Paper Reading
01
T cell receptor gene therapy targeting WT1 prevents acute myeloid leukemia relapse post-transplant
Aude G.Chapuis, Daniel N. Egan, Merav Bar, … Ted A. Gooley and PhilipD. Greenberg et al.
Nature Medicine
Here these authors designed a TCR gene therapy to prevent acute myeloid leukemia relapse. Previously, the major concern in acute myeloid leukemia (AML) is disease relapse after allogeneic hematopoietic cell transplantation (HCT). During the relapse, donor T cells always fail to react with antigens on leukemic cells, reflecting compromised graft-versus-leukemia effects. In some other conditions, graft T cells, which are not suitable for leukemia specificity, frequently recognize proteins expressed by normal host tissues. Therefore, graft-versus-leukemia effects are often accompanied by graft-versus-host disease. To solve these problems, they designed the TCR gene therapy using T cells expressing receptors (TCRs) that target selected AMLantigens. In detail, they isolated the Wilms’ Tumor Antigen 1-specific TCR(TCRC4) from HLA-A2+ normal healthy donor, further inserted TCRC4 into Epstein–Bar virus-specific donor CD8+ T cells (TTCR-C4) to minimize graft-versus-host disease risk and enhance transferred T cell survival. These engineered cells were infused prophylactically post-HCT into 12 patients. And they observed 100%relapse-free survival at a median of 44 months following infusion, while a concurrent comparative group of 88 patients with similar risk AML had 54%relapse-free survival. TTCR-C4 maintained TCRC4 expression, persisted long-term in patients. Therefore, this strategy helps to prevent AML recurrence after HCT.
https://doi.org/10.1038/s41591-019-0472-9
02
Systematic Immunotherapy TargetDiscovery Using Genome-Scale In Vivo CRISPR Screens in CD8 T Cells
Matthew B.Dong, Guangchuan Wang, Ryan D. Chow,…Roy S. Herbst, and Sidi Chen et al.
Cell 2019
As previously reported, CD8 T cells critically exert anti-tumor immune responses. However, systematic immunotherapy target discovery using genome-scale in vivo CRISPR screens in CD8 T cells remains uncommon. Here, these authors designed genome-scale screens of potential regulators of tumor infiltration and degranulation in CD8 T cells, in a cancer immunotherapy model. Inconsistent with previous findings, they confirmed critical roles of immune checkpoint genes, including PD-1 and Tim-3, in CD8 T cells. Moreover, they identified novel regulator, the RNA helicase Dhx37, which regulates the infiltration and degranulation of CD8 T cells. Using gene knockout assays, they further revealed that Dhx37 knockout CD8 T cells have enhanced the efficacy of antigen-specificity against triple-negative breast cancer in vivo. Additionally, DHX37 suppresses effector functions, cytokine production, and T cell activation, by modulating NF-kB signaling pathway. Together, these data designed high-throughput in vivo genetic screens for immunotherapy targets and identified DHX37 as a critical regulator of CD8 T cell function.
https://doi.org/10.1016/j.cell.2019.07.044
END
联系客服
