Memorial Sloan Kettering Researchers Build a New Model of Genetically Engineered Immune Cells That May Combat Solid Tumors in the Future

Bottom Line: Scientists at Memorial Sloan Kettering Cancer Center (MSK) announced that they have built a new model of genetically engineered immune cells in mice that may allow them to fight solid tumors. The new cells combine two of the most promising types of immunotherapy into one sleek package: chimeric antigen receptor (CAR) T cells, which are genetically engineered versions of a patient’s own immune cells, and checkpoint inhibitor antibodies, which take the brakes off immune cells, allowing them to better fight cancer. The early research is promising, and the MSK team hopes to eventually translate their new so-called “armored” CAR platform to the clinic. They are in the process of designing clinical trials in humans.

Background: The newly designed armored CAR T cells secrete a mini-version of a checkpoint-blocking antibody, similar to the drugs nivolumab (Opdivo®) and pembrolizumab (Keytruda®), which are approved for the treatment of melanoma and lung cancer. When secreted into the tumor environment, the antibodies bind to a protein called PD-1 that acts like a brake on immune cells, releasing this brake and allowing the CAR T cells and surrounding immune cells to better fight the disease. The team of MSK researchers made two versions of this armored CAR: One recognizes a molecule called CD19, which is found on certain blood cancers, and the other recognizes MUC16, which is found on some ovarian and pancreatic cancers. Then they tested the cells in several mouse models of cancer.

Findings: In all cases, including in a mouse model of ovarian cancer, the team found that the armored CARs persisted in the body longer than nonarmored CARs, and they produced better results too — namely, the mice lived significantly longer. What’s more, because the checkpoint drugs are released by the CAR T cells into the tumor, they were able to activate nearby T cells, creating a helpful bystander effect. Finally, the team found that levels of the PD-1 antibody were low in the circulating blood, indicating that the checkpoint molecules were not spreading far beyond the site of the tumor — which means there will be fewer side effects throughout the body.

Corresponding Author Comments: “An armored CAR T approach represents the next phase of innovation in T cell therapies,” said Renier Brentjens, MD, PhD, Director of Cellular Therapeutics at MSK and one of the pioneers of CAR therapy. “These data, together with in vivo models, suggest that this is an early step toward exploring how we can make the first iterations of CAR T cell therapies even better.”

He continued, “We took a step back and said, ‘How can we make CAR T cells better?’ That’s when we decided to try to combine these two promising approaches. This proves — at least in a mouse model — that we can now have our cake and eat it too.”

Journal: “Targeted delivery of a PD-1-blocking scFv by CAR-T cells enhances anti-tumor efficacy in vivo.” was published online August 13, 2018, in Nature Biotechnology.

Funding: This study received funding from the National Institutes of Health grants 5 P01 CA190174‑03 and 5 P50 CA192937‑02, the Canadian Association of New York Foundation’s annual Terry Fox Run for Cancer Research in New York City, Kate’s Team, the Carson Family Charitable Trust, the William Lawrence and Blanche Hughes Foundation, the Emerald Foundation, the ARD Foundation, and the Center for Experimental Therapeutics at MSK. Dr. Brentjens is a co-founder of and consultant for Juno Therapeutics, for which he receives royalties.