Zelig Eshhar was an immunologist whose groundbreaking work profoundly influenced cancer therapy. He is widely acknowledged for his pioneering contributions to the development of chimeric antigen receptor (CAR) T-cell therapy. His innovative research laid the foundation for a new approach in the fight against cancer, significantly altering the landscape of treatment options for many patients.
Early Life and Scientific Journey
Born in Petah Tikva, Israel, in 1941, Eshhar grew up in Rehovot. After serving in the Israel Defense Force, he worked as a beekeeper, which sparked an early interest in science. This motivated him to pursue higher education, leading him to study biology at the Hebrew University of Jerusalem, where he earned both his bachelor’s and master’s degrees in biology and biochemistry.
Eshhar continued his academic journey at the Weizmann Institute of Science, completing his doctoral studies in immunology in 1975. His early research focused on monoclonal antibodies and immune modulation. Following his Ph.D., he pursued postdoctoral research at Harvard Medical School in immunology, led by Nobel Prize laureate Baruj Benacerraf. Upon his return to the Weizmann Institute in 1976, Eshhar established Israel’s first laboratory dedicated to producing monoclonal antibodies, advancing his research into immune-cell engineering. In 1982, he became a professor at the Weizmann Institute, beginning his influential work on genetically engineering T-cells.
Pioneering CAR T-Cell Therapy
Zelig Eshhar’s most impactful scientific contribution was his pioneering work on genetically engineering T-cells, leading to the development of CAR T-cell therapy. This therapy involves taking a patient’s T-cells, a type of white blood cell, and genetically modifying them in a laboratory. These modified T-cells are equipped with synthetic proteins called chimeric antigen receptors (CARs), which enable them to specifically recognize and bind to antigens, or markers, present on the surface of cancer cells.
Eshhar’s team developed the first immunoglobulin-T-cell receptor chimeric molecules, initially nicknamed “T-bodies,” in 1989. These constructs aimed to reprogram T-cells to identify and destroy specific target cells, including cancer cells. The goal was to combine the antibody’s ability to recognize a defined antigen with the T-cell receptor’s activation signals, allowing T-cells to specifically target tumor cells.
Making these engineered T-cells effective and persistent enough to combat established tumors was a significant challenge. Eshhar’s preclinical studies in animal models were instrumental in defining optimal CAR specificities and treatment conditions for cancer eradication. This foundational work demonstrated the potential of CAR T-cells to reject tumors and cure tumor-bearing mice.
Revolutionizing Cancer Treatment
CAR T-cell therapy has emerged as a treatment option, particularly for certain blood cancers, offering new hope to patients who previously had limited choices. It has shown substantial success against specific types of leukemia and lymphoma, including B-cell acute lymphoblastic leukemia (ALL) and various B-cell non-Hodgkin lymphomas. The therapy has also gained approval for treating multiple myeloma.
This treatment is considered when cancers have not responded to other therapies (refractory cancer) or when they return after initial treatments (recurrent or relapsing cancer). The reinfused, genetically altered CAR T-cells multiply within the patient’s body, actively seeking out and eliminating cancer cells. This “living drug” approach has demonstrated the potential for long-term remission, with some studies showing sustained remission for years in patients with resistant cancers.
Enduring Legacy and Future Directions
Zelig Eshhar’s foundational work continues to shape the fields of immunology and oncology. He passed away on July 3, 2025, at the age of 84. His pioneering research earned him numerous accolades, including the Israel Prize in Life Sciences in 2015 and the Dan David Prize in 2021. In 2024, he also received the Canada Gairdner International Award, shared with Michel Sadelain, for their contributions to CD19-CAR T-cell therapy.
His work initiated a shift in cancer treatment, moving beyond traditional chemotherapy to cell-based therapies. This shift continues to drive advancements in cellular immunotherapies. Research stemming from his discoveries is exploring broader applications, including the potential for CAR T-cells to treat solid tumors. The ongoing evolution of CAR T-cell therapy and related immunotherapies underscores the lasting impact of Eshhar’s vision.