Tumours evading CARs…are we ready to fight back?
CAR-T therapy has been a major innovation in cancer treatment, revolutionizing the care of patients with various forms of leukaemia. Nonetheless, 7-25% of patients with B-cell acute lymphoblastic leukaemia relapse after a period of therapy. Researchers described the mechanisms through which the tumour escapes the treatment and returns stronger than before.
Not only we harness the immune system against cancer, but we also “weaponize” immune cells with potent tools, such as the CAR (Chimeric Antigen Receptor). This is an artificial receptor engineered in laboratory and inserted into the patient’s T-cells, formerly isolated from its bloodstream and then re-infused back. Once armed with the receptor, the so-called CAR-T cells become extremely good at recognizing cancer cells expressing a particular marker and much more aggressive.
The Food and Drug Administration (FDA) has approved two CAR-T cell products against B cell acute lymphoblastic leukaemia expressing one surface marker called CD19. The presence of CD19 is the signal by which CAR-T identify cancer cells and is therefore necessary for therapy to work. What happens in relapsing patients?
Loss of the marker CD19
Unfortunately, relapsed tumours are often CD19 negative. Since CD19 expression is lost, cancer cells can escape CAR-T and the tumour becomes resistant to therapy. Mutations in the gene encoding CD19 can generate shorter variants lacking the signalling sequence necessary for their localization on the membrane. CAR-T can only bind CD19 when exposed on the surface of cancer cells; as a result, cells bearing this mutation become resistant and so do their descendants. That is a classic example of natural selection: the strongest ones survive and their characters can be transmitted to the progeny and spread in the population.
Careful to CAR insertion site!
Loss of CD19 is quite predictable. It is in fact quite common that cancer cells escape our treatments by downregulating the expression of targeted molecules: we continue to waste munitions, while we no longer see the target. A second mechanism is rarer and associated with CAR-T manufacturing process. This is a unique case report, but is worth to mention it. In a paediatric patient relapsed after CD19 CAR-T treatment, CAR molecule was introduced by mistake into a single leukemic cell, as well as in lymphocytes. Once re-infused back, the single cell expanded, generating a “clone”, a group of identical cell descendants, where CAR has happened to insert on the cell surface right next to CD19…too close! The relapsed tumour was composed of this one clone, which was resistant to therapy because CD19 was “masked” by CAR and therefore inaccessible to CAR-T cells in the patient.
Are we ready to fight back?
Studying the mechanisms through which tumours lose CD19 and escape CAR-T therapy would allow to design more effective CARs in order to overcome these limitations. For example, more stringent methods of CAR-T cells manufacturing may be needed to exclude the possibility (actually quite remote) of tumour cells contamination. In addition, CARs engineering strategies may be improved, as to generate CAR-T that can recognize multiple targets, rendering the onset of resistant clones less likely.
Orlando et al. (2018). Genetic mechanisms of target antigen loss in CAR19 therapy of acute lymphoblastic leukemia. Nature medicine 24, 1504–1506.
Ruella et al. (2018). Induction of resistance to chimeric antigen receptor T cell therapy by transduction of a single leukemic B cell. Nature medicine 24, 1499–1503.