UCART2, in combination with rhIL-7-hyFc, could be a suitable approach for treating T-cell malignancies.
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