Khalid Shah, M.S., Ph.D.
Director, Center for Stem Cell and Translational Immunotherapy, Brigham and Women's Hospital
Professor, Harvard Medical School
The Shah lab seeks to develop and test novel, targeted, cell-based therapies for brain cancers.
Successful treatment of brain tumors remains one of the greatest challenges in oncology. The recognition that different cell types that have therapeutic potential, can integrate appropriately throughout the mammalian brain following transplantation has unveiled new possibilities for their use in transplantation. Our laboratory has shown that different stem cells and cancer cells are home to sites of cerebral pathology and thus can be armed with therapeutic proteins and oncolytic viruses, a strategy that can be used to target tumor cells and immune cells in the tumor microenvironment (TME).
Our research is based on developing clinically translatable models of both primary, recurrent and metastatic brain tumors, and cell based cell surface receptor therapeutics that simultaneously target cell death and proliferation pathways in an effort to eradicate brain tumors. We have engineered different stem cells types to release therapeutic proteins to specifically induce apoptosis in tumor cells and target different populations of immune cells in TME and tested them in primary and metastatic mouse tumor models. Our laboratory has also focused on targeting tumors that are resistant to different therapeutic drugs and oncolytic viruses. Resultantly, we have developed stem cell deliverable bi-modal therapeutic molecules and oncolytic herpes virus and shown their efficacy in mouse models of aggressive and invasive brain tumors. We have created different immunomodulatory stem cells to boost tumor resection induced CD4/8 T cells post-tumor debulking and shown therapeutic efficacy in different mouse tumor models.
Tumor cells hold promise as anti-cancer agents due to its ability to serve as the natural source of patient-specific neoantigens. To take advantage of this as therapeutics, we have recently CRISPR/Cas9 engineered self-targeting tumor cells to knock out cell surface receptors and release targeting ligands to kill the tumor cells. We have shown that re-purposed therapeutic tumor cells (ThTC) specifically home to tumor cells and release targeted ligands that induce tumor cell killing which translates into marked survival benefits in mouse models of primary and brain cancer. More recently, we have engineered tumor cells to release dual immunomodulatory agents and shown the potential of these ThTC to simultaneously kill tumor cells and induce immunological memory. Inherently linked to the brain tumor therapy paradigm are imaging techniques, thus we employ fluorescent/bioluminescent imaging markers and optical imaging techniques to track stem cells, image apoptosis and changes in tumor volumes in real time in vivo.
In an effort to translate cell based therapies into clinical settings, we have shown that encapsulation of receptor targeted stem cells and cancer cells in synthetic extracellular matrix prevents their rapid “wash- out” post-transplantation in the tumor resection cavity and has a significant therapeutic benefit on the survival of mice bearing resected brain tumors. Our research program is committed to achieving the vision of creating an “off-the-shelf” therapeutic offering for cancer that would positively impact the quality of life of individuals affected across the globe.
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