CRISPR-Cas9 technology edited CAR-T cells may enhance the body's potential to fight blood cancer

20, 2020 /PRY/ -- Scientists from the University of Pennsylvania demonstrated their latest preclinical findings at the 62nd Annual Meeting of the American Society of Hematology (ASH) in 2020, finding that USing CRISPR/Cas9 technology to remove specific proteins on CAR-T cells that inhibit T-cell activation may enhance the ability of engineered T cells to remove cancer.
researchers removed the gene called CD5 from car-T cells and then infused it back into mice carrying T-cells and B-cell leukemia/lymphoma, which encodes the CD5 protein on the surface of the T-cell and inhibits its activation.
Compared to mice infused with non-edited CAR-T cells, mice with CD5 rejected CAR-T cells had higher levels of T-cell proliferation in in vitro blood, and tumor size decreased significantly, and mice had better survival outcomes.
CRISPR technology, which helps scientists lock and edit any unwanted gene, in the case of cancer, can help them better protect against tumors by removing specific genes from T-cells, a method closely linked to CAR-T cell therapy, in which researchers engineer and express new subjects by collecting T-cells from the patient's body itself.
'For the first time, we have shown that we can successfully use CRISPR/Cas9 technology to knock out CD5 on the surface of CAR-T cells, thereby enhancing their ability to attack cancer,' said Marco Ruella, M.D., M.D.
photo source: CC0 Public Domain researchers have for the first time tested this new method in a model of T-cell leukemia, in which anti-CD5 CAR-T cells can be genetically engineered to look for and attack CD5 on malignant T cells; Normal T cells are also expressed, and the researchers then removed CD5 from the CAR-T cells, thus avoiding the killing effect on other CAR-T cells, potentially releasing the activation of the CAR-T cells, which would otherwise be inhibited by the presence of CD5 on those cells.
In fact, in vivo and in vitro trials, CD5's rejected anti-CD5 CAR-T cells were more effective than CD5's unsealed CAR-T cells, and more than 50 percent of mice were cured in long-term trials.
To test whether the removal of CD5 increases the anti-tumor effects of CAR-T cells that target acting antigens rather than CD5, the researchers then confirmed that CTL019 CAR-T cells are fighting CD19-plus B cell leukemia, and it is worth noting that in this model, CD5 knock-out significantly enhances the anti-tumor efficiency of CTL019 CAR-T cells, while also prolonging the total alleviate period of disease in most mice.
In a presentation on the day of the meeting, the researchers reviewed genomic data analysis of more than 8,000 patient tumor tissue samples and looked at CD5 levels in those samples, which were found to be closely related to the patient's prognostication, and in most cancer cell types, the less CD5 was expressed in T-cells, the better the patient's prognostication, so the level of CD5 in the body's T-cells was particularly important.
results are expected to help scientists conduct clinical trials later to explore how CAR-T cell therapy can be combined with CRISPR/Cas9 gene editing techniques to improve current and new types of cell therapies.
New CAR-T cell therapy, developed by researchers, may be used in patients with blood cancer in children and adults, but it can also induce dramatic reactions in the bodies of patients with relapsed or incurable B-cell acute lymphoblastic leukemia or non-Hodgkin's lymphoma.
, however, many patients do not respond or eventually relapse.
more importantly, CAR-T cell therapy does not play an effective role in the treatment of a variety of blood malignancies, such as T-cell lymphoma and leukemia, because blood cancers frequently express CD5.
CD5 is expressed in most patients with chronic lymphoblastic leukemia and sleeve lymphoma, and in about 20% of patients with acute myeloid leukemia.
many of the methods that can enhance CAR-T cell therapy today involve treatments that address T-cell depletion, especially the PD-L1/PD-1 axis.
the researchers who spoke at the university had different strategies, with the goal of intervening in the early stages of T-cell activation, providing an opportunity to increase the function of T-cells in tumor micro-environments.
researcher Carl June says that in the long run, this may represent a more general strategy that will enhance the anti-tumor effects of CAR-T cells; we look forward to more in-depth research based on these encouraging findings in the next phase of our work.
that phase 1 clinical trials of CAR-T cell therapy, which investigates CD5 culling, will begin in early 2021, the researchers said.
() References: CRISPR-edited CAR T cells enhance fight against blood cancersKnocking out of a protein name to stifle T cell on CAR T cells using the CRISPR/Cas9 technology enhanced the engineered cells' ability to eliminate blood cancers, according to new new preclinical data from the people of the university and the People's University Cancer Center. The findings will be presented as an oral presentation at the 62nd American Society of Hematology Annual Meeting & Exposition on Dec. 7.The team knocked out the CD5 gene—which encodes for the CD5 protein on the surface of T cells and can inhibit their activation—on CAR T cells using CRISPR-Cas9 and infused them back into mice with T- and B-cell leukemia or lymphoma. Mice infused with the CD5-deleted CAR T cells showed higher levels of T cell proliferation in the peripheral blood, as well as a significant reduction in tumor size and better survival outcomes compared to mice infused with non-edited CAR T cells.。