Rapid progress through the late 2000s quickly led to clinical cancer trials of CAR-T cells that targeted CD19 (Figure 1.6). CD19 is a protein on the surface of immature B cells that remains present until they become fully mature plasma cells. The BCR plays an important role in B cell development: if the receptor recognises an antigen in the right circumstances, the B cell will continue to mature, grow and divide, eventually becoming a plasma cell, at which point it starts secreting its BCR as a soluble antibody. B cell cancers can arise at any time during B cell development; for example, leukaemias can arise from earlier-stage cells and lymphomas from later-stage cells. Generally, the more immature the cell that the cancer originates from, the faster growing the cancer. 

Figure 1.6 Timeline of CAR-T cell development. ALL, acute lymphoblastic leukaemia; AML, acute myeloid leukaemia; CAR, chimeric antigen receptor; FDA, Food and Drug Administration; TCR, T cell receptor. Adapted from Filley et al. 2018.

Most cancerous B cells express CD19 on their surface; in fact, it is probably crucial to their survival. In healthy individuals, much like the CD3ζ protein in T cells, CD19 transmits signals to the B cell to tell it that the BCR has recognised an antigen. In cancer, this signalling becomes dysregulated and it can occur without antigen binding, thus providing inappropriate activation, survival and growth signals to the cell. CD19 is therefore a good CAR-T cell target as cancer cells seem to have a tough time surviving without it. Furthermore, it is only present on immature B cells, not on mature antibody-producing cells, haematopoietic stem cells or other tissues.

As CD19 is not cancer specific, CD19-targeting CAR-T cells wipe out all the healthy B cells as well as cancer cells. However, unlike T cells, B cells are not as crucial to health, particularly as plasma cells remain unaffected. If required, patients can be infused with antibodies from healthy donors – intravenous immunoglobulins.