‘Plug-and-play’ CAR T platform enables post-infusion immune cell reprogramming

Researchers at City of Hope have developed a new ‘plug-and-play’ technology that could allow scientists to modify CAR T cells after they have been administered to patients, potentially helping the treatment adapt as cancers evolve.

The preclinical study describes a platform designed to give researchers greater control over genetically engineered immune cells and redirect them towards different cancer targets.

CAR T-cell therapy genetically reprograms immune cells to identify and destroy cancer. While the personalised treatment has changed the way we treat some blood cancers, current CAR T-cell therapies are largely fixed once the engineered cells have been returned to the patient’s bloodstream.

The bottom line is that tumours adapt to CAR T therapies, leading to treatment failure and cancer relapse. To remain effective, our therapies need to adapt too. City of Hope has created a system that allows us to reconfigure these potent cancer killers as the tumour progresses.”

Dr John Williams, Director, City of Hope’s X-ray Crystallography Core

 

Building a flexible CAR T-cell platform

CAR T cell treatments can have a limited lifespan and cause serious side effects. They also cannot currently be altered after infusion. As tumours evolve and develop mechanisms to evade immune attack, the effectiveness of CAR T cells can decline, potentially allowing cancer cells to survive and contribute to relapse.

Williams worked with co-senior author Dr Christine Brown, Deputy Director of T Cell Therapeutics Research Laboratories at City of Hope, to develop the new approach. The research builds on Williams’ earlier work involving meditope, a molecular ‘docking system’ designed to allow additional capabilities to be added to immunotherapies.

The researchers redesigned CAR T cells so they could connect with a small molecule known as meP, creating a new type of engineered cell called meCAR T.

Laboratory experiments then demonstrated that meCAR T cells could be equipped with different molecular add-ons to help track the cells, support their growth and enable them to recognise a broader range of cancer cells.

“The power of this platform is its flexibility,” said Dr Christine Brown, City of Hope’s Heritage Provider Network Professor in Immunotherapy. “Instead of hardwiring every function into a CAR T cell, we can use protein-adaptor plug-ins to add new capabilities as needed, improving their ability to overcome tumour heterogeneity and other barriers that limit CAR T therapy in solid tumours.”

Clinical trials planned

The researchers are now working towards clinical testing, with two Phase I trials being developed to assess the safety and activity of meCAR T cells in patients with solid tumours and acute myeloid leukaemia.

“We’re excited about this new platform that allows us to control CAR T cells,” said Dr Brown. “Our approach potentially could be applied across many different cancers and other diseases for which CAR T cell therapies are being developed.”

City of Hope has one of the largest cellular therapy programmes in the US and treats about 90 percent of its CAR T patients in an outpatient setting. More than 2,000 patients have taken part in its immune effector and CAR T cell trials.

The organisation said its researchers are continuing to move laboratory discoveries into clinical care, including personalised immunotherapies and other next-generation treatments aimed at improving patient outcomes and quality of life.