Abstract
Peripheral T-cell lymphomas (PTCLS) comprise a diverse group of difficult to treat, very aggressive non-Hodgkin's lymphomas (NHLS) with poor prognoses and dismal patient outlook. Despite the fact that PTCLs comprise the majority of T-cell malignancies, the standard of care is poorly established. Chimeric antigen receptor (CAR) immunotherapy has shown in B-cell malignancies to be an effective curative option and this extends promise into treating T-cell malignancies. Because PTCLS frequently develop from mature T-cells, CD3 is similarly strongly and uniformly expressed in many PTCL malignancies, with expression specific to the hematological compartment thus making it an attractive target for CAR design. We engineered a robust 3rd generation anti-CD3 CAR construct (CD3CAR) into an NK cell line (NK-92). We found that CD3CAR NK-92 cells specifically and potently lysed diverse CD3+ human PTCL primary samples as well as T-cell leukemia cells lines ex vivo. Furthermore, CD3CAR NK-92 cells effectively controlled and suppressed Jurkat tumor cell growth in vivo and significantly prolonged survival. In this study, we present the CAR directed targeting of a novel target - CD3 using CAR modified NK-92 cells with an emphasis on efficacy, specificity, and potential for new therapeutic approaches that could improve the current standard of care for PTCLs.
Highlights
Peripheral T-cell lymphomas (PTCLs) comprise a diverse subset of aggressive, difficult-to-treat hematological malignancies that are derived from mature T-cells [1]
A strong spleen focus forming virus promoter (SFFV) and a CD8 leader sequence were used for efficient expression of the CD3CAR molecule on the Natural killer (NK)-92 cell surface
Current efforts have focused on Chimeric antigen receptor (CAR) T-cells that have been effective in addressing various B-cell malignancies using CD19CAR therapy, and such efforts have been validated in clinical trials to significant curative effect [2, 3]
Summary
Peripheral T-cell lymphomas (PTCLs) comprise a diverse subset of aggressive, difficult-to-treat hematological malignancies that are derived from mature T-cells [1]. While the ideal extracellular target protein for CAR therapy is a surface antigen found on 100% of tumor cells at similar robust intensity, real world leukemia and lymphoma scenarios frequently exhibit less than ideal population homogeneity. We hypothesize that CAR therapy directed against CD3 can be used in order to support the current standard of care as a “bridge to transplant” for patients with severe, relapsing or refractory disease. It can serve as a stand-alone therapy for patients with PTCLs with supportive therapy during reversible T-cell depletion and subsequent infusion [6]. Because normal T cells express CD3, anti-CD3 CAR therapy precludes the use of traditional CAR-modified T-cells
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