CAR-T cell therapy wasn’t invented by a single person. It emerged from the work of three key scientists across two decades: Zelig Eshhar, who built the first prototype in the early 1990s; Michel Sadelain, who solved the problem of keeping engineered cells alive long enough to fight cancer; and Carl June, who led the clinical trials that proved the therapy could save lives. Their combined contributions turned an experimental concept into one of the most significant advances in cancer treatment.
Zelig Eshhar: The Original Concept
Zelig Eshhar, an immunologist at the Weizmann Institute of Science in Israel, is widely credited with creating the first chimeric antigen receptor. In a 1993 paper published in the Proceedings of the National Academy of Sciences, Eshhar described a new kind of engineered gene: a fusion of an antibody’s targeting region with the signaling machinery inside a T cell. The idea was elegant. Antibodies are naturally good at recognizing specific targets, and T cells are naturally good at killing. Eshhar’s invention stitched those two abilities together into a single molecule that could be inserted into a patient’s own immune cells.
These first-generation CARs worked in the lab but had a critical limitation. The engineered T cells could find cancer cells, but they didn’t survive long enough in the body to mount a sustained attack. Without additional activation signals, the cells fizzled out quickly after encountering their target. Solving that problem would take another group of researchers and nearly another decade.
Michel Sadelain: Making the Cells Last
Michel Sadelain, a researcher at Memorial Sloan Kettering Cancer Center in New York, made the breakthrough that turned Eshhar’s concept into something clinically viable. The problem with first-generation CARs was that tumor cells don’t provide the co-stimulatory signals T cells need to stay active and multiply. In healthy immune responses, those signals come from molecules on the surface of the cells presenting a threat. Most cancers don’t express those molecules, so the engineered T cells essentially ran out of fuel.
Sadelain’s team and several other groups incorporated a co-stimulatory signaling component directly into the CAR molecule itself, creating what became known as the second-generation CAR. In clinical testing on lymphoma patients, the difference was stark. T cells carrying the enhanced receptor expanded dramatically in the bloodstream and persisted for weeks. T cells with only the original signaling domain failed to expand after infusion and became virtually undetectable within six weeks. At every time point tested over the first four weeks, the second-generation cells were present at significantly higher levels. This was the engineering fix that made CAR-T therapy practical.
Carl June and the First Pediatric Success
Carl June, an immunologist at the University of Pennsylvania, led the clinical effort that brought CAR-T therapy from the lab into patients. His team first enrolled adult patients with blood cancers, and several responded well. Then, on April 17, 2012, a seven-year-old named Emily Whitehead became the first child to receive the treatment. She had acute lymphoblastic leukemia (ALL), the most common childhood cancer, and had been fighting it for over a year with no lasting success.
The treatment nearly killed her. Emily developed a severe inflammatory reaction, now recognized as cytokine release syndrome, where the activated T cells trigger a dangerous cascade of immune signaling. Her medical team at the Children’s Hospital of Philadelphia, led by oncologist Stephan Grupp, discovered that one particular inflammatory protein was at extraordinarily high levels, and that an existing drug could block it. That intervention changed everything. Three weeks after receiving the engineered T cells, Emily was in remission. Bone marrow checks at three months and six months showed no disease. More than ten years later, the cancer-fighting T cells are still detectable in her body.
Emily’s case proved two things: the therapy could work in children, and the most dangerous side effect could be managed. It also demonstrated that some patients could skip bone marrow transplants entirely.
How CAR-T Cells Work
The therapy starts with collecting a patient’s own T cells through a blood-draw process. Those cells are sent to a manufacturing facility where they’re genetically modified to produce a chimeric antigen receptor on their surface. This receptor has an external portion, derived from an antibody fragment, that locks onto a specific protein found on cancer cells. The internal portion contains the signaling domains that activate the T cell and keep it multiplying. Once enough cells are grown, they’re infused back into the patient.
The manufacturing process typically involves one to two weeks of growing cells in the lab, though newer abbreviated methods can shorten the hands-on time to as little as 24 to 72 hours. The total time from drawing blood to infusing the finished product is often longer, because it includes shipping, quality testing, and preparing the patient with chemotherapy to make room for the new cells.
FDA Approval and Current Therapies
On August 30, 2017, the FDA granted approval to the first CAR-T therapy for patients up to age 25 with B-cell ALL that had relapsed or stopped responding to other treatments. It was a landmark moment: the first gene therapy of any kind approved in the United States.
As of 2025, six CAR-T products have FDA approval, each targeting different blood cancers:
- Kymriah for ALL in young adults, certain large B-cell lymphomas, and relapsed follicular lymphoma
- Yescarta for large B-cell lymphoma that doesn’t respond to or relapses after initial treatment
- Tecartus for mantle cell lymphoma and relapsed B-cell ALL in adults
- Breyanzi for large B-cell lymphoma and chronic lymphocytic leukemia
- Abecma for multiple myeloma after prior treatments
- Carvykti for multiple myeloma after at least one prior treatment line
All currently approved CAR-T therapies target blood cancers. For relapsed ALL, the type Emily Whitehead was treated for, more than 90% of patients who receive CAR-T therapy now go into remission. Roughly half of those patients remain cancer-free long term.
The Challenge of Solid Tumors
The biggest open question in the field is whether CAR-T therapy can work against solid tumors like lung, breast, or colon cancer. Blood cancers are relatively easier targets because the cancer cells float freely and share a common surface protein the CAR can lock onto. Solid tumors are harder for several reasons: the cancer cells within a single tumor don’t all display the same surface proteins, and the environment around the tumor actively suppresses immune cells. Researchers are testing strategies like engineering T cells to target multiple proteins at once and combining CAR-T therapy with checkpoint inhibitors, drugs that release the brakes tumors put on the immune system. No CAR-T therapy for solid tumors has reached FDA approval yet.