CAR-T Cells and the Transformation of Blood Cancer Treatments

Dr. Brentjens obtained an MD/PhD (microbiology) from the University at Buffalo, completed residency in medicine at Yale New Haven Hospital, and a medical oncology fellowship at Memorial Sloan Kettering Cancer Center (MSKCC). As a medical oncology fellow during his training at MSKCC, Dr. Brentjens initiated the initial preclinical studies demonstrating the potential clinical application of autologous T cells genetically modified to target the CD19 antigen through the retroviral gene transfer of artificial T cell receptors termed chimeric antigen receptors (CARs).

Following completion of his medical oncology training, Dr. Brentjens became the principal investigator of his own laboratory. As a principal investigator, Dr. Brentjens successfully translated these studies to the clinical setting treating patients with relapsed CD19+ tumors including chronic lymphocytic leukemia (CLL) and B cell acute lymphoblastic leukemia (B-ALL). Ongoing pre-clinical research in the laboratory is focused on the further development of CAR modified T cells designed to overcome the hostile immunosuppressive tumor microenvironment through the generation of “armored CAR T cells” currently being translated to the clinical setting as second-generation CAR modified T cell clinical trials. Additionally, work in the Brentjens lab has expanded this CAR technology to target additional tumor antigens expressed on other malignancies including solid tumors.

In September 2021, Dr. Brentjens joined Roswell Park Comprehensive Cancer Center as Deputy Director, Chair of Medicine and The Katherine Anne Gioia Endowed Chair in Cancer Medicine, with a goal to advance cell and immune cancer therapies.

Zelig Eshhar received his his B.Sc. in Biochemistry from the Hebrew University in Jerusalem in 1966. In 1968 he received his M.Sc. in Biochemistry and in 1973 he got his Ph.D. from the Weizmann Institute in Chemical Immunology.
He did his Post-Doctoral Felloship at Harvard Medical School in the Dept. of Cellular Immunology led by Prof. Baruch Benasraf (who later won the Nobel Prize), in David Katz's lab.

On his way back to Israel, he joined Prof. Keller's lab at the Immunology Institute of Basel where he learned the method of creating monoclonal antibodies.
In 1976, he returned to Israel and joined the academic staff at the Weizmann Institute as the head of a research group in the Chemical Immunology department.

In 1982, he was awarded professorship and went to California for a sabbatical at the DNAX Institute for Molecular Biology. In 1984, upon his return to the Weizmann Institute, he began to focus on the topic of genetic engineering of T-cells. During those years, Eshhar also worked to create unique antibodies specifically for allergies and cancer cell antigens.

In 1990, he took a sabbatical in the National Institute of Cancer in Maryland, in the lab of Prof. Steven Rosenberg. It is there that he set the groundwork for the clinical application of the T- Bodies technology, an anti-cancer approach which he developed at the Weizmann Institute (Car-T).

Throughout his academic career he organized numerous international courses teaching the monoclonal technique and immunology. Prof. Eshhar was invited to teach in developing countries and has advised many biotech companies. In 2011, he retired from the Weizmann Institute as Prof. Emeritus. His next step was to open the Lab for Immunology Research at the Tel Aviv Sourasky Medical Center. In 2012 he became a guest Professor in the Faculty of Medicine at the Tel Aviv University.

Carl H. June, MD, is the Richard W. Vague Professor of Immunotherapy in the Department of Pathology and Laboratory Medicine. He is currently Director of the Center for Cellular Immunotherapies at the Perelman School of Medicine, and Director of the Parker Institute for Cancer Immunotherapy at the University of Pennsylvania. Dr. June is a graduate of the Naval Academy in Annapolis and Baylor College of Medicine in Houston (1979). He had graduate training in immunology and malaria with Dr. Paul-Henri Lambert at the World Health Organization in Geneva, Switzerland from 1978-1979, and post-doctoral training in transplantation biology with E. Donnell Thomas and John Hansen at the Fred Hutchinson Cancer Research Center in Seattle from 1983-1986. Dr. June is board-certified in Internal Medicine and Medical Oncology. He maintains a research laboratory that studies various mechanisms of lymphocyte activation that relate to immune tolerance and adoptive immunotherapy for cancer and chronic infection. In 2011, his research team published findings detailing a new therapy in which patients with refractory and relapsed chronic lymphocytic leukemia were treated with genetically engineered versions of their own T cells, now called CAR T. The treatment was the first cell or gene therapy to receive FDA approval. CAR T were first approved to treat children and young adults with refractory acute lymphoblastic leukemia, and as of 2023, CAR T is approved for 6 different kinds of blood cancer. Dr. June has published more than 500 manuscripts and was elected to the Institute of Medicine, the American Academy of Arts and Sciences, the National Academy of Sciences and American Philosophical Society. He is the recipient of numerous prizes and honors, including the William B. Coley Award, the Richard V. Smalley, MD Memorial Award from the Society for Immunotherapy of Cancer, the AACR-CRI Lloyd J. Old Award in Cancer Immunology, the Philadelphia Award, the Taubman Prize for Excellence in Translational Medical Science (shared with S. Grupp, B. Levine, and D. Porter), the Paul Ehrlich and Ludwig Darmstaedter Prize (shared with J. Allison), the Novartis Prize in Immunology (shared with Z. Eshhar and S. Rosenberg), the Karl Landsteiner Memorial Award, the Debrecen Award for Molecular Medicine, and a lifetime achievement award from the Leukemia and Lymphoma Society and the American Association for Cancer Research. Most recently, Dr. June was named a winner of the 2024 Breakthrough Prize for Life Sciences.

