Early results of a revolutionary CAR-T cancer therapy fitted with an ‘on-off switch’ were reported at the 63rd annual American Society of Hematology (ASH) meeting in late 2021.
CAR-T – chimeric antigen receptor T-cell – therapy involves tweaking a patient’s immune T cells in a lab to carry a receptor that will target a cancerous cell type. The T cells are engineered and re-infused into the patient. Although CAR-T has proven remarkably effective in treating some unresponsive blood cancers, side effects include cytokine release syndrome and neurotoxicity symptoms. One solution is to build in a switch for T cell activity.
Now, Scripps Research in California, US, reports first-in-human clinical trial results of a CAR-T therapy (CLBR001) controlled through an antibody-based molecule – the switch (SWI019). This strategy is based on research in mice reported in 2016 (Proc. Natl. Acad. Sci., doi: 10.1073/pnas.1524155113).
‘A patient receives a single dose of switchable CAR-T followed by daily infusions of the switch for seven days,’ says Liana Nikolaenko, an oncologist at City of Hope, a national cancer institute and hospital in Los Angeles, California. ‘The switch infusion can continue, every 28 days, for up to six cycles.’
Five patients with non-Hodgkin lymphoma were treated in the Scripps trial (ClinicalTrials.gov id NCT04450069). One of the first three patients who received the lowest dose experienced a complete response to treatment, 11 months on. The trial will now recruit around three dozen patients into a dose-escalating study.
There were no adverse events related to the CAR-T product alone. After the switch molecule SWI019 was administered, which targets a protein on (cancerous) B cells, two of the five patients experienced cytokine release syndrome, an acute inflammatory side effect. This resolved quickly with treatment, followed by holding or reducing the dose of the switch molecule.
The switchable CAR-T was developed by Calibr, a division of Scripps Research focused on bench-to-bedside development of medicines, which has partnered with biopharma company Abbvie.
‘This particular platform was developed by Calibr to mitigate some of the side effects that are associated with other T cell products,’ says Nikolaenko. ‘The benefits would be that the dose administration of the SWI019 [switch] may mitigate the side effects of the therapy by tuning the levels of activity of the CLBR001 cells.’
The trial is currently recruiting patients with relapsed B cell malignancies in eight US medical centres.
‘In theory, toxicity may be controlled by discontinuing dosage of what Calibr calls the ‘switch’, and which I’ll call the ‘connector’ since it is designed to connect their CAR-T cells to tumour target cells,’ comments Bruce Levine, an oncologist at the University of Pennsylvania, US. ‘In my view it is not truly a switch as it does not turn T cells off, but prevents them from being further activated by a target to which the connector has bound.’
Without the connector, the CAR-T cell is not engaged or further activated and may return to a more resting state. ‘The amelioration of toxicity is dependent on how far into an inflammatory response the connector is discontinued,’ explains Levine.
Exerting precise control is the big challenge, he adds. ‘The connector must be given daily and then on a cycle appropriate to maintain CAR-T activity. The pharmacokinetics of conventional CAR-T cells are becoming understood. Understanding the pharmacokinetics of this system is more challenging,’ he warns. ‘To control toxicity, the patient needs to be closely monitored by their oncologist with knowledge of connector dosing. The windows for correct timing and dosing are as yet unknown.’
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