Implanted system rapidly generates CAR-T cells to combat tumors in mice

Reuters Health - 04/04/2022 - An implantable system can both produce and release CAR-T cells in the body to combat cancer, a mouse study shows.

The system, called MASTER (Multifunctional Alginate Scaffolds for T cell Engineering and Release), is a biocompatible, sponge-like material decorated with antibodies. When it comes in contact with patient T cells combined with an engineered virus, the T cells become activated and the engineered virus reprograms them into CAR-T cells.

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

"CAR-T cell production currently involves a sequence of laborious steps, each requiring different biological signals," Dr. Yevgeny Brudno of North Carolina State University in Raleigh told Reuters Health by email. "Biomaterials can present each of these signals to the cells, enabling the manufacturing process to move from the flask into the body."

"Moving CAR-T cells inside the body minimizes the time that cells spend outside the body, which leads to more functional cells that persist longer and have better antitumor function," he said.

When seeded with human peripheral blood mononuclear cells (PBMCs) and CD19-encoding retroviral particles, MASTER provides the appropriate interface for viral vector-mediated gene transfer, Dr. Brudno and colleagues explain in Nature Technology. They showed that after subcutaneous implantation, MASTER mediated the release of functional CAR-T cells in mice.

Further, in a mouse xenograft model of lymphoma, they treated one group of mice with CAR-T cells that were created and delivered using MASTER, and a second group with CAR-T cells that were created conventionally and delivered intravenously. The two groups were compared to a control group receiving non-engineered T cells.

Tumors grew rapidly in controls, whereas MASTER-produced CAR-T cells and conventional intravenously infused CAR-T cells equally controlled tumor progression up to day 45. At 100 days, however, intravenous infusion of 4 million conventionally produced CAR-T cells led to 16.6% tumor-free survival. In contrast, implantation of MASTER with 2 million PBMCs increased tumor-free survival to 50%.

Regarding persistence, compared to conventional CAR-T cells, MASTER-generated CAR-T cells had nearly 30-fold higher absolute counts in the peripheral blood at 22 days and significantly increased counts in the bone marrow and spleen at 32 days.

Dr. Brudno said, "The next step is to apply MASTER to the treatment of solid tumors such as brain cancer and pancreatic cancer. In addition, we believe that the principle enabling MASTER - moving cell manipulation in vivo - could be very promising in other diseases, including fibrosis and inflammatory disease."

"The biggest challenge to moving this approach forward to the clinic is a regulatory one," he noted. "Although the MASTER method for making CAR-T cells is both incredibly fast and therapeutically promising, because the process happens inside the body, the products are not as well defined and can not undergo rigorous quality control that are standard in the conventional CAR-T production process."

"We will need to work with regulatory agencies to think through the ramifications of this (challenge) and balance the significant benefits and potential risks of this technology," he concluded.

Dr. Johanna Olweus, Head, Department of Cancer Immunology at the Institute for Cancer Research at Oslo University Hospital Radiumhospitalet and the University of Oslo, commented on the study in an email to Reuters Health.

"The manufacturing procedure for gene-modified immune cells represents one of the biggest hurdles for development of new cell and gene therapies to treat cancer," she noted. "It is so time-consuming and technically challenging that only a few academic centers can do it, and commercial providers charge extreme prices for cell-manufacturing services. Thus, many promising new concepts for cell and gene therapy never reach patients."

"(The authors) provide a very exciting solution to the problem: the patient becomes the site of cell-manufacturing," she said. "By installation of small 'micro-factories' for production of the gene-modified cells under the skin, the procedure is greatly simplified and costs can be reduced."

"In addition," she noted, "data from mice suggest that the gene-modified T cells will kill the cancer cells more efficiently when produced directly in the patient. The reason for this is most likely that extensive and lengthy handling of cells outside of the patient can be avoided, resulting in better functionality and persistence of the T cells."

"It will be very exciting to see data from clinical trials using (this) approach," Dr. Olweus concluded.

SOURCE: https://go.nature.com/36V72me Nature Biotechnology, online March 22, 2022.

By Marilynn Larkin



Posted on 4 April 20227 April 2022