Scientists develop new immuno-therapeutic approach to target brain metastatic melanomas

In a collaborative effort, a pair of stem cells work together to stimulate the immune system, resulting in the suppression of tumor growth and extended survival in representative preclinical models.

Patients diagnosed with melanoma that has metastasized to the brain typically face a survival period of only four to six months. The field of immunotherapy, which utilizes the immune system to combat cancer cells, has generated significant enthusiasm as a potential game-changer in the treatment of metastatic melanoma. However, early clinical studies have shown limited success, leaving most patients with a bleak prognosis. In a groundbreaking study, scientists from Brigham and Women's Hospital, an integral part of the Mass General Brigham healthcare system, have combined multiple therapeutic approaches to more effectively target melanoma in the brain. Through preclinical experiments utilizing advanced mouse models that closely resemble human conditions, the researchers achieved the activation of immune responses. These promising findings have been published in Science Translational Medicine.

''We know that in advanced cancer patients with brain metastases, systemic drugs, given intravenously and orally, do not effectively target brain metastases. 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."

Scientists have developed a therapy that utilizes an engineered "twin stem cell model" to maximize the attack on cancer cells that have spread to a specific area of the brain called the leptomeninges. In this approach, one stem cell releases an oncolytic virus, which has previously demonstrated promise in reducing tumor growth. By using stem cells as delivery vehicles for the virus, the amount of virus released is amplified, and its degradation by circulating antibodies is prevented until it reaches the cancer cells.

However, the oncolytic virus also destroys the very cells that release it, making it an unsustainable standalone therapy. To address this issue, the researchers employed CRISPR/Cas9 gene editing to create a second stem cell that is resistant to the oncolytic virus. This second stem cell releases proteins known as immunomodulators, which strengthen the immune system's ability to combat the cancer. The twin stem cells can be administered through intrathecal injection, a technique already used in the treatment of other diseases. Unlike many recently emerged immunotherapies, this approach does not require repeated administration. The scientists highlight the potential application of this strategy to other cancers with brain metastasis, such as lung and breast cancer, and are actively working on developing similar treatments for these malignancies.

Significantly, the researchers designed a preclinical mouse model that faithfully replicates the human model of melanoma with leptomeningeal metastasis. This model was used to test the therapy, and the results demonstrated successful activation of immune responses that closely mimic human responses. These findings increase the prospects for success in a Phase I trial, which the authors plan to initiate in the near future.

Shah, one of the authors, highlighted the tendency of many promising biological therapies to fail in clinical trials due to inadequate replication of clinical settings in preclinical models. By addressing this crucial aspect, the researchers believe they are closing the gap in achieving a cure for brain metastases that has persisted for the past two decades.

Source : Brigham and Women's Hospital