Implants could transform CAR-T therapy into one-day procedure

There are three types of white blood cells.  T lymphocytes, B lymphocytes and natural killer cells.

CAR-T therapies have revolutionised the treatment of some blood cancers, but are costly as well as time- and resource-intensive. Now, US researchers think one solution could be an implant that generates T cells within the body to attack the cancer.

It is early days for the concept, but its developers – from North Carolina State University and the University of North Carolina – have completed a proof-of-concept study that shows it works in animal models and could start to attack the cancer in a single day.

At the moment, it can take weeks to complete the CAR-T process, which includes harvesting of T cells from the patient an shipment to a manufacturing unit, engineering, activation, and expansion of the cells, quality control checks and shipment back to the hospital for re-infusion into the patient.

In some cases where the cancer is particularly aggressive, that timeframe may simply be too long to be a viable option for the patient. It is also expensive, at up to $500,000 per procedure.

The UNC and NCSU team, led by biomedical engineer Yevgeny Brudno, report in Nature Biotechnology how they have developed an implant that can generate the CAR-T cells in vivo.

It is based on an FDA-approved biocompatible, sponge-like material called MASTER, which has antibodies that activate T cells as well as interleukins that promote proliferation.

A mixture of T cells isolated from the human donor and viral particles to engineer them is introduced into the sponge, which is then surgically implanted into the patient the same day. The T cells are modified, activated and proliferate – all within the implant – from which they are steadily released as fully functional CAR-T cells to attack the tumour.

In a mouse model carrying human lymphoma cells, the CAR-T cells made in the implants were better at fighting the cancer cells than a control group manufactured using the current production method and delivered intravenously.

They were also healthier, with superior sustainability in the body and more anticancer potency, and showed fewer signs of differentiation or other cellular changes associated with T-cell exhaustion, a condition in which they lose activity.

The CAR-T cells targeted CD19, working in a similar way to current commercial CAR-Ts from Gilead Sciences, Novartis and Bristol-Myers Squibb.

"Our MASTER technology takes the cumbersome and time-consuming activation, reprogramming and expansion steps and performs them inside the patient," said Dr Pritha Agarwalla, one of the researchers behind the work.

"The large pores and sponge-like nature of the MASTER material brings the virus and cells close together, which facilitates cellular genetic reprogramming," she added.

The researchers also found that the improvement in anticancer efficacy was particularly noticeable over the long term, when mice were reimplanted with lymphoma cells to represent a recurrence.

They now want to test the implant approach to see how it performs against solid tumours, which have proved to be a challenging target for current CAR-T therapies.