CRISPR-Edited/Oncolytic Virus Cell Therapy Combo Shows Preclinical Efficacy in Melanoma Brain Metastases


The promising preclinical data, observed in an accurate model of brain metastases, support initiation of a phase 1 trial.

Researchers from Brigham and Women’s Hospital investigated an allogeneic engineered twin stem cell therapy approach and successfully activated immune responses in a next-generation mouse model of metastatic brain melanoma spread to the leptomeninges that mimics human settings.1

“We know that in advanced cancer patients with brain metastases, systemic drugs, given intravenously and orally, do not effectively target brain metastases,” corresponding author Khalid Shah, MS, PhD, director, Center for Stem Cell and Translational Immunotherapy and vice chair, research, Department of Neurosurgery, Brigham and faculty, Harvard Medical School and Harvard Stem Cell Institute, said in a statement.2 “We have now developed a new immunotherapeutic 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.”

One part of the twin stem cell therapy approach consists of an oncolytic virus approach, a strategy currently being investigated on multiple fronts as a cancer therapeutic. Delivering the oncolytic virus by cell therapy amplifies the amount of virus that can be released and protects the virus from the immune system before reaching its targeted cancer cells. The second part of the approach is a CRISPR/Cas9 gene-edited stem cell that releases immunomodulatory proteins to help bolster antitumor activity of the immune system. This cell is also edited to avoid targeting by the oncolytic virus, which destroys the cells that release it and may not be a sustainable option as a monotherapy.1

READ MORE: Advancing Gene and Cell Therapies for Brain Cancer

The twin stem cell therapy is intended to be delivered via intrathecal injection as a one-time treatment. The study authors emphasized that the therapy should be able to target brain metastases of other types of cancers besides melanoma, including breast and lung cancer, and are further investigating the cell therapy approach in these indications.

The study, which was mainly supported by the US Department of Defense, is also notable for designing a PTEN-deficient preclinical mouse model that accurately portrays melanoma with leptomeningeal metastasis in humans, which the authors used to evaluate the cell therapy approach in. The faithful model and the successful immune responses activated with the cell therapy are promising indicators for a potential clinical benefit to be observed in a first-in-human study and the authors postulated that the preclinical findings support the launch of a phase 1 trial in the near future.

“A number of biological therapies that look promising often fail in Phase 1 or Phase 2 clinical trials, in part because the preclinical models do not authentically replicate clinical settings,” Shah said.2 “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.”

1. Kanaya N, Kitamura Y, Vazquez ML, et al. Gene edited and engineered stem cell platform drives immunotherapy for brain metastatic melanomas. Sci Trans Med. Published online May 31, 2023. doi: 10.1126/scitranslmed.ade8732
2. Gene engineered “off the shelf” cell therapy developed to target brain metastatic melanomas. News release. Brigham and Women’s Hospital. May 31, 2023.
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