Engineered T-cell therapy, and in particular CAR T-cells, have shown efficacy in CD-19+ blood cancer such as lymphomas and leukemias. However, to date, T-cell therapies have found little success in solid tumors – in part due to the immunosuppressive tumor microenvironment. Checkpoint inhibitors, on the other hand, have been proven effective at empowering the immune system to fight a variety of solid tumors. The checkpoint inhibitor antibody binds to a protein called PD-1 and shields the T-cell from the immunosuppressive response generated by the cancer cell, thus activating the potential of the T-cell to kill the cancer cell. However, checkpoint inhibitors can unbalance the immune system and induce toxicity and severe immune-related adverse event (irAEs).
Eureka Therapeutics, Inc., a clinical stage biopharmaceutical company with the goal of curing cancer by developing novel T-cell therapies that harness the evolutionary power of the immune system, announced the publication of a proof-of-concept study in Nature Biotechnology entitled “Targeted delivery of a PD-1-blocking scFv by CAR-T cells enhances anti-tumor efficacy in vivo.” The publication details the approach of combining CAR and PD-1 checkpoint inhibitor antibodies on the same engineered T-cell, creating what is often described as an “armored T-cell” or “armored CAR”. This approach was developed in collaboration with Renier J. Brentjens, M.D., Ph.D., Director of the Cellular Therapeutics Center at Memorial Sloan Kettering Cancer Center (MSKCC).
The study analyzed two versions of the armored CAR in mouse models – one against CD-19 positive targets, and the second against MUC-16 positive targets. CD-19 antigens are found on B-Cell malignancies, while MUC-16 antigens are found on some ovarian and pancreatic cancers. The study showed that by co-expressing a PD-1 inhibiting antibody on a CAR-T cell, the CAR-T cells tend to stay locally around the tumor site, therefore potentially avoiding toxicities associated with systematic checkpoint inhibition. In addition, since the checkpoint drugs were released directly into the tumor, they activated nearby T-cells, creating a positive bystander effect. In both mouse models, the armored CARs persisted longer than standard CARs.
“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,” said Dr. Brentjens, corresponding author.
The PD-1 antibody used in this study was developed using Eureka’s proprietary E-ALPHA® phage display library for the discovery and engineering of human antibodies. The publication is the result of a joint collaboration initiated in 2013 between Eureka and MSKCC to develop T-cell therapies.
“We are encouraged by the observed safety and anti-tumor activity profile of PD-1 antibodies expressed on engineered T-cells,” said Dr. Cheng Liu, President and Chief Executive Officer of Eureka Therapeutics and co-author on the paper. “Armoring an engineered T-cell against an antigen target with a PD-1 checkpoint inhibitor antibody is an innovative and novel approach to make T-cell therapies more effective, in particular, against solid tumors. We are excited about the possibility of applying this approach to our proprietary ARTEMIS™ T-cell receptor platform.”
Eureka’s proprietary ARTEMIS™ T-cell receptor platform was designed to create potentially safer and more effective T-cell therapies. In proof-of-concept clinical studies against CD19+ malignancies, Eureka’s ARTEMIS™ T-cells demonstrated robust cancer-killing potency but with a dramatic reduction in the levels of inflammatory cytokines released when compared to currently approved CAR-T therapies. Cytokine release syndrome (CRS) and neurotoxicity are other forms of serious side effects associated with CAR-T therapies.
Eureka Therapeutics, Inc. is a privately held clinical stage biopharmaceutical company focused on developing novel T-cell therapies that harness the evolutionary power of the immune system. Its core technology platforms center around its proprietary ARTEMIS™ T-cell receptor platform and E-ALPHA® antibody discovery platform for the discovery and development of potentially safer and more effective T-cell therapies for the treatment of multiple hematologic and solid tumors.
Eureka Therapeutics, Inc. is headquartered in the San Francisco Bay Area. For more information on Eureka Therapeutics, please visit www.eurekatherapeutics.com.