WEHI Wednesday Seminar hosted by Professor Shalin Naik

Dr Miles Horton

Research Officer – Naik Laboratory, Immunity division, WEHI

Correct-and-select: Multiplex prime editing enables drug-controllable cell therapies for blood and immune disease

Davis Auditorium

Join via SLIDO enter code #WEHIWednesday

Including Q&A session

There are many clinical situations in which selectively expanding therapeutically beneficial cells over pathogenic ones, inside the patient, would lead to better outcomes. They are surprisingly diverse: the need to promote some arms of immunity while simultaneously suppressing others, as is often necessary after a blood stem cell transplant; the need to favour engraftment of therapeutic CAR T cells over a patient’s own T cells; or the need for gene-corrected blood stem cells to outcompete the uncorrected, disease-causing ones that remain after gene therapy. The underlying problem is common to all of them. We can engineer a better cell, but once it is infused, we have no practical way to tilt the balance in its favour short of toxic chemotherapy.

Here we approached this problem with three guiding principles, the selecting drug should be one clinicians already prescribe routinely and know how to manage, resistance should come from rewriting single letters in the cell’s own genes rather than adding new genetic material, and those changes must neither impair the gene’s normal function nor involve any gene linked to cancer. From these we conceived CELECT, in which therapeutic cells are made selectively resistant to standard-of-care drugs, so that a drug the patient is already taking becomes the agent that selects for them.

Using multiplex prime editing, a precise form of CRISPR editing that rewrites single DNA letters without cutting the genome, we corrected driver mutations in T cells from patients with inherited immune dysregulation syndromes while simultaneously installing drug resistance. Corrected cells expanded selectively under immunosuppressive pressure in vivo, with minimal off-target editing or disturbance to the cells, and retained sensitivity to alternative agents, so the same cells can be rapidly suppressed if needed. We extend this platform across multiple modalities of adoptive T cell therapy. This lays the foundation for a correct-and-select platform for the 600-plus inherited blood and immune disorders, in which a patient’s own blood stem cells are corrected, made drug-selectable, and expanded under a tablet rather than chemotherapy.

Dr Miles Horton is a postdoc in the Immunology division at WEHI and a training paediatrician at the Royal Children’s Hospital. His work focuses on improving outcomes for patients with inherited blood and immune disease.

All welcome!