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Two-Pronged Cell Therapy Targets Melanoma Spread to the Brain

3D, computer-generated image of cancer cells.
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A two-pronged stem cell therapy has been developed in a new study and is designed to target melanoma that has spread to the brain. The research, published in Science Translational Medicine, shows that the therapy can suppress tumor growth and prolong survival in preclinical animal models.

Poor prognoses with brain metastases

Melanoma is an aggressive skin cancer that frequently spreads to other distant sites in the body, known as metastasis. The brain is a common site for melanoma metastases and these are especially difficult to treat – patients typically have a median survival of just four to six months.


The development of new and innovative treatments such as immunotherapies – which help patients’ immune systems to fight cancer – has shown some promise. However, some small clinical studies suggest that the prognosis for the majority of patients remains poor.


In the current study, researchers have combined multiple therapeutic approaches that have shown potential in preclinical studies activating immune responses and targeting melanoma metastases in the brain.

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“We know that in advanced cancer patients with brain metastases, systemic drugs, given intravenously and orally, do not effectively target brain metastases,” said Prof. Khalid Shah, senior author of the study and vice chair of research in the Department of Neurosurgery at Brigham and Women’s Hospital. “We have now developed a new immuno-therapeutic approach that is sustainable and delivered locally to the tumor. We believe that locally delivered immunotherapies represent the future of how we will be treating metastases to the brain.”

Testing in preclinical models

The researchers from Brigham and Women’s Hospital designed their therapy by engineering a “twin stem cell model.” This consists of two different types of stem cells – one stem cell releases a cancer-killing (oncolytic) herpes simplex virus. The viruses infect and kill the target cells, and their production by the stem cells decreases the chance they will be degraded by circulating antibodies before reaching the cancer cells.


The second cell type is a stem cell engineered by CRISPR-Cas9 genome editing to resist destruction by the oncolytic virus, as the viruses destroy the very cells that produce it. These engineered cells produce proteins known as immunomodulators that strengthen the immune system and help it to attack cancer cells.


Together, these cell therapies help to effectively target cancer cells that have spread to a part of the brain known as the leptomeninges, the thin layers of tissue that cover the brain and spinal cord. The researchers tested the therapy in mouse models of melanomas lacking the protein PTEN (which are associated with brain metastases) as well as models of melanoma that have spread to the brain. In the latter, the therapy was administered via intrathecal injection, meaning it is delivered straight into the fluid-filled space between the brain and spinal cord and the leptomeninges.


Findings from the preclinical mouse models showed the therapy successfully activated immune cell responses, while also showing some therapeutic benefit in metastatic models by suppressing tumor growth and prolonging survival. These encouraging results suggest that the therapy may be more likely to succeed in a Phase I trial in humans.


“A number of biological therapies that look promising often fail in Phase I or Phase II clinical trials, in part because the preclinical models do not authentically replicate clinical settings,” said Shah. “We realized that if we did not fix this piece of the puzzle, we would always be playing catch-up. I don’t think we have been at a point in the last 20 years where we have been as close to curing metastases in the brain as we are now.”

Future clinical trials in humans

One important aspect of this potential therapy is that it does not need to be repeatedly administered, unlike other similar immunotherapies in the clinic. Additionally, the authors emphasize that this approach has the potential to be applied to other cancers, such as lung and breast cancer, which also spread to the brain. The researchers also hope to launch a Phase I trial soon to assess its efficacy in humans.


Reference: Kanaya N, Kitamura Y, Vazquez ML, et al. Gene-edited and -engineered stem cell platform drives immunotherapy for brain metastatic melanomas. 2023. Sci Transl Med. doi: 10.1126/scitranslmed.ade8732


This article is a rework of a press release issued by Brigham and Women's Hospital. Material has been edited for length and content.