Next-generation immunotherapy offers new hope for beating brain cancer

High-grade glioma is the most aggressive form of brain cancer. Despite improvements in surgical procedures, chemotherapy, and radiotherapy, this type of brain tumour is still notoriously hard to treat: less than 10% of patients survive beyond five years. Researchers from KU Leuven, Belgium, have now shown that next-generation cell-based immunotherapy may offer new hope in the fight against brain cancer.

Cell-based immunotherapy involves the injection of a therapeutic anticancer vaccine that stimulates the patient’s immune system to attack the tumour. Thus far, the results of this type of immunotherapy have been mildly promising. However, Abhishek D. Garg and Professor Patrizia Agostinis from the KU Leuven Department of Cellular and Molecular Medicine have now found a novel way to produce more effective cell-based anticancer vaccines.

The researchers induced a specific type of cell death in brain cancer cells from mice. The dying cancer cells were then incubated together with dendritic cells, which play a vital role in the immune system. The researchers discovered that this type of cancer cell killing releases ‘danger signals’ that fully activate the dendritic cells.

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The researchers induced a specific type of cell death in brain cancer cells from mice. The dying cancer cells were then incubated together with dendritic cells, which play a vital role in the immune system. The researchers discovered that this type of cancer cell killing releases ‘danger signals’ that fully activate the dendritic cells. “We re-injected the activated dendritic cells into the mice as a therapeutic vaccine”, Professor Patrizia Agostinis explains. “That vaccine alerted the immune system to the presence of dangerous cancer cells in the body. As a result, the immune system could recognize them and start attacking the brain tumor.”
CREDIT©KU Leuven Laboratory of Cell Death Research & Therapy – Dr. Abhishek D. Garg

We re-injected the activated dendritic cells into the mice as a therapeutic vaccine“, Professor Patrizia Agostinis explains. “That vaccine alerted the immune system to the presence of dangerous cancer cells in the body. As a result, the immune system could recognize them and start attacking the brain tumour.

Combined with chemotherapy, this novel cell-based immunotherapy drastically increased the survival rates of mice afflicted with brain tumours. Almost 50% of the mice were completely cured. For the sake of comparison: none of the mice treated with chemotherapy alone became long-term survivors.

The major goal of any anticancer treatment is to kill all cancer cells and prevent any remaining malignant cells from growing or spreading again“, Professor Agostinis continues. “This goal, however, is rarely achieved with current chemotherapies, and many patients relapse. That’s why the co-stimulation of the immune system is so important for cancer treatments. Scientists have to look for ways to kill cancer cells in a manner that stimulates the immune system. With an eye on clinical studies, our findings offer a feasible way to improve the production of vaccines against brain tumours.”

Garg et al. Dendritic cell vaccines based on immunogenic cell death elicit danger signals and T cell–driven rejection of high-grade glioma. Science Translational Medicine, 2016;8:328ra27 DOI: 10.1126/scitranslmed.aae0105 [Abstract]

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Harnessing the power of light to fight cancer

By controlling the actions of immune cells, they could be ‘instructed’ to kill cancerous tumor cells. Immunotherapy is one of the hottest emerging areas of cancer research. After all, using the body’s own cells to fight cancer can be more effective and less invasive than flooding the entire system with toxic chemicals.

Yubin Zhou, Ph.D., assistant professor at the Center for Translational Cancer Research at the Texas A&M Health Science Center Institute of Biosciences & Technology, is studying how to use light to control the immune system and induce it to fight cancer.

Although neuroscientists have been using light to stimulate neurons for years, this is the first time the technique, called optogenetics, has been used in the immune system,” Zhou said. In neuroscience, the process involves genetically engineering cells to produce proteins from light-sensitive microbes and results in nerve cells that will either send–or stop sending–nerve impulses when they are exposed to a particular color of light. “Neuroscientists have learned a lot about brain circuits using the technique,” Zhou said, “and now researchers in many other fields are giving it a try.”

Zhou and his collaborators have modified the technique for the immune system. It wasn’t easy: unlike nerve cells, immune cells don’t use tiny electrical impulses to communicate. Additionally, immune cells are located deep in the body and are constantly moving around, so getting the light to them can be difficult.

The development took some ingenuity and cooperation. “We collaborated with Dr. Gang Han at the University of Massachusetts Medical School who does bionanotechnology and photomedicine development,” Zhou said. “Together, we were able to combine state-of-the-art optogenetic approaches with cutting edge nanotechnology.” Called optogenetic immunomodulation, their method was featured in a recently published article in eLife.

This work was driven by talented scientists in the lab: graduate students Lian He and Peng Tan and postdoctoral research fellow Guolin Ma, Ph.D.,” Zhou said, “who fearlessly undertook this daunting project and overcame all the challenging obstacles to make this technique into reality.”

