Allogeneic engineered mesenchymal stem cells (MSCs) are a promising option for treating residual glioblastoma after surgery. Several studies have shown that in response to chemotactic signals released by glioblastoma, engineered MSCs hone to and incorporate into the tumor microenvironment to release a cytotoxic agent. Adult bone marrow MSCs are only weakly immunogenic, so immunosuppressive therapy is unnecessary.
What’s more, allogeneic cells can be banked, allowing the development of “off-the-shelf” commercial therapeutics that are readily available and of consistently high quality.
Researchers at Brigham and Women’s Hospital have designed a biologic agent, dubbed EnMSCBif, to bind to death receptor 5 (DR5) on the surface of glioblastoma cells and trigger extrinsic programmed cell death. Khalid Shah, MS, PhD, director of the Center for Stem Cell and Translational Immunotherapy and Vice Chairman of Research in the Department of Neurosurgery, and colleagues report in Nature Communications on the high potential of encapsulated bifunctional MSC (EnMSCBif) to be translated into clinical use.
Features of EnMSCBif
Suitable candidates can be identified—EnMSCBif is meant to be implanted in the tumor resection bed at the time of glioblastoma debulking/resection. Because of the short time from diagnosis of glioblastoma to surgery, it’s crucial to determine which patients are likely to respond.
Candidates will be those with DR5 identified on circulating tumor cells, obtained from a simple blood test. The researchers confirmed that DR5 is detectable in blood samples from patients with glioblastoma.
Encapsulated—The engineered MSCs are encapsulated in a biodegradable hydrogel capsule. That prevents them from being washed out of the treatment site by cerebrospinal fluid or blood.
Dual action—MSCs derived from the bone marrow of healthy adults deliver a DR5-specific ligand to target glioblastoma without harming surrounding healthy tissue. These MSC also expresses a “safety switch,” herpes simplex virus–thymidine kinase (HSV-TK). The idea is that once activated via injection of ganciclovir, HSV-TK will eliminate engineered MSC from the body.
Efficacy in Mice
In two mouse models, the researchers labeled patient-derived glioblastoma with a fluorescent protein and implanted it into mice, then two weeks later resected it and treated the animals with EnMSCBif. They found:
Primary tumor— All mice that received the gel encapsulated MSC-based therapeutic after surgery were still alive 90 days post-treatment, compared to mice that solely underwent surgery, which exhibited a mean survival time of 55 days. To activate the HSV-TK safety switch, ganciclovir injections were started on after EnMSCBif implantation, This reduced the tumor burden further indicating that HSV-TK activation contributed to killing glioblastoma cells (P<0.05 compared with resection alone). On day 150 after surgery, 100% of mice treated with EnMSCBif were still alive. The built-in safety switch into the MSC also allows tracking MSC by PET imaging.
Recurrent tumor—100% of mice were alive 90 days after treatment with EnMSCBif (ganciclovir was also administered). The median survival of mice treated with control MSCs was 55 days.
Safety and Commercial Feasibility
For separate experiments, the researchers generated EnMSCBif under Good Manufacturing Practice standards. Laboratory studies verified genetic stability, robust homing capabilities, low immunogenicity, and therapeutic stability, including during shipping.
Extensive dose-escalation studies in tumor-bearing mice and single-dose toxicity studies in non–tumor-bearing mice did not demonstrate any local or systemic toxicities.
This research was performed in consultation with the FDA, and an Independent New Drug Application has been filed for a first-in-human study of encapsulated and engineered MSC in patients with glioblastoma.