2013: First CAR-T Cell Therapy Success (2013)

In 2013, Carl June's group at the University of Pennsylvania published landmark results in the New
England Journal of Medicine documenting complete remissions in two adult patients with refractory
chronic lymphocytic leukaemia (CLL) treated with CD19-directed chimeric antigen receptor T (CAR-T)
cells. Simultaneously, reports of dramatic responses in paediatric acute lymphoblastic leukaemia
(ALL) captured global attention—most notably the case of Emily Whitehead, a six-year-old with
relapsed/refractory ALL who achieved complete remission in 2012 after CAR-T infusion and remained
disease-free years later.

The CAR-T concept originated with Zelig Eshhar at the Weizmann Institute in the late 1980s:
a chimeric receptor that fused an antibody-derived antigen-binding domain (single-chain variable
fragment, scFv) to intracellular T-cell signalling domains, enabling antigen recognition without
MHC restriction—bypassing a key mechanism of tumour immune evasion. Second-generation CARs added
co-stimulatory domains (CD28 or 4-1BB) to promote T-cell persistence and memory, dramatically
improving in vivo efficacy.

For CD19-directed therapy, T cells are harvested from the patient (autologous), transduced
ex vivo with a retroviral or lentiviral vector encoding the CAR construct, expanded to billions
of cells, and reinfused after lymphodepleting chemotherapy. The engineered cells then seek and
destroy B cells expressing CD19—eliminating both malignant and normal B cells. The cytokine
release syndrome (CRS) that can accompany rapid tumour cell killing, sometimes life-threatening,
was characterised and later managed with the IL-6 receptor antagonist tocilizumab.

These clinical results directly enabled the approvals of tisagenlecleucel (Kymriah) in 2017 and
axicabtagene ciloleucel (Yescarta) in 2017, the first commercial CAR-T products.