Sauer et al. demonstrated that in patients, CD70 is highly expressed in AML, but not in normal bone marrow. They then designed a panel of CD70scFv-based CAR T cells with different spacers (IM, LF) and costimulatory molecules (CD27, CD28, and 4-1BB) and one CD27 (the CD70 ligand)-based CAR. IM-based CAR T cells resulted in decreased T cell viability and terminal differentiation. scFV-LF-28z and CD27z CAR T cells showed significant T cell expansion and antitumor activity in two different AML xenograft models and against primary AML blast cells. CD70-CAR T cells recognized activated virus-specific T cells, but did not impair normal hematopoiesis.
Contributed by Shishir Pant
ABSTRACT: The prognosis of patients with acute myeloid leukemia (AML) remains dismal, highlighting the need for novel innovative treatment strategies. The application of chimeric antigen receptor (CAR) T-cell therapy to patients with AML has been limited, in particular by the lack of a tumor-specific target antigen. CD70 is a promising antigen to target AML, as it is expressed on most leukemic blasts, whereas little or no expression is detectable in normal bone marrow samples. To target CD70 on AML cells, we generated a panel of CD70-CAR T cells that contained a common single-chain variable fragment (scFv) for antigen detection, but differed in size and flexibility of the extracellular spacer and in the transmembrane and the costimulatory domains. These CD70scFv CAR T cells were compared with a CAR construct that contained human CD27, the ligand of CD70 fused to the CD3_ chain (CD27z). The structural composition of the CAR strongly influenced expression levels, viability, expansion, and cytotoxic capacities of CD70scFv-based CAR T cells, but CD27z-CAR T cells demonstrated superior proliferation and antitumor activity in vitro and in vivo, compared with all CD70scFv-CAR T cells. Although CD70-CAR T cells recognized activated virus-specific T cells (VSTs) that expressed CD70, they did not prevent colony formation by normal hematopoietic stem cells. Thus, CD70-targeted immunotherapy is a promising new treatment strategy for patients with CD70-positive AML that does not affect normal hematopoiesis but will require monitoring of virus-specific T-cell responses.
Author Info: (1) Center for Cell and Gene Therapy, Baylor College of Medicine, Houston Methodist Hospital-Texas Children's Hospital, Houston, TX. Department of Internal Medicine V, Heidelberg U
Author Info: (1) Center for Cell and Gene Therapy, Baylor College of Medicine, Houston Methodist Hospital-Texas Children's Hospital, Houston, TX. Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany. (2) Center for Cell and Gene Therapy, Baylor College of Medicine, Houston Methodist Hospital-Texas Children's Hospital, Houston, TX. (3) Center for Cell and Gene Therapy, Baylor College of Medicine, Houston Methodist Hospital-Texas Children's Hospital, Houston, TX. (4) Center for Cell and Gene Therapy, Baylor College of Medicine, Houston Methodist Hospital-Texas Children's Hospital, Houston, TX. (5) Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany. (6) Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany. (7) Department of Internal Medicine A, University Hospital of Muenster, Muenster, Germany; and. (8) Department of Internal Medicine A, University Hospital of Muenster, Muenster, Germany; and. (9) Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany. (10) Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany. (11) Department of Bone Marrow Transplantation and Cellular Therapy, St Jude Children's Research Hospital, Memphis, TN. (12) Center for Cell and Gene Therapy, Baylor College of Medicine, Houston Methodist Hospital-Texas Children's Hospital, Houston, TX.
