CAR-T cells are specialized immune cells genetically modified to recognize and attack cancer cells. Researchers at Nagoya University in Japan and their collaborators have developed new CAR-T cells to target malignant tumors. While similar treatments have worked well for blood cancers, treating solid tumors is more difficult. Their method, published in the Journal for ImmunoTherapy of Cancer , targeted a protein found in high amounts on many types of cancer cells (Eva1), and successfully eliminated tumors in lab mice.
CAR-T or Chimeric Antigen Receptor T-cell therapy works by genetically modifying a patient's own T cells—a type of immune cell—so that they can recognize specific markers (molecules) on cancer cells. This allows them to find and attack cancer cells more effectively.
The researchers developed CAR-T cells to recognize and attack cancer cells with the Eva1 protein. They focused on the Eva1 protein because it is abundant on the cell surfaces of lung, pancreatic, and liver malignant tumors, and is expressed at lower levels in most normal cells compared to cancer cells. Its small size may help immune cells connect to it more easily, which could improve the efficiency of the CAR-T therapy.
Our immune system produces antibodies to protect us when foreign substances, called antigens, enter our bodies. The researchers started with a mouse-derived antibody that recognizes Eva1. Since mouse antibodies would be recognized as antigens and trigger an immune response in humans, they modified it to make it similar to human antibodies.
The researchers changed two important features of the T cells: the "spacer," which determines the physical distance between the immune cell and the cancer cell when they connect, and protein components called "intracellular domains," which enhance the T cells' immune response and control how aggressively they attack cancer cells. Sixteen different versions of this humanized antibody were created to find which one best recognized Eva1 and effectively activated immune cells.
The most successful design used a short spacer combined with either of two specific intracellular domains (4-1BB or CD79A/CD40). This helped the modified immune cells effectively eliminate malignant tumors in lab mice with lung or pancreatic cancer.
Eva1 is sometimes found in small amounts on normal white blood cells called monocytes, so tests were conducted to see if this treatment harmed healthy cells. It was found that the modified immune cells only became activated when they encountered cells with high amounts of Eva1 (cancer cells) and largely ignored white blood cells with low amounts. This suggests the treatment is both effective and safer for patients.
"These findings are an important step toward a new treatment option for cancers that have been difficult to treat. Patients with various types of tumors that express the Eva1 protein may be helped with this approach," Dr. Seitaro Terakura from Nagoya University Graduate School of Medicine explained.
"Our team will now focus on confirming the treatment's safety in humans before moving toward clinical trials. To determine if Eva1 CAR-T is safe to administer to humans, we are currently generating a mouse CAR-T that recognizes mouse Eva1. If we can demonstrate that the mouse CAR-T does not cause severe toxicity in mice due to recognition and tissue damage targeting Eva1 expressed in normal mouse cells, we will be able to move closer to human administration. Following the accumulation of such data, we would like to collaborate with companies and others to advance toward clinical application."
