Nat Commun: SynNotch CAR-T cells targeting GD2 and B7H3 are expected to treat neuroblastoma

January 26, 2021 /---/ ----embedded antigen-inset antigen -T-cell therapy has revolutionized the treatment of leukemia.
, the treatment is not effective in treating solid tumors, including childhood cancers such as neuroblastoma.
preclinical study of neuroblastoma using certain CAR-T cells revealed toxic effects.
Now, in a new study, researchers at Children's Hospital Los Angeles have developed an improved version of car-T cells that show hope in targeting neuroblastoma: killing cancer cells more effectively without harming healthy brain tissue.
the study is still in its preclinical stage, it reveals the potential for life-saving treatments for children and adults with solid tumors.
study was published in the journal Nature Communications on 21 January 2021 under the title "Preclinical assessment of of the efficacy and specificity of GD2-B7H3 SynNotch CAR-T metastatic neuroblastoma".
build highly specific and efficient GD2-B7H3 T cells, pictured from Nature Communications, 2021, doi:10.1038/s41467-020-20785-x.
Shahab Asgharzadeh, co-author of the paper and a clinical scientist at the Institute of Cancer and Hematology at Children's Hospital Los Angeles, is working to improve life-saving CAR-T cell therapy.
, scientists genetically modified the patient's own immune system T cells to identify and destroy cancer cells.
, "CAR-T cell therapy works in the treatment of leukemia by targeting unique proteins (or antigens) on the surface of leukemia cells."
when treated, leukemia cells are killed.
CAR-T cells have turned a patient's immune system into a powerful, targeted cancer killer among leukemia patients.
the antigen is also present in normal B cells in the blood, but the side effects can be treated with medication.
, on the other hand, solid tumors such as breast cancer or neuroblastoma face a challenge: many of the antigens on their surface are also present in healthy tissues and do not control toxicity as safely as leukemia.
in solid tumor patients, car-T cell therapy kills cancer cells and healthy tissue indiscriminately.
because of this and the inhibitory immune environment in solid tumors, preclinical studies of these cancers have resulted in low efficacy or unacceptable toxicity levels.
, lead author of the study, said, "CAR-T cell therapy is very powerful, but for solid tumors, it's a big barrier.
we need a way to strengthen CAR-T cells and make them work harder and smarter against cancer.
, we also want to save brain cells and other healthy tissues.
" and that's exactly what these researchers are doing.
the researchers used a new CAR-T technique called synthetic Notch.
SynNotch CAR-T cells have a unique property called gate control that allows them to target specific cancers with great precision.
this gate-controlled feature works similar to the logic gate that computer programmers often use: if condition A is met, take action B.
Moghimi said, "It works in a really unique way.
"he explains, the special synNotch protein on the surface of T cells has been modified to identify the antigen GD2.
when it is erred, the synNotch protein instructs T cells to activate its CAR-T properties, allowing them to identify the second antigen, B7H3.
these T-cells must follow these specific instructions, which means they can only kill cells with both antigens.
these gate-controlled properties are key to minimize toxicity; healthy cells sometimes express one of these antigens at a low level, but not both.
solid tumors such as neuroblastoma have both GD2 and B7H3 antigens, and the Asgharzadeh team modified the SynNotch cells to identify both.
Asgharzadeh team was able to overcome another challenge.
Asgharzadeh said, "For common CAR-T cell therapy, CAR-T cells fail over time and become less active.
, however, we found that synNotch CAR-T cells were more metabolically stable because they were not continuously activated.
means they consume less energy, which allows them to continue fighting cancer for longer periods of time.
" (Bioon.com) Reference: 1. Babak Moghimi et al. Preclinical assessment of the efficacy and specificity of GD2-B7H3 SynNotch CAR-T in metastatic neuroblastoma. Nature Communications, 2021, doi:10.1038/s41467-020-20785-x.2.Creating a safe CAR T-Cell therapy to fight solid tumors in children