Immunotherapy has revolutionized the way physicians treat patients with cancer. Various immunotherapies have been developed to activate antitumor immunity. A specialized immunotherapy, known as chimeric antigen receptor (CAR) T cell therapy has driven successful clinical outcomes. Specifically, CAR T cell therapy has significantly improved efficacy in hematological malignancies but is limited in solid tumors.
Researchers are working to enhance CAR T cell efficacy in solid tumors and discover new solutions to overcome tumor burden. A recent article in Science, by Dr. Michel Sadelain and others, describes a new CAR T cell therapy using HLA-independent T cell (HIT) receptor and how it can effectively eliminate different tumor types. Sadelain is a physician scientist and Director of the Columbia Initiative in Cell Engineering and Therapy at Columbia University, Vagelos College of Physicians and Surgeons. He is internationally known for his work on CAR T cell therapy and has been recognized with the Canada Gairdner International Award, Warren Alpert Foundation Prize, and the Breakthrough Prize in Life Sciences.
Sadelain and his group worked to find an ideal tumor marker to target for CAR T cell therapy. They accessed markers based on restricted expression on all tumor cells and common between tumor types. Based on these criteria the CD70 marker was identified as an optimal therapeutic target. While CD70 is restrictively expressed on tumors within different tumor types, it was thought to not be consistently expressed throughout the entire solid tumor. However, Sadelain and his group suspected that conventional CD70 may be expressed on all tumor cells, but under the threshold of sensitivity for detection.
To effectively target solid tumors, scientists developed a novel CAR T cell therapy to detect low expression of CD70 using the HIT receptor. These HIT engineered cells are a more sensitive CAR T cell design that were found to effectively eradicate solid tumors. Sadelain and his team developed tumor models to test their therapy. They generated mice that grew human tumors with varying CD70 expression. The different tumor types tested included kidney, ovarian, and pancreatic cancer – all clinically hard-to-treat tumors. One group of mice were treated with conventional CAR T cell therapy while the other were treated with the new HIT design. In comparison, the HIT cells effectively targeted CD70 and completely eradicated all three tumor types. This is a major discovery because it demonstrates that CD70 is expressed on all tumor cells, but at varying levels. Additionally, scientists have developed an effective approach to combat heterogenous tumors, which has been a major obstacle to cancer treatment.
Researchers confirmed that cancer cells that appeared CD70-neagative actually retained CD70 expression. The team computationally analyzed patient tumors and found low-level expression at the DNA level. Due to a biological mechanism that silences gene expression, scientists were previously unable to observe CD70 expression. Overall, the article reveals CD70 expression throughout tumors that were initially thought to be CD70-heterogenous. To demonstrate their discovery, scientists developed HIT therapy that was highly reactive to three distinct solid tumors. This work is groundbreaking and the first to report CD70 expression throughout the entire tumor. Consequently, these findings have the potential to improve patient care and enhance solid tumor therapy.
Article, Science, Michel Sadelain, Columbia University, Vagelos College of Physicians and Surgeons
