AI Article Synopsis
- Genetically targeted T cells could improve the effectiveness of adoptive T-cell therapy for various cancers by focusing on the CD44 adhesive receptor, which is involved in tumor growth and is widely expressed in different tumor types.
- In experiments, silencing the CD44v6 variant prevented the growth of acute myeloid leukemia and multiple myeloma cells in mice, while T cells designed to target CD44v6 showed strong anti-tumor effects without harming normal stem cells.
- The research emphasizes the potential for clinical use of these modified T cells, especially when combined with a suicide gene to eliminate them if necessary, reducing risks associated with aggressive immune responses.
Article Abstract
Genetically targeted T cells promise to solve the feasibility and efficacy hurdles of adoptive T-cell therapy for cancer. Selecting a target expressed in multiple-tumor types and that is required for tumor growth would widen disease indications and prevent immune escape caused by the emergence of antigen-loss variants. The adhesive receptor CD44 is broadly expressed in hematologic and epithelial tumors, where it contributes to the cancer stem/initiating phenotype. In this study, silencing of its isoform variant 6 (CD44v6) prevented engraftment of human acute myeloid leukemia (AML) and multiple myeloma (MM) cells in immunocompromised mice. Accordingly, T cells targeted to CD44v6 by means of a chimeric antigen receptor containing a CD28 signaling domain mediated potent antitumor effects against primary AML and MM while sparing normal hematopoietic stem cells and CD44v6-expressing keratinocytes. Importantly, in vitro activation with CD3/CD28 beads and interleukin (IL)-7/IL-15 was required for antitumor efficacy in vivo. Finally, coexpressing a suicide gene enabled fast and efficient pharmacologic ablation of CD44v6-targeted T cells and complete rescue from hyperacute xenogeneic graft-versus-host disease modeling early and generalized toxicity. These results warrant the clinical investigation of suicidal CD44v6-targeted T cells in AML and MM.
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| http://dx.doi.org/10.1182/blood-2013-04-493361 | DOI Listing |
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