CAR-Based Approaches to Cutaneous T-Cell Lymphoma
Conclusions
The major challenges in the development of adoptive cell therapy for T cell tumors, as mentioned above, remain fratricide, T cell aplasia and the potential for leukemic transduction or poor T cell function if used in the autologous setting. Approaches to overcome fratricide include the genetic modification and deletion of the T cell antigen in the case of long-term CAR-T cell persistence or regulated CAR-T expression. To ensure restoration of T cell immunity, transient CAR expression can be achieved incorporation of a CAR suicide gene, transient CAR expression using mRNA electroporation, or short-lived NK cell lines. Finally, given that these toxicities may be tolerable initially, CAR-T cells followed by an ablative hematopoietic stem cell transplant may allow for hematologic rescue following CAR-T mediated disease clearance. As most of the models to date have utilized normal donor human T cells for CAR manufacturing, we must also consider the underlying fitness of the starting cell product. Peripheral T-cells from patients with underlying T cell malignancy routinely demonstrate impairments in T cell function as well as reduced quantities in peripheral blood, given the extensive prior treatment burden and immune-dysregulation. Approaches utilizing allogeneic donors and gene-editing techniques to remove the endogenous TCR, or CAR products generated from autologous or allogeneic NK cells may offer creative solutions. These include the potential for multiple allogen...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
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