Abstract
Peripheral T-cell lymphomas (PTCLs) are a group of very aggressive non-Hodgkin's lymphomas (NHLs) with poor prognoses and account for a majority of T-cell malignancies. Overall, the standard of care for patients with T-cell malignancies is poorly established, and there is an urgent clinical need for a new approach. As demonstrated in B-cell malignancies, chimeric antigen receptor (CAR) immunotherapy provides great hope as a curative treatment regimen. Because PTCLs develop from mature T-cells, these NHLs are commonly CD4+, and CD4 is highly and uniformly expressed. Therefore, CD4 is an ideal target for PTCL CAR immunotherapy. To that effect, we created a robust third-generation anti-CD4 CAR construct (CD4CAR) and introduced it into clonal NK cells (NK-92). CD4CAR NK-92 cells specifically and robustly eliminated diverse CD4+ human T-cell leukemia and lymphoma cell lines (KARPAS-299, CCRF-CEM, and HL60) and patient samples ex vivo. Furthermore, CD4CAR NK-92 cells effectively targeted KARPAS-299 cells in vivo that modeled difficult-to-access lymphoma nodules, significantly prolonging survival. In our study, we present novel targeting of CD4 using CAR-modified NK cells, and demonstrate efficacy. Combined, our data support CD4CAR NK cell immunotherapy as a potential new avenue for the treatment of PTCLs and CD4+ T-cell malignancies.
Highlights
Peripheral T-cell Lymphomas (PTCLs) are typically aggressive lymphomas that develop from mature T cells [1]
We found that CD4-specific CAR (CD4CAR) Natural killer (NK)-92 cells exhibit robust anti-tumor cytotoxicity ex vivo against both adult and pediatric CD4+ lymphoma/leukemia cell lines, CD4+ T-cells isolated from umbilical cord blood, as well as against untreatable primary CD4+ T-cell malignancies from adult and pediatric patients
The single-chain variable fragment nucleotide sequence of the anti-CD4 molecule was derived from the humanized monoclonal antibody ibalizumab (Hu5A8 or TNX-355)− a well-studied and characterized mAb with well-defined and avid binding capability previously used in clinical trials for HIV [42, 43]
Summary
Peripheral T-cell Lymphomas (PTCLs) are typically aggressive lymphomas that develop from mature T cells [1]. Most T-cell malignancies are PTCLs, which account overall for 10–15% of all non-Hodgkin lymphomas (NHLs). Compared to B-cell NHLs, PTCLs are more difficult to treat, have poorer outcomes and lower median survival [1,2,3,4]. Chimeric antigen receptor (CAR) therapy is a promising strategy for the treatment of PTCLs. To date, most chimeric antigen receptor (CAR) hematological immunotherapy has been directed against B-cell malignancies, with many instances of complete response, reports of CAR targeting T-cell malignancies are increasing [7,8,9,10,11,12]
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