25 April 2022

An implantable biotechnology has been developed that produces and releases CAR-T cells to help attack cancer. The inventors believe it could help significantly reduce treatment delays.

The work was led by researchers from North Carolina State University and the University of North Carolina at Chapel Hill, USA. Writing in Nature Biotechnology, they say their proof-of-concept study, which involved mice carrying lymphoma cells, demonstrated that treatment with the implants was faster and more effective than that with conventionally-produced CAR-T cells.

Senior author Yevgeny Brudno, assistant professor in the joint biomedical engineering department at NC State and UNC, said: “A major drawback to CAR-T cell treatment is that it is tremendously expensive – hundreds of thousands of dollars per dose.

“Due to its cost, many people are shut out from this treatment. One reason for the high cost is that the manufacturing process is complex, time-consuming and has to be tailored to each cancer patient individually.

“We wanted to address challenges in CAR-T treatment related to both manufacturing time and cost.”

The research team created Multifunctional Alginate Scaffolds for T cell Engineering and Release (MASTER), a biocompatible, sponge-like material.

They isolated T cells from a human donor and mixed these naïve T cells with the engineered virus. This mixture was then poured on top of the MASTER, which has antibodies that activate the T cells.

In this study, the MASTER was surgically implanted into mice. As the T cells became activated, the modified viruses reprogrammed them into CAR-T cells.

First author Dr Pritha Agarwalla, a postdoctoral researcher in the joint biomedical engineering department, said: “Our MASTER technology takes the cumbersome and time-consuming activation, reprogramming and expansion steps and performs them inside the patient. This transforms the multi-week process into a single-day procedure.

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

The MASTER material is also impregnated with interleukins that foster cell proliferation. After implantation, the interleukins began to leach out, promoting rapid proliferation of the CAR-T cells.

In this mouse study, one group of mice with lymphoma was treated with CAR-T cells that were created and delivered using MASTER, while a second group was treated with CAR-T cells that were created conventionally and delivered intravenously. These two groups were compared to a control group that received non-engineered T cells.

While it would take at least two weeks to create CAR-T cells from naïve T cells for clinical use, the team introduced the MASTER into a mouse within hours of isolating naïve T cells.

The team says that because cells are implanted within hours of isolation, there is minimal manipulation, which creates healthier cells that exhibit fewer markers associated with poor anti-cancer performance in CAR-T cells.

The MASTER technique specifically results in cells that are less differentiated, which leads to superior sustainability in the body and more anti-cancer potency. The cells also display fewer markers of T-cell exhaustion, which is defined by poor T cell function.

Dr Agarwalla said: “The end result is that the mice that received CAR-T cell treatment via MASTER were far better at fighting off tumours than mice that received conventional CAR-T cell treatment.”

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

While the technology has worked well against lymphomas, the team now wants to test how it performs against solid tumours.

Source: Agarwalla P, Ogunnaike EA, Ahn S, Froehlich KA, Jansson A, Ligler FS, Dotti G, Brudno Y. (2022) “Bioinstructive Implantable Scaffolds for Rapid In Vivo Manufacture and Release of CAR-T Cells.” Nature Biotechnology, doi: 10.1038/s41587-022-01245-x

Link: https://www.nature.com/articles/s41587-022-01245-x

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