A cancer vaccine has been developed that kills and prevents brain cancer at the same time
Abstract: A new approach to stem cell therapy eliminates existing brain tumors and provides long-term immunity, training the immune system to prevent cancer from returning.
Source: Brigham and Women’s Hospital
Scientists are using a new way to turn cancer cells into powerful anti-cancer agents.
In the latest work from the laboratory of Khalid Shah, MS, Ph.D., at Brigham and Women’s Hospital, founder of the Mass General Brigham Health System, researchers have developed a new approach to cell therapy to eliminate existing tumors and induce long-term immunity, training the immune system to that it can prevent the recurrence of cancer.
The team tested their dual-action cancer-killing vaccine in an advanced mouse model of the deadly glioblastoma brain cancer, with promising results.
The findings were published in Science translational medicine.
“Our team pursued a simple idea: take cancer cells and transform them into cancer killers and vaccines,” said corresponding author Khalid Shah, MS, Ph.D., director of the Center for Stem Cell and Translational Immunotherapy (CSTI) and vice president of research at Department of Neurosurgery at Brigham University and professor at Harvard Medical School and the Harvard Stem Cell Institute (HSCI).
“Using genetic engineering, we repurpose cancer cells to develop a drug that kills tumor cells and stimulates the immune system to destroy primary tumors and prevent cancer.”
Cancer vaccines are an active area of research for many labs, but the approach taken by Shah and his colleagues is different. Instead of using inactivated tumor cells, the team is repurposing living tumor cells, which possess an unusual feature. Like pet pigeons returning to the roost, living tumor cells will travel long distances through the brain to return to the site of their fellow tumor cells.
Taking advantage of this unique property, Shah’s team engineered living tumor cells using the gene-editing tool CRISPR-Cas9 and re-engineered them to release a tumor-killing agent.
In addition, the engineered tumor cells were designed to express factors that would make it easier for the immune system to spot, tag, and remember them, priming the immune system for a long-term antitumor response.
The team tested their repurposed CRISPR-enhanced and reverse-engineered therapeutic tumor cells (ThTC) in different strains of mice including one bearing human-derived bone marrow, liver and thymus cells, mimicking the human immune microenvironment. Shah’s team also built a double-layer safety switch into the cancer cell that, when activated, eradicates TTCs if needed.
This dual-acting cellular therapy was safe, applicable, and effective in these models, suggesting a plan toward therapy. Although further testing and development is needed, Shah’s team specifically chose this model and used human cells to ease the path to translating their findings to patient settings.
“Through all the work we do at the Center, even when it’s very technical, we never lose sight of the patient,” Shah said.
“Our goal is to take an innovative yet translatable approach so that we can develop a therapeutic cancer vaccine that will ultimately have lasting impact in medicine.”
Shah and colleagues note that this therapeutic strategy is applicable to a wider range of solid tumors and that further research into its application is warranted.
About this brain cancer research news
Original research: Open access.
“A bifunctional cancer cell-based vaccine simultaneously promotes direct tumor killing and antitumor immunity” Kok-Siong Chen et al. Science translational medicine
A bifunctional cancer cell-based vaccine simultaneously promotes direct tumor killing and antitumor immunity
Administration of inactivated tumor cells is known to induce a strong antitumor immune response; however, the effectiveness of such an approach is limited by its inability to kill tumor cells before inducing immune responses. Unlike inactivated tumor cells, live tumor cells have the ability to track and target tumors.
Here we have developed a bifunctional therapy based on cancer cells with direct tumor killing and immunostimulatory role. We reprogrammed tumor cells from interferon-β (IFN-β) sensitive to resistant using CRISPR-Cas9 by knocking out the IFN-β-specific receptor and subsequently engineered them to release the immunomodulatory agents IFN-β and granulocyte-macrophage colony-stimulating factor.
These engineered therapeutic tumor cells (ThTCs) eliminated established glioblastoma tumors in mice by inducing caspase-mediated cancer cell apoptosis, downregulating fibroblast-derived growth factor β receptor platelet expression, and activating antitumor immune cell trafficking and antigen-specific T cell activation signaling.
This mechanism-based efficacy of ThTCs translated into survival benefit and long-term immunity in primary, recurrent, and metastatic cancer models in immunocompetent and humanized mice. Incorporation of a dual off switch consisting of herpes simplex virus-1 thymidine kinase and rapamycin-activated caspase 9 in the TTC ensured the safety of our approach.
Arming natural neoantigen-rich tumor cells with bifunctional therapeutics represents a promising cellular immunotherapy for solid tumors and establishes a roadmap toward clinical translation.