Newly developed gel helps improve the effectiveness of immunotherapy for glioblastoma



Combination of a newly developed gel with immunotherapy given to brains of post-operative mice with glioblastoma, a highly malignant and fatal cancer, improved the efficacy of immunotherapy, report researchers from the Lineberger Comprehensive Cancer Center from the University of North Carolina and their colleagues. The results appeared on October 6, 2021 in Scientists progress.

The researchers used CAR-T cell immunotherapy (chimeric antigen receptor T cells), which involves harvesting T cells from a patient’s immune system and engineering them genetically in the lab to recognize targets at the surface of cancer cells. In this mouse study, CAR-T cells and gel were placed to fill the area where a glioblastoma tumor had just been surgically removed. Previous studies have shown that administration of T cells alone produced a limited benefit.

Glioblastoma is an aggressive tumor that can form quickly in the brain and is diagnosed most often in people in their 60s. Only 40 percent of people live one year after diagnosis; only 17 percent survive for two years. Surgery is the first treatment used, but presents many challenges in removing the tumor while allowing wounds to heal.

We have developed a gel based on fibrin, a protein most often associated with blood clotting. The application of a gelled substance to an area of ​​the brain to facilitate CAR-T cell therapy is unique in the treatment of glioblastoma. The gel aided the distribution of CAR-T cells in the brain by acclimating the T cells to the post-surgical wound environment while preventing the tumor from reproducing. “

Edikan Ogunnaike, PhD, lead study author and biomedical engineer, Lineberger Comprehensive Cancer Center, University of North Carolina

The researchers used concentrations of human fibrinogen, a protein produced by the liver, which was transformed into fibrin with enzymes to develop a porous gel that was mixed with CAR-T cells and placed in the post-surgical brain area. . The gel created web-like scaffolds of fibrin in the brain, in which the CAR-T cells evenly become entangled in the pores of the scaffolds. Scaffolds are biodegradable and do not cause inflammation, tissue death or scarring.

Nine of 14 mice (64%) that received the gel and T cells were tumor-free 94 days after treatment, compared to two in 10 (20%) mice that received only T cells. The researchers said that if these findings could be replicated in human studies – they warn that many early lab results do not lead to clinical studies or new therapies – it would lead to a vast improvement in current treatment rates.

“Our approach has been beneficial in glioblastoma and we believe it may also control the growth or return of tumors in the brain, eyes and other organs,” said Gianpietro Dotti, MD, professor in the department of microbiology and Immunology at the UNC School of Medicine, co-chair of the immunology program at UNC Lineberger and corresponding author of this article. “It should be noted that the direct delivery of CAR-T cells to a post-surgical area must result in wide coverage of the surgical cavity surface to maximize the possibility of the T cells coming into contact with residual tumor cells, ie. This is where our flexible scaffolding has proven to be very beneficial. “

Researchers are currently planning to inject CAR-T cells into other parts of the brain. The process is being tested in pilot clinical studies to assess safety as well as to see if it elicits greater distribution of CAR-T cells.

“We hope that our gel will provide anti-tumor activity over a prolonged period after surgery in patients without inducing toxicity, which appears to be the case in mice,” Ogunnaike said. “The gel could also allow local administration of other biological agents that could support the growth of T cells and counter the suppression of immunotherapy.”

Besides Ogunnaike and Dotti, other authors of the article at UNC include Alain Valdivia, Mostafa Yazdimamaghani, PhD, Ernesto Leon, Seema Nandi, PhD, Hannah Hudson, Hongwei Du, PhD, Simon Khagi, MD, Barbara Savoldo, MD , PhD, Frances S. Ligler, PhD, and Shawn Hingtgen, PhD. Zhen Gu, PhD, is at the University of California in Los Angeles and Zhejiang University in China.

Source:

UNC Lineberger Complete Cancer Center

Journal reference:

Ogunnaike, EA, et al. (2021) Fibrin gel enhances the antitumor effects of chimeric antigen receptor T lymphocytes in glioblastoma. Scientists progress. doi.org/10.1126/sciadv.abg5841.


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