Reminiscent of a Trojan horse, researchers adapt their ability to attract and find cancer cells … [+]
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Glioblastoma is one of the most lethal and intractable cancers affecting the brain. Cancer forms masses of tumors on the surface of the brain while simultaneously migrating and taking root in nerve pathways. Glioblastoma patients—children and adults alike—suffer from headaches, nausea, dizziness, and more. Worse, some existing immunosuppressive treatments are ineffective, severely affect the brain, and create spillover effects on cognition, mood, behavior, and physical function.
The average survival rate has been unchanged for many years, at about eight months. A study published in the journal Science Translational Medicine Start building on options that can strengthen the sector.
Researchers at Brigham and Women’s Hospital tested a Trojan horse approach: using cancer cells to fight cancer. The team investigated the efficacy of their dual-function cancer vaccine in mice with glioblastoma and found potential in this unique method. As the first steps are accomplished, the hope is to continue this path of research and reach clinical translation for humans.
Current frontiers of cancer cell-based therapy
Killing cancer with cancer sounds deceptively simple, but is actually a concept under thorough research. Basically, cancer cells are surprised and suppressed by the immune system to grow largely unhindered. But cancer cells like glioblastoma cells have a unique infrastructure to attract one type of cell. Using this feature against itself, the Trojan horse method aims to borrow the ability to accurately find and destroy cancer itself.
Researchers also see promise in cell therapies that use tumor-specific biological tags found on the surface of cancer cells to boost immune responses that normally arise from cancer. Cell therapy ideally introduces these biological tags into immune cells; With target recognition and memory, the immune system is stimulated to act and starts fighting against tumor cells sharing the same neoantigens.
This dream has not yet been fulfilled. Both dormant and living tumor cells have had limited success in the treatment and prevention of cancer. Tumor cells inactivated by lysis or radiation may encourage immune cells to travel to tumor sites, but they lack killing power. The resulting antitumor response proves too weak or indirect to be clinically viable. In contrast, surviving tumor cells can home and target tumors, but often die prematurely from their own toxicity. The answer to cancer cell-based therapy may lie in the gap between living and dormant tumor cell performance.
Investigating bifunctional cancer cell vaccines
The team at Brigham and Women’s Hospital realized the need for a cancer cell-based therapy to join the homing and cytotoxic capabilities of living tumor cells with robust immune responses generated from dormant tumor cells. Accordingly, they created a bi-functional cancer cell-based therapy using gene editing.
The researchers engineered the cells to release interferon-β (IFN-β), an immune chemical that directly inhibits tumor cell proliferation and the formation of new blood vessels in the tumor. To do this, they took living tumor cells from mice and used CRISPR-Cas9 gene editing to knock out interferon-β-specific receptors. By knocking out the receptor gene, the team programmed the cells to produce interferon-β (IFN-β) without fear of autotoxicity.
To bolster indirect immune responses, the team engineered the tumor cells to also express another immune chemical called granulocyte-macrophage colony-stimulating factor (GM-CSF). This growth factor promotes the maturation and proliferation of dendritic immune cells (see Figure 1 ) which, in turn, primes the immune system for long-term antitumor responses.
Finally, the team included a safety switch. Using it as a treatment for cancer carries potential risks if left unchecked, and can possibly start unwanted secondary tumors. A switch consisting of two enzymes triggers a dual suicide system that ultimately leads to tumor cell death before cell proliferation. A graphic summary of the study process can be seen in Figure 2.
Figure 1: Illustration of a dendritic cell before and after maturation. These cells play an important role … [+]
Designua / Shutterstock
Figure 2: Overview of the study process. In this study, researchers used CRISPR gene editing to make the change … [+]
Chen et al., 2023.
results
The team began a series of experiments to see if their reconstituted cancer cells could eliminate tumors and stimulate the immune system in mice with transplanted glioblastoma brain tumors.
Transformed living cancer cells naturally proliferate at high rates, and are useful neoantigens for building antitumor immunity. Knocking down interferon-beta receptors does not affect cell viability. The expression of interferon-β proved to be essential for the direct elimination of tumor cells. Expression of the growth factor successfully induced long-term immunological memory, thus proving to be a beneficial change.
Tumor eradication and antitumor immunity
Engineered tumor vaccines performed well. The treatment inhibited the growth of brain tumors in mice even when vital T cells were experimentally removed. It showed how killer and helper T cells, when reinforced by two types of cancer cells, act independently to attack and encircle solid tumors. Helper T cells, in particular, appear to be essential in inhibiting tumor growth and progression.
Interferon-β expression appears to trigger downstream antitumor effects. Expression of STAT 1, a downstream gene of interferon-β, appears to decrease expression levels of glioblastoma genes that normally promote tumor growth and activity. Notably, the experiment yielded comparable results when applied to humanized mouse models as well.
Figure 3: Schematic of the mechanisms behind the therapeutic tumor cell strategy. Mechanisms explain … [+]
Chen et al., 2023.
Study implications
Glioblastoma is a brain disease that resists treatment. All the current drugs and devices used to combat the disease only extend the patient’s life by months. New treatments are needed to survive effectively.
This study raises hope for a possible solution. A dual function cancer vaccine successfully attacks tumors and simultaneously promotes immunity that inhibits tumor recurrence and progression in the mouse and human immune microenvironment. As unexpected as it may be, further development in this field may prove that the cancer itself—albeit heavily engineered—could be a viable solution to treat recurrent cancers such as glioblastoma in humans.
