A new study has developed a two-pronged stem cell therapy targeting aggressive skin cancer melanoma that has spread to the brain. The study published in Science Translational Medicine shows that the therapy can suppress tumor growth and prolong survival in preclinical animal models. Although new and innovative treatments such as immunotherapies are very promising, the prognosis remains poor for most patients, as clinical trials show. Their results provide a promising allogeneic SC – based immunotherapeutic strategy against CNS melanoma and a roadmap for clinical implementation.
Due to the fact that in patients with advanced cancer and brain metastases, systemic drugs such as oncolytic virus do not effectively target brain metastases, mainly because of their medication administration routes as well as immunosuppressive nature of tumors in the brain, in the current study, researchers from Brigham and Women’s Hospital, Boston (USA) combined multiple immunotherapeutic approaches that have shown potential in preclinical studies activating immune responses and targeting melanoma metastases in the brain.
To address this challenge, scientists first created PTEN-deficient melanoma brain metastasis mouse models (BRAFV600E/PTEN−/− and BRAFV600E/wt/PTEN−/− ) and characterized them as more immunosuppressive than primary melanoma to mimic clinical conditions. Next, they developed an allogeneic twin stem cell (TSC) system composed of two different types of tumor-targeting stem cell (SC) populations. One population released a cancer-killing (oncolytic) herpes simplex virus (oHSV). The viruses infect and kill the target cells, while their production by the stem cells reduces the likelihood that they will be cleared by circulating antibodies before they reach the cancer cells. The other SC population was CRISPR-Cas9 gene-edited to knock out nectin 1 (N1) receptor (N1KO) and resist destruction by oHSV. These SCs release immunomodulators such as granulocyte-macrophage colony-stimulating factor (GM-CSF) that strengthen the immune system and help it to attack cancer cells. The therapeutic efficacy of this strategy was increased when combined with existing oncolytic viral therapeutic approaches.
In models of melanoma that have spread to the brain at leptomeninges, therapy has been administered via intrathecal injection, delivered directly into the fluid-filled space between the brain or spinal cord and the leptomeninges. The researchers believe that locally delivered immunotherapies represent the future of brain metastatic treatments and hope to launch a Phase I trial in humans. An important aspect of this potential therapy is that, unlike other similar immunotherapies, it does not require repeated administration in the clinic. In addition, 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.
Reference: Kanaya N, Kitamura Y, Vazquez ML, et al. (2023). Gene-edited and -engineered stem cell platform drives immunotherapy for brain metastatic melanomas. Sci Transl Med. doi: 10.1126/scitranslmed.ade8732
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