Recently, scientists from the Memorial Sloan Kettering (MSK) Cancer Center announced that they have established the latest engineered cells with powerful efficiency, which combine chimeric antigen receptor (CAR) -T cells and checkpoint inhibitors, the two most potential immunotherapies, to effectively fight against solid tumors. This groundbreaking study was co-authored by Eureka Therapeutics and MSK, led by Dr. Liu Cheng and Dr. Renier Brentjens, and published in Nature Biotechnology on August 13, 2018.CAR-T that secretes PD-1 antibody directly
Despite significant success in treating certain hematological cancers, so far, CAR-T cells don’t have enough ability to eliminate solid tumors. Meanwhile, checkpoint inhibitors have proven to be much effective in enhancing the immune system against various solid tumors, but such therapies may produce severe immune-related side effects.
Dr. Renier Brentjens, director of the MSK Cell Therapy Center and one of the pioneers of CAR treatment, said: “Take a step back, we focused on bettering CAR-T cells and so tried to combine two promising methods.” By designing checkpoint inhibitors directly into CAR-T cells, the MSK team believes CAR-T’s powerful immunostimulatory capabilities can be used to limit the side effects of these drugs.
The newly designed CAR-T cells secrete a mini-version of checkpoint blocking antibodies, which are similar to the approved PD-1 antibody drugs nivolumab (Opdivo) and pembrolizumab (Keytruda). This antibody binds to a protein called PD-1, which is equivalent to the brake protein of T cells. So theoretically, releasing this brake can make CAR-T cells and surrounding immune cells better fight disease.
Highlight anti-cancer persistence and effectiveness
MSK and the Uric team produced two versions of the “armored CAR“. One of them targets CD19, which is expressed on the surface of most B-cell blood tumors; the other is targeting MUC16, expressed in some ovarian and pancreatic cancers. The team then tested the two versions of CAR-T cells in several different mouse cancer models.
It was found that the “armored CAR” lasts longer in the body than the standard CAR in all cases, including in the mouse solid tumor model. Compared to the conventional CAR, armored CAR has better treatment effects and the mice lifespan was significantly longer compared to conventional CAR.
More importantly, because the checkpoint drug is released directly into the tumor and activates nearby T cells, creating a favorable bystander effect. In other words, CAR-T cells are able to get help from other T cells to fight tumors. Finally, the team also found that levels of PD-1 antibodies were lower in circulating blood, indicating that the checkpoint molecules did not leave far away the tumor site, which means that the side effects of the whole body are reduced.
At the same time, Dr. Brentjens emphasized that this approach can be considered a new platform for CAR treatment. Based on this, the CAR-T cells secreting various molecules can be tailored according to the needs of patients, not limited to PD-1 antibodies. Now, the research team hopes to transfer their “armored CAR” technology platform to the clinic and is designing clinical trials.