Stop relapses
A new cell therapy for glioblastoma has been proposed
Elena Kleshchenko, PCR.news
Glioblastoma is an aggressive brain cancer that often recurs after surgery. Researchers from the USA have proposed a strategy to prevent relapses. It combines the detection of target receptors on circulating cancer cells in the patient's blood and therapy with donor stem cells in a biodegradable hydrogel.
Hydrogel-encapsulated stem cells (green) track and destroy glioblastoma cells (red). Credit: Shah lab (CSTI).
Glioblastomas are highly aggressive cancerous tumors of the brain and spinal cord. They are difficult to treat, including because many antitumor drugs cannot pass through the blood-brain barrier. More than 90% of glioblastomas recur after surgical removal. Data from the Cancer Genome Atlas (TCGA) of patients with glioblastomas show only a 6% five-year survival rate.
A new study led by scientists from Brigham and Women's Hospital in Boston, USA and Harvard Medical School has developed a new strategy for the treatment of glioblastoma after surgery. This is a cell therapy using donor stem cells modified so that they attack glioblastoma cells. A hydrogel containing cells is placed on the site of the removed tumor
The patient's own stem or immune cells are often used for cell therapy. But patients with glioblastoma are usually operated on within a week due to the rapid progression of the disease, and there is not enough time to develop individual therapy. The new approach involves the use of "blanks" — allogeneic (taken from a donor, not from the patient himself) stem cells.
To identify a group of patients who could benefit from therapy, the researchers identified potential targets — "death receptors" (DR) on circulating tumor cells (CCCs) in the bloodstream of mice or people with glioblastomas. The CD146 biomarker, usually expressed on tumor cells, was used for enrichment.
"As far as we know, this is the first study that identifies target receptors on tumor cells prior to therapy and uses a biodegradable, gel-encapsulated, standard therapy based on modified stem cells after tumor surgery," he said. The head of the study is Khalid Shah. "In the future, we will use this strategy to quickly identify target receptors after a person receives a diagnosis of glioblastoma, and then introduce a ready—made gel-encapsulated therapeutic agent with stem cells from a pre-prepared reservoir."
The researchers took stem cells from the bone marrow of healthy donors and transformed them with a specially developed lentiviral vector so that they expressed the TRAIL ligand DR, which initiates cell death. To make the therapy safer, a "kill switch" was also built into the cells — Herpes simplex virus thymidine kinase (HSV-TK). The "switch" is activated by the antiviral drug ganciclovir, while not only the modified cells die, but additional death of cancer cells is observed due to the transfer of HSV-TK through intercellular contacts.
Therapeutic cells called MSC bif (bifunctional mesenchymal stem cells) provided stable ligand expression and at the same time did not express HLA antigens of classes I and II, that is, they were non-immunogenic. Cell kinetics was evaluated in bioprinted brain models.
The therapy demonstrated high efficacy in mouse models of glioblastoma: 100% of mice receiving encapsulated MSCbif lived more than 90 days after treatment. The average survival time of mice who underwent surgery alone was 55 days. The researchers further assessed safety by conducting several studies on mice using different doses of cell therapy, and found no signs of toxicity.
According to the authors, phase 1 clinical trials of the therapy may be initiated within the next two years. Similar therapy can be applied to other solid tumors. "This work lays the foundation for the creation of a biobank of engineered therapeutic stem cells targeting various tumor cell receptors and immune cells in the tumor microenvironment, which we will one day be able to use to treat a wide range of difficult—to-treat cancers such as glioblastomas," says Khalid Shah. He and some other co-authors of the article are associated with AMASA Therapeutics, a company developing methods of cell therapy for cancer.
Article by Bhere et al. Target receptor identification and subsequent treatment of resected brain tumors with encapsulated and engineered allogeneic stem cells is published in the journal Nature Communications.
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