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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Two studies examine long-term outcomes in childhood and young adult cancer survivors

JAMA Oncology published two studies and a related editorial focused on long-term outcomes in survivors of childhood or young adult cancer.

In the first study, Kathrine Rugbjerg, PhD, and Jørgen Olsen, MD, DMSc, of the Danish Cancer Society Research Center, Copenhagen, examined the risk for hospitalization up to 34 years after a diagnosis of adolescent and young adult cancer survivors. The study included 33,555 five-year cancer survivors diagnosed from 1943 through to 2004 with a comparison group from the general population. The authors identified 53,032 hospitalizations in cancer survivors for one or more of 97 disease categories.

Cancer survivors had an overall increased risk of hospitalization compared with those in the general population. Cancer survivors at highest risk for hospitalizations were leukemia, brain cancer and Hodgkin lymphoma survivors.

Survivors of adolescent and young adult cancers face persistent risks for a broad range of somatic diseases requiring hospitalization. The morbidity pattern, which is highly dependent on the type of cancer being treated, underscores the need for further implementation of strict evidence-based sex-, age- and cancer-specific follow-up plans for survivors, thereby increasing the likelihood for early detection and ultimately prevention of treatment-induced morbidities.

In the second study, Kevin Krull, PhD, of St. Jude Children’s Research Hospital, Memphis, and coauthors examined neurocognitive and patient-reported outcomes in adult survivors of childhood osteosarcoma, a type of bone cancer. The study included 80 survivors of osteosarcoma who were an average age of nearly 39 years and almost 25 years past diagnosis. The cancer survivors were compared with 39 community members unrelated to the cancer survivors. Long-term survivors had lower average scores in reading skills, attention, memory and processing speed. However, plasma concentration of methotrexate following high-dose intravenous administration during chemotherapy was not associated with neurocognitive outcomes at nearly 25 years after diagnosis.

Long-term survivors of osteosarcoma are at risk for neurocognitive impairment, which is related to current chronic health conditions and not to original treatment with high-dose methotrexate. … Our results demonstrate the need for increased attention in this diagnosis, with prospective studies to delineate the evolution of impairment over the course of therapy and long-term survival,” the authors conclude.

In a related editorial, Karen E. Effinger, MD, MS, and Michael P. Link, MD, of the Stanford University School of Medicine, California, write: “Advances in cancer therapy have led to increased survival; there are more than 9 million 5-year survivors of cancer in the United States. As this number continues to grow, focus on improved health and quality of life becomes a priority. … Going forward, we must apply our knowledge of late effects to improve monitoring and interventions for patients. While the progress made in the management of cancer in children and young adults has been gratifying, we must remember the words of Giulio D’Angio, who reminds us that ‘cure is not enough.'”Rugbjerg et al. Long-term Risk of Hospitalization for Somatic Diseases in Survivors of Adolescent or Young Adult Cancer. JAMA Oncol. Published online November 19, 2015. doi:10.1001/jamaoncol.2015.4393 [Article]Krull et al. Neurocognitive and Patient-Reported Outcomes in Adult Survivors of Childhood Osteosarcoma. JAMA Oncol. Published online November 19, 2015. doi:10.1001/jamaoncol.2015.4398 [Abstract]

Microencapsulation produces uniform drug release vehicle

Consistently uniform, easily manufactured microcapsules containing a brain cancer drug may simplify treatment and provide more tightly controlled therapy, according to Penn State researchers.

“Brain tumors are one of the world’s deadliest diseases,” said Mohammad Reza Abidian, assistant professor of bioengineering, chemical engineering and materials science and engineering. “Typically doctors resect the tumors, do radiation therapy and then chemotherapy.”

The majority of chemotherapy is done intravenously, but, because the drugs are very toxic and are not targeted, they have a lot of side effects. Another problem with intravenous drugs is that they go everywhere in the bloodstream and do not easily cross the blood brain barrier so little gets to the target tumors. To counteract this, high doses are necessary.

Perfect microspheres were produced using 4 percent by weight of the polymer.
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Current treatment already includes leaving wafers infused with the anti-tumor agent BCNU in the brain after surgery, but when the drugs in these wafers run out, repeating invasive placement is not generally recommended.“We are trying to develop a new method of drug delivery,” said Abidian. “Not intravenous delivery, but localized directly into the tumor site.”

“BCNU has a half life in the body of 15 minutes,” said Abidian. “The drug needs protection because of the short half life. Encapsulation inside biodegradable polymers can solve that problem.”

Encapsulation of BCNU in microspheres has been tried before, but the resulting product did not have uniform size and drug distribution or high drug-encapsulation efficiency. With uniform spheres, manufacturers can design the microcapsules to precisely control the time of drug release by altering polymer composition. The tiny spheres are also injectable through the skull, obviating the need for more surgery.

Microfibers were produced using 10 percent by weight solutions of the polymer.
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Abidian, working with Pouria Fattahi, graduate student in bioengineering and chemical engineering, and Ali Borhan, professor of chemical engineering, looked at using an electrojetting technique to encapsulate BCNU in poly(lactic-co-glycolic) acid, an FDA-approved biodegradable polymer. In electrojetting, a solution containing the polymer, drug and a solvent are rapidly ejected through a tiny nozzle with the system under a voltage as high as 20 kilovolts but with only microamperage. The solvent in the liquid quickly evaporates leaving behind anything from a perfect sphere to a fiber.

“Electrojetting is a low cost, versatile approach,” said Abidian. “We can produce drug-loaded micro/nano-spheres and fibers with same size, high drug-loading capacity and high drug-encapsulation efficiency.”

The researchers tested solutions of polymer from 1 percent by weight to 10 percent by weight and found that at 1 to 2 percent they obtained flattened microspheres, at 3 to 4 percent they had microspheres, at 4 to 6 percent they had microspheres and microfibers, at 7 to 8 percent they had beaded microfibers and above 8 percent they obtained only fibers. They report their results in the current issue of Advanced Materials.


This is a scanning electron micrograph of BCNU-loaded microspheres (black and white background) with 3D rendered images of brain cancers cells (yellow) and released BCNU (purple).
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The researchers also investigated the sphericality of the spheres.“Depending on the desired applications, all the shapes are useful except for the beaded fibers,” said Abidian. “While fibers are not good for drug delivery, they are good for tissue engineering applications.”

“We looked at how spherical they were and found they were perfect,” said Abidian. They have a height versus width ratio of 1.05 and they have size uniformity. A perfect sphere would have a ratio of 1.

The researchers also looked into how BCNU releases from the microcapsules. Using mathematics, the researchers established a drug diffusion coefficient for the encapsulation system. This helps in designing how much drug to include in each microcapsule and how long the microcapsules will deliver the required dosage.

The researchers note that BCNU is not the only drug that can be encapsulated in polymer beads for drug delivery. Other drugs can be used but would have their own diffusion coefficients and half lifes.

Fattahi et al., (2013). Microencapsulation: Microencapsulation of chemotherapeutics into monodisperse and tunable biodegradable polymers via electrified liquid jets: Control of size, shape, and drug release.Adv. Mater., 25: 4529 [Abstract]