Dual Stem Cell Treatment Targets Melanoma Brain Metastases in Mice

Overall survival for patients with melanoma that has spread to the brain is only four to six months. Immunotherapies, which harness the power of the immune system to attack cancer cells, have garnered excitement in recent years for their potential to revolutionize the treatment of metastatic melanomas, but results from early clinical studies indicate that the prognosis for most patients with brain metastatic disease remains poor.

Scientists from Brigham and Women’s Hospital, a founding member of the Mass General Brigham healthcare system, have integrated multiple therapeutic approaches to more effectively target melanoma in the brain. They developed an allogeneic twin stem cell (TSC) system composed of two tumor-targeting stem cell (SC) populations which they found successfully activated immune responses in metastatic melanoma mouse models that mimic human disease, to suppress tumor growth and prolong survival. The dual stem cell treatment comprised one set of stem cells engineered with a cancer cell-killing virus and another stem cell set engineered to produce immunomodulating proteins that ease the way for the virus to enter cells. The treatment boosted immune cell responses against humanized mouse models of brain metastatic melanoma and was more effective at treating the melanoma than oncolytic virus therapy alone.

“We know that in advanced cancer patients with brain metastases, systemic drugs, given intravenously and orally, do not effectively target brain metastases,” said corresponding author Khalid Shah, MS, PhD, director of the Center for Stem Cell and Translational Immunotherapy (CSTI) and the vice chair of research in the Department of Neurosurgery at the Brigham and faculty at Harvard Medical School and Harvard Stem Cell Institute (HSCI). “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.”

Shah and colleagues reported on their studies in Science Translational Medicine, in a paper titled “Gene-edited and -engineered stem cell platform drives immunotherapy for brain metastatic melanomas,” in which they concluded, “Our findings provide a promising allogeneic SC-based immunotherapeutic strategy against melanomas in the CNS and a road map toward clinical translation.”

Patients with advanced melanoma have limited survival prognosis, with brain metastases contributing to half of all melanoma-related deaths, the authors wrote. “Advanced-stage melanomas have a high propensity to metastasize to the brain, with 60% of patients developing brain metastases at some point.”

Immunotherapy has “revolutionized treatment for melanoma,” the authors continued, but clinical studies evaluating immune checkpoint inhibitor (ICI) therapy for metastatic melanoma suggest that the treatment doesn’t generate intracranial responses that are as effective as extracranial responses, partially because the ICI antibodies (Abs) don’t easily penetrate into the brain and cerebrospinal fluid. “Therefore, alternative therapeutic agents and strategies are urgently needed,” the team continued.

The therapy designed by the scientists uses an engineered “twin stem cell” model to maximize an attack on cancer cells that have spread to a part of the brain known as the leptomeninges. One stem cell releases a cancer-killing (oncolytic) herpes simplex virus (oHSV), a strategy that has previously shown promise in reducing tumor growth. Using stem cells to deliver the virus amplifies the amount of virus that can be released and ensures that the virus will not be degraded by circulating antibodies before it is released on the cancer cells.

However, the oncolytic virus also destroys the very cells that release it, making it an unsustainable therapeutic option on its own. To address this, the scientists used CRISPR-Cas9 gene editing to a create a second stem cell that cannot be targeted by the oncolytic virus, and which instead releases proteins (immunomodulators) that fortify the immune system to help fight off the cancer. Removing the nectin-1 receptor made it easier for oHSV to enter cells, while also prompting the release of immunomodulators to target the tumors. “The other SC was CRISPR-Cas9 gene-edited to knock out nectin 1 (N1) receptor (N1KO) to acquire resistance to oHSV and release immunomodulators, such as granulocyte-macrophage colony-stimulating factor (GM-CSF),” they explained.

The twin stem cells can be delivered via intrathecal injection, a technique already used in the treatment of other diseases. But unlike other immunotherapies that have emerged in recent years, it does not need to be repeatedly administered.

Notably, the authors were able to design a preclinical mouse model that faithfully represents a human model of melanoma with leptomeningeal metastasis, which they used to test their therapy. They found that the TSC therapy successfully activated immune responses in their models that mimic human responses. “… the TSCs composed of SC-oHSV and SCN1KO–releasing GM-CSF and single-chain variable fragment anti–PD-1 (TSC-G/P) had therapeutic efficacy in both syngeneic and patient- derived humanized mouse models of leptomeningeal metastasis,” they wrote. The authors are hoping to launch a Phase I trial in the near future. “…. our study reveals that locoregional delivery of oHSV and immunomodulators from two SC populations successfully induces activation of DCs [dendritic cells] and CD4+ and CD8+ cells in the human and the mouse immune system … These results support translation of our TSC-G/P strategy to a Phase I clinical trial for patients with LM to confirm the safety of IT injection of these therapeutic SCs and to ultimately help improve overall survival and quality of life.”

“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,” Shah said. “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.”

The authors emphasize that this approach can be used in other cancers with brain metastasis, such as lung and breast cancer, and are working to design similar treatments for these cancers. “ … the therapeutic efficacy of the TSC-G/P platform should be explored for other metastatic lesions and other cancer types to broaden its the therapeutic applications,” they noted. “However, we anticipate that optimization of immunomodulators and delivery routes will be required for different disease conditions.”

Shah owns equity in and is a member of the Board of Directors of AMASA Therapeutics, a company developing stem cell-based therapies for cancer.


Read more here: Source link