Tras varios días cacharreando con la tabla del artículo de Schaker y Seimetz, y la propia información de ClinicalTrials.gov, comparto la observación de que PD-1 y CCR-5 son los objetivos más deseados en los CT de edición génica.
Nueve CT´S tienen por objetivo el gen PD-1.
| NCT Number | Title |
| NCT03747965 | Study of PD-1 Gene-knocked Out Mesothelin-directed CAR-T Cells With the Conditioning of PC in Mesothelin Positive Multiple Solid Tumors |
| NCT03399448 | NY-ESO-1-redirected CRISPR (TCRendo and PD1) Edited T Cells (NYCE T Cells) |
| NCT03081715 | PD-1 Knockout Engineered T Cells for Advanced Esophageal Cancer |
| NCT02793856 | PD-1 Knockout Engineered T Cells for Metastatic Non-small Cell Lung Cancer |
| NCT02863913 | PD-1 Knockout Engineered T Cells for Muscle-invasive Bladder Cancer |
| NCT02867332 | PD-1 Knockout Engineered T Cells for Metastatic Renal Cell Carcinoma. |
| NCT02867345 | PD-1 Knockout Engineered T Cells for Castration Resistant Prostate Cancer |
| NCT03044743 | PD-1 Knockout EBV-CTLs for Advanced Stage Epstein-Barr Virus (EBV) Associated Malignancies |
| NCT03545815 | Study of CRISPR-Cas9 Mediated PD-1 and TCR Gene-knocked Out Mesothelin-directed CAR-T Cells in Patients With Mesothelin Positive Multiple Solid Tumors. |
No obstante, los NCT02863913, NCT02867332, NCT02867345 han sido retirados
La causa, entiendo que es, la importantísima función de autoregulación inmunitaria que queda reflejada en sus múltiples ubicaciones y funciones. (The PD1:PD-L1/2 Pathway from Discovery to Clinical Implementation):
Programed cell death 1 is expressed on activated CD4 and CD8 T cells, B cells, monocytes, natural killer (NK) cells, and dendritic cells (DCs) (23, 35, 36). PD-1 expression can also be induced on APCs, myeloid CD11c+ DCs, and monocytes (37, 38). ---
PD-1 expression is also upregulated and sustained on “exhausted” virus-specific T cells during chronic viral infection preventing their proliferation and function in clearing the virus (46, 47).
Respecto de los ligandos:
PD-Ls have distinct expression patterns:
- PD-L1 is constitutively expressed on T and B cells, DCs, macrophages, mesenchymal stem cells and bone marrow-derived mast cells (35). In addition, PD-L1 is expressed on a wide variety of non-hematopoietic cells including lung, vascular endothelium, fibroblastic reticular cells, liver non-parenchymal cells, mesenchymal stem cells, pancreatic islets, astrocytes, neurons, and keratinocytes (36). It has also been shown to be expressed on placental syncytiotrophoblasts and functions in the placenta to induce fetal–maternal tolerance (48, 49). PD-L1 is expressed constitutively in the cornea and retinal pigmented epithelium (RPE) and PD-1–PD-L1 interaction protects the eye from activated T cells (50–53).
- In contrast, PD-L2 expression is restricted to activated DCs, macrophages, bone marrow derived mast cells, and more than 50% of peritoneal B1 cells (54). In the thymus, PD-L1 is expressed mostly in the cortex, while PD-L2 expression is confined in medullary stromal cells (55, 56). PD-L1 expression on human T cells are induced by common γ chain cytokines IL-2, IL-7, and IL-15, whereas IL-21 can stimulate PD-L1 expression on B (CD19+) cells from peripheral blood mononuclear cells (PBMCs). LPS or BCR activation also result in induction of PD-L1 and PD-L2 in human B cells (14, 15, 28). ---
En ct.gov solo veo la información sobre el medio de "Delivery" de las herramientas a las células a modificar en el NCT03399448: "NY-ESO-1 redirected autologous T cells with CRISPR edited endogenous TCR and PD-1 Autologous T cells transduced with a lentiviral vector to express NY-ESO-1 and electroporated with CRISPR guide RNA to disrupt expression of endogenous TCRα, TCRβ and PD-1 (NYCE T Cells)."
Los nueve CT´s se basan en la modificiación de linfocitos T y 3 de ellos son un CART además del KO del PD-1.
Le ruego evalúe la presente entrada asignando un valor de 1 a 5, de peor a mejor valorada, usando la opción de comentarios
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