Michel Sadelain is Director of the Columbia Initiative in Cell Engineering and Therapy (CICET) and Director of the Cancer Cell Therapy Initiative in the Herbert Irving Comprehensive Cancer Center at Columbia University. He joined Columbia University from Memorial Sloan Kettering Cancer Center (MSK)  where was the founding director of the Center for Cell Engineering. He received his M.D. from the University of Paris (Pierre et Marie Curie) in 1984 and his Ph.D. from the University of Alberta (Edmonton) in 1989. Following his post-doctoral research at the Whitehead Institute at MIT, he joined MSK in 1994. Dr Sadelain founded the Center for Cell Engineering in 2008.

Sadelain has made several key contributions to the emergence and success of CD19 chimeric antigen receptor (CAR) therapy. His research contributed to all facets of CAR therapy, including T cell engineering methodologies (via retroviral vectors or gene editing), CAR design (dual-signaling receptor concept, known as second generation CAR), the identification of CD19 as an effective CAR target, T cell manufacturing (GMP processes, in collaboration with Dr. Isabelle Rivière at MSK) and clinical translation (in acute lymphoblastic leukemia and other cancers).

In 1992, Sadelain reported the first successful genetic engineering of primary T cells. In 2002, his lab was the first to report the design of receptors for antigen that comprise both activating and costimulatory domains, thereby enabling the generation of effective therapeutic T cells from peripheral blood cells. All current FDA-approved CARs follow this dual-signaling paradigm. In 2003, Sadelain identified CD19 as an optimal CAR target and provided the first experimental evidence that engineered human T cells could eradicate CD19+ lymphomas and leukemias in mice. After establishing cGMP vector production and CAR T cell manufacturing at MSK, Sadelain and his team reported in 2013 the first dramatic responses to CD19 CAR therapy in adults with relapsed and refractory ALL, highlighted in Science’s “Scientific breakthrough of the year” and later earning FDA’s “Breakthrough designation”. The Center for Cell Engineering team has by now treated >550 patients with CAR T cells produced at MSK.

CD19 CAR therapy is a true paradigm shift: it has not only changed the standard of care for B cell malignancies but ushered a new class of drugs (engineered T cells directed by synthetic receptors, which Dr Sadelain nicknamed “living drugs”) and served as a catalyst for evolution in the pharmaceutical industry (which had not embraced cell-based medicines before the advent of CD19 CAR T cells). There are today >100 potential CAR targets reported in the literature, >1000 CAR trials listed at clinicaltrials.gov. CARs are now investigated worldwide for cancer, infectious diseases, autoimmunity and senescence-associated pathologies. CAR T cells targeting CD19 have shown promising early results for the treatment of systemic lupus erythematosus.

Dr. Sadelain remains very engaged in CAR research, combining basic innovation and clinical relevance to pursue the goal of making CAR therapy more effective, more broadly applicable and safer. His lab has modeled and unraveled some of the mechanisms of CAR toxicity, augmented the potency of CAR T cells based on signaling, genome editing and epigenetic programming and demonstrated that CAR T cells could be derived from pluripotent stem cells, which may eventually forego the need to collect and process T cells from patients.

Michel Sadelain is the recipient of the Cancer Research Institute’s Coley Award for Distinguished Research in Tumor Immunology, the Sultan Bin Khalifa International Award for Innovative Medical Research on Thalassemia, the NYPLA Inventor of the Year award, the Passano, Gabbay, Pasteur-Weizman/Servier and Leopold Griffuel awards, the INSERM International Prize, the Breakthrough Prize for Life Sciences and the Gairdner International Award. He previously served as President of the American Society for Gene and Cell Therapy.