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Cancer vaccine to kill and prevent brain cancer simultaneously

Summary: A new approach to stem cell therapy eliminates established brain tumors and provides long-term immunity by training the immune system to prevent the cancer from returning.

Source: Brigham and Women’s Hospital

Scientists are taking advantage of a new way to turn cancer cells into potent 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 novel cell therapy approach to eliminate established tumors and induce long-lasting immunity to long term by training the immune system so that it can prevent the cancer from recurring.

The team tested their cancer-killing dual-action vaccine in an advanced mouse model of the deadly glioblastoma brain cancer, with promising results.

The findings are published in Science Translational Medicine.

“Our team pursued a simple idea: take cancer cells and turn them into vaccines and cancer killers,” said corresponding author Khalid Shah, MS, Ph.D., director of the Center for Stem Cells and Translational Immunotherapy (CSTI). and vice chair of research in the Department of Neurosurgery at Brigham and professor at Harvard Medical School and the Harvard Stem Cell Institute (HSCI).

“Using genetic engineering, we are repurposing cancer cells to develop a therapeutic 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 repurposes live tumor cells, which have an unusual feature. Like homing pigeons returning to roost, live tumor cells 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 live tumor cells using the CRISPR-Cas9 gene editing tool and repurposed them to release the tumor cell killing agent.

Furthermore, the engineered tumor cells were engineered to express factors that would make them easy for the immune system to detect, mark and remember, priming the immune system for a long-term anti-tumor response.

This shows a diagram of the study
Scientists have developed a bifunctional therapeutic strategy, transforming live tumor cells into a therapeutic. Shah’s team engineered live tumor cells using the CRISPR-Cas9 gene-editing tool and repurposed them to release the tumor cell-killing agent. Furthermore, the engineered tumor cells were engineered to express factors that would make them easy for the immune system to detect, mark and remember, priming the immune system for a long-term anti-tumor response. The team tested their therapeutic tumor cells (ThTC) repurposed with CRISPR and reverse engineering in different strains of mice, including one that contained human-derived bone marrow, liver, and thymus cells, mimicking the human immune microenvironment. Shah’s team also built a two-layer safety switch into the cancer cell that, when activated, eradicates ThTCs if necessary. Credit: Kok Siong Chen and Khalid Shah.

The team tested their therapeutic tumor cells (ThTC) repurposed with CRISPR and reverse engineering in different strains of mice, including one that contained human-derived bone marrow, liver, and thymus cells, mimicking the human immune microenvironment. Shah’s team also built a two-layer safety switch into the cancer cell that, when activated, eradicates ThTCs if necessary.

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

“In 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 vaccine that will ultimately have a lasting impact on medicine.”

Shah and colleagues note that this therapeutic strategy is applicable to a wide range of solid tumors and that further investigation of its applications is needed.

About this brain cancer research news

Author: Press office
Source: Brigham and Women’s Hospital
Contact: Press Office – Brigham and Women’s Hospital
Image: The image is credited to Kok Siong Chen and Khalid Shah

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“Bifunctional cancer cell-based vaccine concomitantly boosts direct tumor killing and anti-tumor immunity” by Kok-Siong Chen et al. Science Translational Medicine


Summary

Bifunctional cancer cell-based vaccine concomitantly boosts direct tumor killing and anti-tumor immunity

Administration of inactivated tumor cells is known to induce a potent anti-tumor 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 therapeutic based on whole cancer cells with direct tumor killing and immunostimulatory functions. We repurpose sensitive to resistant interferon-β (IFN-β) tumor cells using CRISPR-Cas9, knocking out the specific IFN-β receptor, and subsequently engineering them to release immunomodulatory agents IFN-β and granulocyte colony-stimulating factor -macrophages.

These modified therapeutic tumor cells (ThTCs) eliminated established glioblastoma tumors in mice by inducing caspase-mediated cancer cell apoptosis, down-regulating platelet-derived growth factor receptor β expressed by cancer-associated fibroblasts, and activating cell trafficking Antitumor immune agents and the specific antigen Signaling of T cell activation.

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

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

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