Stem cell-based therapy for targeting skin-to-brain cancer

July 10, 2017
Credit: CC0 Public Domain

Investigators from Brigham and Women's Hospital (BWH) and the Harvard Stem Cell Institute have a potential solution for how to kill tumor cells that have metastasized to the brain. The team has developed cancer-killing viruses that can deliver stem cells via the carotid artery, and applied them to metastatic tumors in the brain of clinically relevant mouse models. The investigators report the elimination of metastatic skin cancer cells from the brain of these preclinical models, resulting in prolonged survival. The study, published online this week in the journal PNAS, also describes a strategy of combining this therapy with immune check point inhibitors.

"Metastatic tumors - often from lung, breast or skin cancers - are the most commonly observed tumors within the brain and account for about 40 percent of advanced melanoma metastases. Current therapeutic options for such patients are limited, particularly when there are many metastases," says Khalid Shah, MS, PhD, director of the Center for Stem Cell Therapeutics and Imaging (CSTI) in the BWH Department of Neurosurgery, who led the study. "Our results are the first to provide insight into ways of targeting multiple brain metastatic deposits with stem-cell-loaded oncolytic viruses that specifically kill dividing ."

In their search for novel, tumor-specific therapies that could target multiple brain metastases without damaging adjacent tissues, the research team first developed different BRAF wild type and mutant mouse models that more closely mimic what is seen in patients. They found that injecting patient-derived, brain-seeking melanoma cells into the carotid artery of these preclinical models resulted in the formation of many metastatic tumors throughout the brain, mimicking what is seen in advanced melanoma cancer patients. The injected cells express markers that allow them to enter the brain and are labelled with bioluminescent and fluorescent markers to enable tracking by imaging technologies.

To devise a potential new therapy, the investigators engineered a population of bone marrow derived mesenchymal loaded with oncolytic herpes simplex virus (oHSV), which specifically kills dividing cancer cells while sparing normal cells. Previous research by Shah and his colleagues shows that different stem cell types are naturally attracted toward tumors in the brain. After first verifying that stem cells injected to the brain would travel to multiple metastatic sites and not to tumor-free areas in their model, the team injected stem cells loaded with oHSV into the carotid artery of metastasis-bearing mice.. Injecting the stem cells loaded with oHSV into the , a likely strategy for clinical application, led to significantly slower tumor growth and increased survival, compared with the models that received unaltered stem cells or control injections. The oHSV loaded stem cells are ultimately killed by oHSV mediated oncolysis, preventing the engineered cells from persisting within the brain, which is an important safety component in the therapeutic use of these stem cells.

Due to an increasing body of evidence which suggests that the host immune response may be critical to the efficacy of oncolytic virotherapy, Shah and his colleagues also developed an immunocompetent melanoma mouse model and explored treating with both stem cell loaded oHSV and immune checkpoint blockers such as the ones that target the PD-1/PD-L1 pathway. They found that PD-L1 immune checkpoint blockade significantly improved the therapeutic efficacy of stem cell based oncolytic virotherapy in melanoma brain metastasis.

"We are currently developing similar animal models of brain metastasis from other cancer types as well as new oncolytic viruses that have the ability to specifically kill a wide variety of resistant ," said Shah, who is also a professor at Harvard Medical School and a principal faculty member at the Harvard Stem Cell Institute. "We are hopeful that our findings will overcome problems associated with current clinical procedures. This work will have direct implications for designing clinical trials using for in the brain."

Explore further: Stem-cell-based therapy promising for treatment of breast cancer metastases in the brain

More information: Wanlu Du el al., "In vivo imaging of the fate and therapeutic efficacy of stem cell-loaded oncolytic herpes simplex virus in advanced melanoma," PNAS (2017). www.pnas.org/cgi/doi/10.1073/pnas.1700363114

Related Stories

Stem-cell-based therapy promising for treatment of breast cancer metastases in the brain

April 24, 2015
Investigators from Massachusetts General Hospital (MGH) and the Harvard Stem Cell Institute have developed an imageable mouse model of brain-metastatic breast cancer and shown the potential of a stem-cell-based therapy to ...

Histone deacetylase 6 inhibition enhances oncolytic viral therapy

October 20, 2015
Gliomas are extremely aggressive brain tumors that are resistant to standard cancer therapeutics. Oncolytic viral (OV) therapy, which uses engineered viruses to infect and target tumor cells for destruction by the immune ...

Herpes-loaded stem cells used to kill brain tumors

May 16, 2014
(Medical Xpress)—Harvard Stem Cell Institute (HSCI) scientists at Massachusetts General Hospital have a potential solution for how to more effectively kill tumor cells using cancer-killing viruses. The investigators report ...

Scientists engineer toxin-secreting stem cells to treat brain tumors

October 24, 2014
Harvard Stem Cell Institute scientists at Massachusetts General Hospital have devised a new way to use stem cells in the fight against brain cancer. A team led by neuroscientist Khalid Shah, MS, PhD, who recently demonstrated ...

MicroRNA molecule may serve as biomarker, target for brain metastases in breast cancer patients

February 5, 2013
Researchers have identified two molecules that could potentially serve as biomarkers in predicting brain metastases in patients with breast cancer, according to data published in Cancer Research, a publication of the American ...

Oncolytic viruses effectively target and kill pancreatic cancer stem cells

May 9, 2011
Oncolytic viruses quickly infect and kill cancer stem cells, which may provide a treatment for tumors that are resistant to conventional chemotherapy and radiation, particularly pancreatic cancer, according to new research ...

Recommended for you

Physical activity could combat fatigue, cognitive decline in cancer survivors

July 25, 2017
A new study indicates that cancer patients and survivors have a ready weapon against fatigue and "chemo brain": a brisk walk.

Breaking the genetic resistance of lung cancer and melanoma

July 25, 2017
Researchers from Monash University and the Memorial Sloan Kettering Cancer Center (MSKCC, New York) have discovered why some cancers – particularly lung cancer and melanoma – are able to quickly develop deadly resistance ...

Anti-cancer chemotherapeutic agent inhibits glioblastoma growth and radiation resistance

July 24, 2017
Glioblastoma is a primary brain tumor with dismal survival rates, even after treatment with surgery, chemotherapy and radiation. A small subpopulation of tumor cells—glioma stem cells—is responsible for glioblastoma's ...

New therapeutic approach for difficult-to-treat subtype of ovarian cancer identified

July 24, 2017
A potential new therapeutic strategy for a difficult-to-treat form of ovarian cancer has been discovered by Wistar scientists. The findings were published online in Nature Cell Biology.

Immune cells the missing ingredient in new bladder cancer treatment

July 24, 2017
New research offers a possible explanation for why a new type of cancer treatment hasn't been working as expected against bladder cancer.

No dye: Cancer patients' gray hair darkened on immune drugs

July 21, 2017
Cancer patients' gray hair unexpectedly turned youthfully dark while taking novel drugs, and it has doctors scratching their heads.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.