Chimeric antigen receptor T-cell (CAR-T) therapies that are made from a patients own T cells haveproven effective in blood cancers, and they are showingpromise for treating solid tumors, too. But scientists are still looking for ways to fine-tune this form of immunotherapy.

Now, scientists at the University of North Carolina (UNC) at Chapel Hill havefound new methods for either dialing up CAR-T cells cancer-killing effects when needed or dampening their activity to avoid severe side effects. The technique involvestwo proteins that are responsible for stimulating the cells. The team published the results in Cancer Cell.

In immunology, its always about balance; you don't want to have too much T-cell activation, and you don't want T-cell activation to be too low, the studys co-first author Peishun Shou, Ph.D., said in a statement. We wanted to keep the T-cell activation and tumor killing at a suitable or sustainable level.

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Shou worked in a team led by UNC Lineberger Comprehensive Cancer Centers Gianpietro Dotti, M.D. In 2018, Dottis team developed CARs that can target a protein called CSPG4, and they showed the treatment worked in mice with glioblastoma.

For the current study, the researchers zeroed in on two different types of CARs, whichare differentiated by the signals that activate them. CAR-T cells tumor-regression ability is first triggered by a signal called CD3-zeta, which is commonly used as the main CAR component to recognize markers on tumors. But the cellsalso require co-stimulatory moleculeseither CD28 or 4-1BB proteinin addition to CD3-zeta to further boosttheir activation.

The UNC team found that they could improvethe activityof T cellsthat areco-stimulated by 4-1BBby increasing the expression of a tyrosine kinase called LCK.

What we found is that the LCK molecule can bind to the CAR, enhancing the CAR-T cell activation and signaling transduction, which therefore will help CAR-T cells get a better tumor-killing effect, Shou said.

RELATED:Redesigned CAR-T eliminates dangerous cytokine release syndrome in lymphoma trial

Use of CAR-T therapy has been linked to a dangerous side effect called cytokine release syndrome, so scientists have also been working on methods to rein in CAR-T activitywhen necessary.

Shou and colleagues found such a safety switch in CAR-T cells that are co-stimulated by CD28. They showed that an enzyme called SHP1 attenuates T-cell activity. They discovered that adding a drug named AP21967which is an analog to Pfizers immunosuppressive drug Sirolimus (rapamycin)can pull SHP1 to the CAR to reduce cytokine release. Whats more, the transient recruitment of SHP1 didnt kill the CAR-T cells or impair their antitumor effects, the researchers demonstrated in a mouse model.

Many other efforts have been made to reduce CAR-Ts toxic side effects. For example, a research team led by the University of Southern California Norris Comprehensive Cancer Center developed a CAR variant called CD19-BBz(86) that didnt trigger any serious side effect in 25 lymphoma patients.

As for4-1BB, it's a target that has already attracted some interest among drug developers. Pfizer is developing utomilumab (PF-05082566), a 4-1BB agonist, to leverage the receptors T-cell stimulation effect. The drug is being paired with Pfizer and Merck KGaAs anti-PD-L1 immunotherapy Bavencio in a phase 2 study in solid tumors.

The UNC scientists want to use their findings on CD28 and 4-1BB to improve CAR-T treatments against blood cancers and to potentially make them viable for solid tumors.

Researchers in the CAR-T immunotherapy field now want to solve the solid tumor problem, Shou said. Solid tumors have an immunosuppressive microenvironment, so you need stronger CAR-T activation.

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Improving CAR-T therapy for cancer by regulating 2 proteins - FierceBiotech