Timeline of Progress
Click right to see how CAR T science developed and what MSK investigators contributed to this important field.
—Immune cells shown to protect mice from cancer
Scientists show that immune cells can kill cancer in mice. The exact cell types involved are not completely understood.
—Origin of T cells discovered
Immunologist Jacques Miller, while studying for his PhD at the University of London, identifies the thymus gland as the place where T cells develop.
—Bone marrow transplants used in cancer treatment
MSK scientists use bone marrow stem cells from an unrelated donor to replenish a patient’s blood cells after intensive chemotherapy. T cells from the donor kill cancer cells in the recipient. Many consider this to be one of the first successful immunotherapies.
—Tumor-infiltrating lymphocytes used to treat cancer
Steven Rosenberg and colleagues at the Surgery Branch of the National Cancer Institute treat patients with tumor-infiltrating lymphocytes. These cells are removed from a tumor and expanded in the lab before being given back to the patient in large numbers. A few patients are cured of advanced cancer, showing that a person’s own immune cells can fight cancer.
—T cell engineering begins
As a postdoctoral student at the Whitehead Institute at MIT, immunologist Michel Sadelain begins using newly developed genetic engineering tools, specifically retroviral vectors, to introduce genes into T cells, with the goal of making souped-up cancer fighters. This idea would bear fruit in the coming years.
—First-generation CARs developed
Immunologist Zelig Eshhar, of the Weizmann Institute in Israel, engineers T cells with the first chimeric molecule, a portion of an antibody fused to part of a T cell receptor. These will become known as first-generation CARs. While technologically innovative, these early CARs do not persist in the body and are not clinically effective.
—Antigen-specific T cells used in humans
The field takes a step forward when MSK scientists learn to isolate virus-specific T cells for use in stem cell transplants. These cells help prevent post-transplant infections and virally caused cancers in patients, and also limit graft-versus-host disease, a dangerous side effect.
—Co-stimulation shown to provide a necessary boost
Dr. Sadelain and colleagues show that introducing a co-stimulatory molecule (in this case CD28) into engineered T cells allows them to persist and remain active in the body, setting the stage for a new generation of CARs.
—First effective CAR T cells developed
The MSK team builds the first effective CAR T cells, targeted against a prostate cancer antigen. These second-generation CARs T cells are able to survive, proliferate, and kill prostate cancer cells in the lab, establishing the feasibility of CAR T cell therapy. An even more promising CAR target lay ahead.
—Second-generation CARs built to target CD19
Dr. Sadelain and colleagues publish a seminal paper showing that human CD19-directed CAR T cells can kill leukemia cells in a mouse model. This is the first time that CD19 is shown to be an effective target for CAR T cells. The field quickly follows suit.
—Recipe for CD19 CARs published
Dr. Sadelain and colleagues, including Isabelle Rivière, publish details of their manufacturing process for CD19 CAR T cells, to be used in patients with relapsed, chemorefractory leukemia. They show that the manufacturing process works and the cells are effective.
—Coley Award given for CAR T cell therapy
The Cancer Research Institute bestows the 2012 Coley Award for Tumor Immunology, jointly, to Michel Sadelain of MSK and Carl June of the University of Pennsylvania for their work contributing to the development of CAR T therapy.
—Results of CAR T leukemia clinical trial published
MSK physician-scientist Renier Brentjens and colleagues publish results of a clinical trial using CD19 CAR T cells in adults with acute lymphoblastic leukemia (ALL). This is the first published study using CARs to treat ALL in humans.
—Cancer immunotherapy voted “Breakthrough of the Year”
Science magazine votes cancer immunotherapy the 2013 “Breakthrough of the Year.” Among the approaches discussed is CAR T cell therapy.
—FDA designates CARs a “breakthrough” therapy
The FDA grants Breakthrough Designation status to CD19-directed CAR T cells, signaling the field’s scientific and clinical progress.
—Mesothelin-directed CARs developed
MSK physician-scientist Prasad Adusumilli publishes results on CARs built to recognize an antigen on solid tumors called mesothelin. Solid tumors require a different approach since they do not make CD19.
—Armored CARs developed
MSK scientists build CAR T cells that produce other molecules — so-called “armored CARs.” The cells are being tested as a treatment for ovarian cancer.
—CRISPR’d CARs built
Dr. Sadelain and colleagues show that the genome-editing tool CRISPR can be used to place a CAR at a specific genetic location in T cells, for improved functioning.
—First CARs cross the regulatory finish line
The FDA approves CD19-directed CAR T cells for the treatment of relapsed, refractory acute lymphoblastic leukemia in children and young adults.