Predicting and Managing Cytokine Release Syndrome in CART-19 Therapy
Modifying patient T-cells with chimeric antigen receptors (CARs) and then reinfusing them has been shown in clinical trials to be an effective treatment for certain forms of cancer. However, the use of a CART-19 therapy (a specific CAR T-cell) has been associated with a significant increase in the production of cytokines that can make a patient very ill.
A cytokine is a chemical that helps mobilize the cells of the immune system when a response is required. In the case of CART-19 in leukemia patients, the cytokine overexpressed is interleukin-6 (IL-6). While the CART-19 is effectively killing leukemic cells, the modified T-cells (likely in conjunction with other cells in the immune system) are also producing IL-6 at extremely high levels in some patients, making those patients extremely ill.
This is particularly worrisome since CAR T-cell therapy involves the permanent modification of T-cells — once reinfused into the body they cannot be removed, and the toxic effects of the therapy would be perpetuated indefinitely. Fortunately, there is an antidote for IL-6, called tocilizumab.
Researchers at the Center for Childhood Cancer Research, including David M. Barrett, MD, PhD, are studying T-cells from patients enrolled in a CART-19 clinical trial for leukemia. Using the cells in vitro and in mouse models, they hope to identify the genes that trigger the excessive release of IL-6.
Once those biomarkers have been discovered, at-risk children can be identified and earlier intervention provided should cytokine release syndrome occur.
If patients at a higher risk for developing cytokine release syndrome can undergo co-therapy of CART-19 and tocilizumab from the outset of treatment, perhaps the release of IL-6 can be stemmed at the start, allowing the CART-19 to work without the concomitant toxic effects associated with cytokine release syndrome.
Researchers are also hoping to determine whether co-therapy with tocilizumab as a matter of course in all patients treated with CART-19 will impair the effectiveness of CART-19.
If IL-6 is not necessary for the clinical response to CART-19, then all patients undergoing CART-19 therapy can be co-administered tocilizumab at the start of therapy. If, however, this IL-6 antidote in some way impairs clinical response, its use needs to be limited to the population of patients most likely to be sickened by CART-19 therapy.
A Phase II registration trial for submission to the FDA is presently underway to understand, predict and prevent cytokine release syndrome; an international clinical trial of CART-19 will begin soon.