With this method, the researchers can control the action of immune cells and “instruct” them to kill cancerous tumor cells. They use a near-infrared laser beam, which can penetrate deep–in this context, deep means a centimeter or two–into the tissue, where a nanoparticle turns the near-infrared light into blue light, and that directs the activity of genetically engineered immune cells. “
” Zhou said.

The team genetically engineered immune cells so that a calcium gate-controlling protein became light sensitive. When they are exposed to the blue light emitted by the nanoparticle, their calcium ion gates open. When the light is turned off, the gates close. More light leads to a greater flow of calcium, so the researchers are able to finely tune the calcium-dependent actions of immune cells to fight against invading pathogens or tumor cells.

When an animal tumor model was injected with both the nanoparticle and the light-sensitive genetically engineered immune cells, the near-infrared laser beam caused calcium channels to open, which boosted an immune response to aid the killing of cancer cells. “The technique reduced tumor size and metastasis, so there are lots of applications,” Zhou said.

One advantage of this method is that it only activates a certain type of immune cell, the dendritic cell or T-cell, and only in one part of the body, near the draining lymph nodes or tumor, which helps cut down on the system-wide side effects often seen with chemotherapy. It’s also light-tunable, non-invasive and has great temporal resolution–in other words, it can be turned on when it is needed and turned off when it is not.

The implications of the research are far-reaching. “Other scientists will likely use the technique to help them study immune, heart and other types of cells that use calcium to perform their tasks,” Zhou said. “It’s quite a cool technology. With these tools, we can now not only answer fundamental questions of science that we never could before but also translate it into the clinic for disease intervention.”

In parallel, the Zhou lab has been applying this technique to establish a way to screen potential cancer drugs more effectively. “If successful,” Zhou said, “all these efforts would remarkably improve the current cancer immunotherapies by personalizing the treatment to exactly where and when it is needed, while reducing side effects.

He et al. Near-infrared photoactivatable control of Ca2+ signaling and optogenetic immunomodulation. eLife 2015;4:e10024 [Article]

Breaking down cancer’s defense mechanisms

A possible new method for treating pancreatic cancer which enables the body’s immune system to attack and kill cancer cells has been developed by researchers.

The method uses a drug which breaks down the protective barrier surrounding pancreatic cancer tumours, enabling cancer-attacking T cells to get through. The drug is used in combination with an antibody that blocks a second target, which improves the activity of these T cells.

Initial tests of the combined treatment, carried out by researchers at the University’s Cancer Research UK Cambridge Institute, resulted in almost complete elimination of cancer cells in one week. The findings, reported in the journal PNAS, mark the first time this has been achieved in any pancreatic cancer model. In addition to pancreatic cancer, the approach could potentially be used in other types of solid tumour cancers.

Pancreatic cancer is the fifth most common cause of cancer-related death in the UK and the eighth most common worldwide. It affects men and women equally, and is more common in people over the age of 60. As it has very few symptoms in its early stages, pancreatic cancer is usually only diagnosed once it is relatively advanced, and prognosis is poor: for all stages combined, the one and five-year survival rates are 25% and 26% respectively. Tumour removal is the most effective treatment, but it is suitable for just one in five patients.

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Left: pancreatic cancer cells (in green) Right: after six days of combined tumour immunotherapy, the cancerous cells had been killed. Credit: Douglas Fearon

Immunotherapy – stimulating the immune system to attack cancer cells – is a promising therapy for several types of solid tumours, but patients with pancreatic cancer have not responded to this approach, perhaps because the human form of the cancer, as in animal models, also creates a protective barrier around itself.

The research, led by Professor Douglas Fearon, determined that this barrier is created by a chemokine protein, CXCL12, which is produced by a specialised kind of connective tissue cell, called a carcinoma-associated fibroblast, or CAF. The CXCL12 protein then coats the cancer cells where it acts as a biological shield that keeps T cells away. The effect of the shield was overcome by using a drug that specifically prevents the T cells from interacting with CXCL12.

“We observed that T cells were absent from the part of the tumour containing the cancer cells that were coated with chemokine, and the principal source of the chemokine was the CAFs,” said Professor Fearon. “Interestingly, depleting the CAFs from the pancreatic cancer had a similar effect of allowing immune control of the tumour growth.”

The drug used by the researchers was AMD3100, also known as Plerixafor, which blocks CXCR4, the receptor on the T cells for CXCL12, enabling T cells to reach and kill the cancer cells in pancreatic cancer models. When used in combination with anti-PD-L1, an immunotherapeutic antibody which enhances the activation of the T cells, the number of cancer cells and the volume of the tumour were greatly diminished. Following combined treatment for one week, the residual tumour was composed only of premalignant cells and inflammatory cells.

“By enabling the body to use its own defences to attack cancer, this approach has the potential to greatly improve treatment of solid tumours,” said Professor Fearon.

Feig et al., (2013).Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti–PD-L1 immunotherapy in pancreatic cancer. PNAS110, 20212-20217 [pdf]