The first generation of CAR-T cells were developed almost 25 years ago but were not very effective in the clinic – likely because they received a single signal upon their activation and did not proliferate or persist long-term after their infusion.

Second generation of CAR-T cells (developed over the last decade) receive two signals upon their activation and have been shown to rapidly proliferate and persist for more than a year following their transfer into patients. More importantly, these second generation CAR-T cells targeting CD19, initially evaluated at various academic centers, have shown remarkable efficacy in phase 1 and phase 2 trials in patients with aggressive and indolent B-cell leukemias and lymphomas that have failed all standard therapies.

The promising results observed in the single institution studies led to licensing of these products to pharmaceutical companies that have initiated multicenter studies with the intent of obtaining approval from FDA and other registration authorities.

 

Side effects

 

The therapy can be associated with two common side effects, cytokine release syndrome and neurological side effects, which usually occur within the first one to two weeks after the CAR-T cell infusion.

Cytokine release syndrome is typically characterised by high fevers and flu-like illness. Drop in blood pressure, breathing difficulty, and organ dysfunction occur less commonly. Patients with neurological side effects are typically confused and disoriented for a few hours to a few days.

While a few patients had fatal complications in the early trials with CAR-T cell therapy, there is now better understanding of the mechanism of these side effects and this has led to improved management strategies. Consequently, these side effects are now generally reversible and most patients are able to resume their normal activities, including returning to work by four to six weeks. These extraordinary results from both of these multicenter trials are currently under review by regulatory agencies in multiple countries and both physicians and patients eagerly await their decision.

If approved, CD19 CAR-T cell therapy is likely to usher in a new era and substantially change the management of B-cell leukemias and lymphomas in the future. Moreover, CAR-T cell approaches against other targets such as CD22, CD30, and BCMA are also showing encouraging results in early trials and are likely to further improve outcomes not just in B-cell leukemias and lymphomas but also in patients with other cancers including Hodgkin lymphoma, T-cell lymphomas, and multiple myeloma.