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A cancer vaccine has been developed to both kill and prevent brain cancer

A cancer vaccine has been developed to both kill and prevent brain cancer

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Summary: A new approach to stem cell therapy eliminates established brain tumors and provides long-term immunity by 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, a founding member of the Mass General Brigham Health System, researchers have developed a new cell therapy approach to eliminate established tumors and induce of long-term immunity, training the immune system so 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 brain cancer glioblastoma, with promising results.

The findings are published in Scientific Translational Medicine.

“Our team pursued a simple idea: to 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 the vice chair for research in the Department of Neurosurgery at Brigham and faculty members at Harvard Medical School and the Harvard Stem Cell Institute (HSCI).

“Using genetic engineering, we are rewiring cancer cells to develop a therapeutic that kills tumor cells and stimulates the immune system to both destroy primary tumors and prevent cancer.”

Cancer vaccines are an active area of ​​research for many labs, but the approach Shah and his colleagues have taken is different. Instead of using inactivated tumor cells, the team re-used living tumor cells that possessed an unusual characteristic. Like homing pigeons returning to 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 CRISPR-Cas9 gene-editing tool and re-engineered them to release a tumor-cell-killing agent.

In addition, the engineered tumor cells were engineered to express factors that would make them easy for the immune system to spot, tag and remember, priming the immune system for a long-term anti-tumor response.

Scientists have developed a bifunctional therapeutic strategy by transforming living tumor cells into therapeutic ones. Shah’s team engineered living tumor cells using the CRISPR-Cas9 gene-editing tool and re-engineered them to release a tumor-cell-killing agent. In addition, the engineered tumor cells were engineered to express factors that would make them easy for the immune system to spot, tag and remember, priming the immune system for a long-term anti-tumor 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 two-layer safety switch in the cancer cell that, when activated, destroys ThTCs as needed. Credit: Kok Siong Chen and Khalid Shah.

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 two-layer safety switch in the cancer cell that, when activated, destroys ThTCs as needed.

This dual-action cell therapy is safe, applicable, and efficacious in these models, suggesting a roadmap to therapy. Although further testing and development is needed, Shah’s team specifically chose this model and used human cells to ease the path of translating their findings to patient settings.

“Throughout all the work we do at the Center, even when it’s highly 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-killing vaccine that will ultimately have a 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 applications is warranted.

About this brain cancer research news

Author: Press office
source: Brigham and Women’s Hospital
Contact: Press Office – Brigham and Women’s Hospital
Image: Image attributed to Kok Siong Chen and Khalid Shah

See also

A cancer vaccine has been developed to both kill and prevent brain cancer

Original research: Free access.
Bifunctional cancer cell-based vaccine simultaneously induces direct tumor killing and antitumor immunity” by Kok-Siong Chen et al. Scientific Translational Medicine


Summary

Bifunctional cancer cell-based vaccine simultaneously induces direct tumor killing and antitumor immunity

Administration of inactivated tumor cells is known to induce a potent antitumor immune response; however, the efficacy of such an approach is limited by its inability to kill tumor cells prior to induction of immune responses. Unlike inactivated tumor cells, living tumor cells have the ability to track and target tumors.

Here, we developed a bifunctional therapy based on whole cancer cells with direct tumor killing and immunostimulatory roles. We rerouted 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 colony-stimulating factor- macrophages.

These engineered therapeutic tumor cells (ThTCs) eliminate established glioblastoma tumors in mice by inducing caspase-mediated cancer cell apoptosis, downregulating cancer-associated fibroblast-expressed platelet-derived growth factor β receptor, and activating antitumor immune trafficking. cells and antigen-specific signaling to activate T cells.

This mechanism-based efficacy of ThTCs translated into a survival benefit and long-term immunity in primary, recurrent, and metastatic cancer models in immunocompetent and humanized mice. The inclusion of a dual kill switch involving herpes simplex virus-1 thymidine kinase and rapamycin-activated caspase 9 in ThTCs ensures the safety of our approach.

Arming naturally neoantigen-rich tumor cells with bifunctional therapeutics represents a promising cell-based immunotherapy for solid tumors and establishes a roadmap to clinical translation.


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