Car T-cell immunotherapy has shown results where it has cleaned swept the diseases in terminal cases, however, still, there are cases where there are not successes and patients still suffer some fatal side effects. Hopefully, a study conducted by Seattle’s Fred Hutchinson Cancer Research Center might eradicate these side effects and look into differing aspects of these treatments.
Researchers examined the two main parts of CAR T-cell therapy; the T-cells of the patients that fight against the disease and a synthetic CAR (chimeric antigen receptor), fed into those T-cells to assist them finding and destroying cancer cells, through the process of signaling.
Dr. Stan Riddell, Fred Hutch’s immunotherapy research center’s leader, says that the mechanism of this signaling by the receptors is learned in the study, as this has not been previously understood well. Dr. Riddell along with Dr. Amanda Paulovich (mass spectrometry expert) and Alex Salter examined and compared two different molecules used in CAR T therapy, CD28 and 4-1BB.
Previously scientist thought that these molecules influenced the behavior of the treatment because they used different proteins for signaling. However, this is not the case. Salter from this study mentions that the difference of behavior of the treatments originates from the two receptor molecules themselves. They vary in the speed and strength of their signaling. 4-1BB emits a weaker and slower signal in contrast to CD28 emitting a faster and stronger signal. Surprisingly, the stronger and faster receptor CD28 performs worse than 4-1 BB when they were observed in mice with lymphoma.
CD28 had a strong anti-tumor action in the start but it receded as it exhausted the T-cells. Whereas 4-1 BB did not exhaust the T-cells and they retained their function. CD28 also leads to higher level of cytokines due to its rapid signaling, which may have adverse side effects.
Salter modified CD28 CAR to weaken its signal, increasing the effectiveness of treatment by nulling the side effects. This design should be followed in future CAR treatments, Salter says.
Understanding the mechanism of the CAR T treatment can reveal more effective ways to tune the therapy to work better for the patients. This way CAR T-cell therapies could become safer for people with the passage of time and study.