Assoc. Prof. Melissa Call: Improving the Safety and Efficacy of Chimeric Antigen Receptor (CAR) T Cell Therapies
CAR T-cell therapy is a revolutionary new type of treatment that ‘trains’ a patient’s own immune cells (T cells) to seek out and kill cancer. Dr Call and her team at WEHI have developed an innovative new technology that maintains the potent anticancer activity of CAR T-cell treatments while offering improved patient safety. This project aims to identify the best candidate therapies to bring to initial clinical trials. Improved CAR T cell therapies will provide better health outcomes and lower treatment cost with fewer dangerous side effects, ultimately allowing more patients with a broader spectrum of blood cancers to be treated with CAR T cells.
Blood cancers are the first to benefit from FDA/TGA-approved CAR T cell treatments, with this being shown to be a highly effective form of treatment for advanced B-cell acute lymphoblastic leukaemia (B-ALL) and a subset of non-Hodgkin lymphomas (NHL). This highly effective treatment comes with side effects that can be life-threatening and require additional critical hospital care for almost half of the patients who receive this treatment.
CAR T-cell treatment can be a very effective therapy for some blood cancers, however it can have serious and sometimes deadly side effects. Release of inflammatory cytokines is a normal function of the killer immune cells (T cells) that are used in CAR T-cell therapy, but these can reach dangerously high levels in some patients causing fever, hypotension, multiple organ failure and death is not rapidly treated. This is known as Cytokine Release Syndrome (CRS). The potentially lethal side effects of CAR T-cell therapy severely limit their use to patients with late-stage relapsed or otherwise untreatable disease.
Current strategies manage CRS risk by reducing the CAR T-cell dose or administering treatments that suppress the immune system. These strategies risk dampening or reversing the anticancer effect of CAR T-cells. The team at WEHI have been able to design a CAR T-cell that elicits much lower levels of inflammatory cytokines and CRS compared to the current CAR T-cells, while providing predictable and adjustable anti-cancer potency. This research will enable the team to identify the optimal balance of safety and anti-cancer potential for these new CAR T-cells and ultimately, transition this revolutionary treatment from an intervention for people with late-stage relapsed or otherwise untreatable disease to a font-line cancer treatment.
Associate Professor Melissa Call received her PhD in Molecular Medicine from the University of Auckland and was a Postdoctoral Fellow at the Dana-Farber Cancer Institute and Harvard Medical School where she studied the mechanisms of peptide-exchange in the MHC class II peptide-presentation pathway. She has been Laboratory Head in the Structural Biology Division at the Walter and Eliza Hall Institute since 2011. Her research, focussed on the single-pass receptors of white blood cells, brings novel approaches to elucidating how membrane embedded sequences dictate receptor function and brings engineering solutions to improve chimeric antigen receptor design.