CAR-T 2.0? A split, universal and programmable system

Recent FDA approvals have validated the use of chimeric antigen receptor T cells (CAR-Ts) to fight blood cancers, but the technology is still far from perfect. Researchers working on CAR-T therapies have run into problems with patient relapse, toxicity and specificity, and not all patients respond well. Wilson Wong and his team at Boston University have devised what they call the "Swiss army knife" of CAR-T to address these issues. 

CAR-T treatments involve collecting T cells from a patient's blood, and then engineering them to express CARs on their surface. The new CAR T cells are then grown in the lab and then re-infused into the patient, where they can target and attack the specific antigens expressed by their own cancer cells. 

What limits current CAR-T systems, Wong says, is that the receptor is a fixed molecule. Once the T cells are engineered, they can't be altered—you put them in the patient and hope nothing goes wrong, he said in an interview with FierceBiotechResearch. This may not always be the case. The CAR-T cells might work too well, activating the immune system too strongly and causing a dangerous side effect called cytokine release syndrome. And patients may relapse if their cancer "figures out a way to not express the target antigen," he said, hiding from the CAR-T cells in a process called antigen escape. The logical solution would be engineer T cells for a different antigen, but the patient may not have the time or the T cells for a do-over.

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And there's another challenge that makes it difficult to apply CAR-T technology to other cancer types, like solid tumors. "It's hard to find the one magic bullet marker on a cancer cell that is not found in any other cell type. The challenge is how to find cancer cells and kill them without killing anything else," Wong said.  

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. 

In the lab, the team found that they could switch off T-cell activation by delivering a competitive adaptor molecule. Moreover, they found they could control the strength of T-cell activation by using adaptor molecules with different binding strengths. They also tested a two-pronged attack, treating cultured cells with engineered T cells and adaptor molecules that targeted the antigens Her2, Axl or both.

"As expected, the addition of zipFv targeting either Her2, Axl, or both led to high killing efficiency, illustrating the potential of programming the SUPRA CAR system to combat antigen escape," they wrote in the study, which appears in the journal Cell. Targeting more than one antigen not only combats cancer relapse, but also makes the treatment more specific. 

Then Wong's team 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 team is working with Senti Biosciences on translating the technology into clinical trials and beyond, said Wong, a scientific cofounder of Senti. The biotech launched in February, with $53 million in series A funding. And while cancer is the focus of Senti's research today, it might also someday be applied to autoimmune disease. The technology works with other types of immune cells than killer T cells and could be used to suppress the immune response in autoimmune diseases such as arthritis and multiple sclerosis, as well as in organ transplant rejection. 

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