Inhaled CBD shrinks glioblastoma’s measurement in an animal mannequin

Inhaled CBD reduces the size of the highly aggressive, fatal brain tumor glioblastoma in an animal model by reducing the essential support of its microenvironment, researchers report.

“We saw a significant reduction in the size of the tumor and its microenvironment,” says Dr. Babak Baban, immunologist and assistant dean of research at Augusta University’s Dental College of Georgia, after just seven days of treatment.

Researchers at DCG and the Medical College of Georgia say that not only did the inhalation approach help the compound in cannabis reach the brain, but that the method of delivery, much like asthma inhalers, eventually became easy for patients to use.

It was the first study to use CBD in an animal model of glioblastoma, they report in the journal Cannabis and Cannabinoid Research.

Using modified human glioblastoma cells, they created what is known as an orthotopic glioblast model to provide the most realistic model of this most common and deadly malignant brain tumor. On the eighth day the aggressive tumor was established in the brains of the mice, and on day 9 they began to administer daily doses of inhaled CBD or a placebo that lasted for seven days. Then they looked at an image of the tumor again and looked directly at the tumor tissue.

While the approach is likely to be easily applicable to humans, they are currently primarily studying the tumor’s biological response to CBD, says Dr. Martin Rutkowski, MCG neurosurgeon, whose expertise includes operating on patients who are prone to operating after a seizure or sudden loss of consciousness or with slower onset of neurological deficits such as a weak arm, visual impairment or cognitive problems.

“It’s probably one of the most aggressive periods of cancer. We urgently need research and more treatments,” says the neurosurgeon and co-author of the study. “What we have right now isn’t working very well,” he says.

Family members bring patients to themselves and say that they just don’t think right, that their memory is everywhere, or that they have been fired from their job for not doing the things right they have been doing for 30 years. “

Dr. Martin Rutkowski, MCG neurosurgeon

Treatment today includes surgery, followed by chemotherapy and radiation therapy. “Surgery offers no cure, but it does offer an important first step in maximizing quality of life and prognosis,” says Rutkowski. There is a clear correlation between the amount of tumor that can be surgically removed and survival time.

They found that CBD appears likely to alter the tumor ecosystem or tumor microenvironment, including restoring inflammation that attacks rather than protects glioblastoma, which could make it a safe, effective, and novel add-on therapy for these patients .

“It’s about the immune balance,” says Baban, correspondent author. Inflammation is increased in response to a frontal attack on a tumor, which is a normal response; In fact, our immune system regularly attacks cancer cells or precancerous cells. But when a tumor manages to establish itself, the tumor takes responsibility and shifts into a more chronic inflammatory state that ultimately protects it from the immune system, he says.

The tumor microenvironment that cancer cells create includes things like immune cells, as well as blood vessels and growth factors to allow more blood vessel growth, which is key to tumor growth and survival, so that it can thrive where it starts and where it can spread.

In glioblastoma, the tumor microenvironment has increased activity of natural immune checkpoints which, as the name suggests, help prevent an overzealous immune response that could harm the body, as happens in autoimmune diseases such as rheumatoid arthritis. But in this case, the cushioning means protecting the tumor. There is also a remarkably low presence of cytotoxic T cells, which are particularly adept at targeting a tumor or other invader.

CBD was able to improve the immune mix against the tumor, including reducing the co-optation of glial cells by the tumor -; a type of brain cell that normally protects neurons, including producing inflammation to fight off invaders -; instead, a major component of the tumor now known as the glioblastoma-associated macrophage that helps support and protect it.

It also suppresses the protein P-selectin, which is typically involved in important functions like injury repair, and one of the things it recruits to help is platelets. In cancer, however, P-selectin helps tumors spread and become resistant to treatment. In fact, it’s a focus for new cancer treatments. As for many other residents of the microenvironment, there is evidence that P-selectin works on tumors by also serving as an immune checkpoint.

Apelin, a penetrating enzyme made by many different types of cells, is usually found in small amounts in the brain. But in glioblastoma, its expression is much higher, the researchers say, and it supports the growth of critical blood vessels, in addition to promoting the cancer stem cells believed to give birth to the tumor, as well as being key to the tumor’s resistance to treatment. There is also evidence that apelin acts as an immune checkpoint in the tumor microenvironment, and others have shown that inhibiting apelin, which causes CBD, reduces the rate of growth of the deadly brain tumor.

CBD also suppresses IL-8, which macrophages normally release to promote inflammation and help repair injury, by recruiting other immune cells. But glioblastoma also secretes IL-8 to promote cell migration and angiogenesis, and its levels are high in many cancers, including glioblastoma. In fact, these fast-growing tumors are good at making blood vessels grow, which in turn aids their growth, and drugs that target this particular ability have been shown to be helpful.

CBD also reduces other key immune checkpoints, such as the enzyme indolamine-2,3-dioxygenase or IDO, another localized blockade of the immune response that tumors are known to use.

CBD also improved the mix by increasing the expression of some good things, like CD103, a complex thought that helps the immune system recognize cancer and which is generally linked to better cancer prognosis, as well as CD8, a sugar-coated protein that also supports an immune response. There is evidence that immune checkpoints are suppressed, which is what CBD does, and which boosts levels of both.

“It’s a mystery and that’s why we need good immune regulators,” says Baban. “CBD is a very smart regulator” that can make adjustments based on its environment, like turning Apelin down for glioblastoma and up for lungs damaged by COVID, he says. DCG and MCG investigators reported last year that CBD actually increases apelin levels, which have decreased significantly in patients’ lungs with SARS-CoV-2 infection.

“At the moment we are happy that the tumor is shrinking,” says Baban about the effects of cannabinoids on glioblastoma. He and Rutkowski note that the positive results from inhaled CBD occurred without being performed in conjunction with other therapies such as surgery. They anticipate that when CBD is eventually used for these patients, CBD will be a new addition to these therapies.

The next steps include seeing how long the positive changes last and taking a closer look at the effects on cancer stem cells. They also want to evaluate the impact of CBD on high glioblastoma recurrence rates. They have further evidence of hope: in a previous study, they incubated the tumor cells in CBD before implanting them, and no tumors developed, Baban says.

The most recent major advancement in glioblastoma treatment came more than 15 years ago with the addition of the chemotherapy drug temozolamide, which increased survival by about a month and a half and was celebrated by patients and caregivers alike, Rutkowski says.

CBD’s ability to control inflammation and their research experience with other conditions where inflammation is key, including Alzheimer’s, led Baban and colleagues to develop the cannabis derivative for glioblastoma. Other researchers are studying CBD in combination with other cannabis derivatives, including THC, but since CBD is such an interactive compound, including with other active ingredients in cannabis such as THC, the DCG and MCG researchers thought it would be more effective on its own.

Source:

Medical College of Georgia at Augusta University

Journal reference:

Khodadadi, H., et al. (2021) Inhalation cannabidiol inhibits the progression of glioblastoma by regulating the tumor microenvironment. Cannabis and cannabinoid research. doi.org/10.1089/can.2021.0098.