SUPRA CAR: The “Swiss Army Knife” of CART is Here
T cells expressing chimeric antigen receptors (CARs) are promising cancer therapeutic agents, with the prospect of becoming the ultimate smart cancer therapeutics. To expand the capability of CAR T cells, scientists at Boston University and Massachusetts Institute of Technology (MIT) have now developed a new CAR technology, called split, universal, and programmable (SUPRA) CAR, that they believe, has the potential to overcome some of the big issues that continues to plague the first generation of drugs now on the market.
Wilson Wong, of the Boston University, working alongside graduate student Jang Hwan Cho and MIT’s Jim Collins, has devised what they call the “Swiss army knife” of CAR-T to address issues correlating CART Therapy and technology such as patient relapse, toxicity and specificity, and not all patients respond well.
Wong’s team created a split, universal, and programmable (SUPRA) CAR system. Instead of relying on a single fixed CAR, the technology splits the molecule into a two-component receptor system.
It comprises universal receptors, dubbed zipCARs, expressed on the T cells, plus adaptor molecules, called zipFv molecules, which carry an antibody that targets a specific antigen on the tumor cell. Both components use leucine zippers to bind to each other
, allowing the engineered T cells to seek and destroy cancer.Normally, the immune system requires T-cells to sense two targets coming from an invader cell before it attacks it. SUPRA CAR-T works in the same way-before it attacks cancer cells, it needs to sense that both targets are present on the cell. If you have a lightning cable and a micro USB cable plugged into the adapters, both devices would need to connect to activate the killer T-cell response. If only one is present, the system isn’t activated.
SUPRA CAR-T also splits the T-cell from the target-sensing portion of the system-the adapter from the cable. The antigen is chosen is sought out by an antibody on the CAR T-cells. The new system breaks apart the T-cell from the antibody and allows for the ability to switch targets; unplugging a lightning cable from an adapter and plugging in a different charging cable.
The ability to switch targets is what can prevent relapse in patients. Cancer cells are smart and will mutate to no longer display the target when they sense the T-cells attacking after attaching to it.
The SUPRA CAR-T system allows the T-cells to attack a new target by simply injecting the patient with a new batch of antibodies rather than having to re-engineer the T-cells, which is the most expensive portion of the treatment.
The team also tested their system in mouse models. Mice injected with Her2-positive breast cancer cells were given a dose of zipCAR-expressing T cells, followed by the appropriate adaptor molecules every other day for two weeks.
While the SUPRA CAR treatment showed “robust tumor burden clearance” over traditional CAR-T, the researchers took care to note that the engineered T cells alone could not reduce tumor burden. As for the blood cancer model, mice were injected with adaptor molecules every day for six days after receiving the engineered T cells.
The results were similar, demonstrating the “potential of the SUPRA CAR system to combat many different cancers.”
“Our most immediate work is to figure out what type of cancer would really benefit from this type of combinatorial targeting and control,” Wong said. This could include cancers with a lot of heterogeneity that don’t have a single good marker, he said. The rest will be a major engineering challenge, he added. “Every cancer is probably going to need some fine-tuning in the adaptor molecule.”
“The way I imagine it is a tricked-out cell,” he says. “We want something off-the-shelf so we wouldn’t have to make it for every patient, which would bring the cost down, with the capability to switch it on or off. We’d also want it to be able to make certain proteins it might need–proteins that chew up solid-tumor boundaries for example. Lots of sensors, lots of switches, all these bells and whistles that make a very smart cell.”
