Developing a Cancer Vaccine to Simultaneously Kill and Prevent Brain Cancer

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

Source: Brigham and Women’s Hospital

Scientists are exploiting a new way to transform 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 long-term immunity, training the immune system so it can prevent cancer from recurring.

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

The findings are published in Science Translational Medicine.

“Our team pursued a simple idea: take cancer cells and turn 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 Brigham’s Department of Neurosurgery and faculty at Harvard Medical School and the Harvard Stem Cell Institute (HSCI).

“Using genetic engineering, we are repurposing cancer cells to develop a treatment 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 taken by Shah and his colleagues is distinct. Instead of using inactivated tumor cells, the team reuses living tumor cells, which have an unusual characteristic. Like carrier pigeons returning to roost, living tumor cells travel long distances through the brain to return to the site of their tumor counterparts.

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 a tumor cell-killing agent.

Additionally, the engineered tumor cells were engineered to express factors that would make them easy to spot, mark and remember by the immune system, preparing the immune system for a long-term anti-tumor response.

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

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

This dual-action cell therapy was safe, applicable, and effective 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 help translate their findings to patients.

“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 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: The image is attributed to Kok Siong Chen and Khalid Shah

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Original research: Free access.
“Bifunctional Cancer Cell-Based Vaccine Simultaneously Induces Direct Tumor Killing and Anti-tumor Immunity” by Kok-Siong Chen et al. Science Translational Medicine


Abstract

Bifunctional Cancer Cell-Based Vaccine Simultaneously Induces Direct Tumor Killing and Anti-tumor Immunity

Administration of inactivated tumor cells is known to induce a potent 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 developed a bifunctional therapy based on whole cancer cells with roles of direct tumor destruction and immunostimulation. We repurposed interferon-β (IFN-β) susceptible to resistant tumor cells using CRISPR-Cas9 by knocking out the specific IFN-β receptor and then engineered them to release IFN immunomodulatory agents -β and granulocyte-macrophage colony-stimulating factor.

These modified therapeutic tumor cells (ThTC) eliminated established glioblastoma tumors in mice by inducing caspase-mediated cancer cell apoptosis, downregulating the platelet-derived growth factor receptor β expressed by fibroblasts associated with cancer and by activating antitumor immune cell trafficking and antigen specificities. T cell activation signaling.

This mechanism-based efficacy of ThTCs has translated into survival benefit and long-term immunity 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 therapies represents a promising cellular immunotherapy for solid tumors and establishes a roadmap towards clinical translation.

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