​  Oncology

Glioblastoma

Activating an immune response

By Clark C. Chen, MD, PhD

lioblastoma is the most common form of brain cancer in adults, with some 14,000 cases diagnosed each year in the United States. It is also among the most deadly of human cancers. Most patients afflicted with glioblastoma die within two years of diagnosis. Famous individuals have suffered from this disease in recent years. Sen. Edward Kennedy died of glioblastoma in 2009. Vice President Joe Biden’s son, Beau Biden, died from the same cancer in 2015, and Sen. John McCain succumbed to the disease in 2018. Glioblastoma affects two to three per 100,000 people in the United States.

As a disease of the brain, glioblastoma corrodes our ability to feel, see, speak, walk, and think—the qualities that make us human. Further magnifying the ramification of these effects, available research suggests that glioblastoma preferentially affects both male and female patients with higher levels of education, according to a Swedish study (https://tinyurl.com/mp-chen01). While the reasons for this are not clear, it is possible that these patients are more aware of symptoms and may seek treatment earlier.

Standard treatment strategies

The standard-of-care treatment involves maximal surgical removal followed by combined chemotherapy and radiation therapy. Because the glioblastoma cells continuously evolve and adapt to the effects of these therapies, recurrence after treatment is nearly universal. Novel therapeutic approaches beyond standard radiation and chemotherapy is imperative in this context.

​Most patients afflicted with glioblastoma die within two years of diagnosis.

Recent success in immunotherapy as cancer treatment offered a glimmer of hope that such approaches may be beneficial to glioblastoma patients. In melanoma, for instance, application of immunotherapies that activate T cells, one of the key immune cells that initiate anti-tumor responses, has radically improved survival expectation and revolutionized cancer care. The 2018 Nobel Prize in Physiology or Medicine was awarded for this discovery.

Unlike chemotherapy, which directly kills the cancerous cells, immunotherapy activates and bolsters the patient’s immune system to harness its natural power to recognize, target, and eliminate cancer cells. There are several aspects of immune therapy that render it particularly attractive as a cancer therapy.

First, the immune system can continuously and dynamically adapt to the cancer cells with potential to launch multiple rounds of attack on cancer cells as they evolve.

Second, in contrast to chemotherapy and radiation therapy, which induce significant damage to normal cells, immune response is typically precise in its tumor kill, and spares healthy cells.

Finally, each immune response is associated with a “memory” that can be triggered to attack the cancer again if it were to return.

Bolstering immunotherapy with ultrasound

Despite these potential benefits, initial clinical application of immunotherapy as glioblastoma treatment has been disappointing. Subsequent studies revealed that glioblastoma cells are particularly adept at suppressing the patient’s immune response. For instance, there are very few T cells in regions infested with glioblastomas. Moreover, the few T cells that are found do not appear to be capable of mounting an immune response. T cell-activating immunotherapies are ineffectual against glioblastomas in this context.

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With this understanding, a major focus in glioblastoma research has shifted toward developing therapies that would quench the immune-suppressive effects of glioblastoma cells. One promising approach involves induction of damages that would naturally attract active T cells into the regions infested with glioblastoma.

To achieve this end, we injected hollowed particles made of silica, or glass, called microshells, and filled these fragile particles with near body-temperature fluorocarbon liquid into the tumor. Ultrasound waves are then directed to blow up these shells inside the tumor to induce immune response.

Ultrasound are sound waves with high frequency that can pass through a variety of tissues, including the skin and skull. By converging multiple ultrasound beams at a single point, ultrasound can be focused in a manner similar to the convergence of sun rays by a magnifying glass. Analogous to the magnifying glass, a specially designed “acoustic lens” concentrates multiple, intersecting beams of ultrasound to a precisely defined location. Each ultrasound beam delivers a limited amount of energy such that no injury is induced in each beam path. However, energy deposition from the convergence of multiple beams induce thermal destruction or mechanical shear at the target site, depending on how the ultrasound is configured. Because focused ultrasound can pass through skin and skull, targeted destruction of tumor can be achieved without the need for traditional open surgery.

​The study represents innovations that emerge when experts in apparently unrelated fields collaborate.

When focused on glioblastomas injected with microshells, the ultrasound induces explosions of the microshells to rupture the cancer cells. These ruptured cells, in turn, release tumor proteins that attract the infiltration of T cells into the regions infested with glioblastoma. In contrast to the T cells normally found in these regions, the newly recruited T cells have not been inactivated by glioblastoma cells and are capable of initiating anti-tumor immune response.

Most importantly, the immune-activating capacity of these T cells can be further augmented by the Nobel-prize winning immunotherapies that are now commercially available.

In animal models, the application of immunotherapy to microshell/ultrasound-treated glioblastoma has led to impressive tumor shrinkage. In many instances, this combination has cured animals of glioblastomas. The treated animal remained healthy without evidence of neurologic injury or weight loss as the tumor regressed. These findings suggest that the immune response initiated was causing specific destruction of the tumor without unintended side-effects.  Moreover, the immune systems of these cured animals were capable of fighting off glioblastoma cells that were subsequently re-injected.

Finding the ideal temperature

An important finding in our study (https://tinyurl.com/mp-chen02) is that ultrasound rupture of the microshells must be carried out at the body’s natural temperature. If excess heat is produced in the rupturing process, the anti-tumor immune response would be lost, since the immune cells are destroyed by the elevated temperature. Temperatures that deviate too much from the body temperature appear to compromise the effectiveness of the white blood cells. This “Goldilocks” aspect of immunotherapy was not previously appreciated. As such, sophisticated ultrasound engineering and precise control of focused ultrasound are required in this particular application.

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Fortuitously, decades of work by researchers at the University of Minnesota Medical School have yielded a focused ultrasound unit that is ideal for the described application. The safety of this unit has been demonstrated in clinical trials. The unit has been shown to be capable of inducing shearing of tumor tissue while maintaining body temperature.

Of note, the microshells utilized in our study were previously approved by the U.S. Food and Drug Administration (FDA) for clinical use. As the remaining components of the combined therapy (the immunotherapy and the focused ultrasound unit) have been FDA-cleared for clinical use, we will be initiating a first-in-human study to test this combination as glioblastoma therapy with the goal of patient enrollment in 2020.

Collaborations across fields

The study represents innovations that emerge when experts in apparently unrelated fields collaborate, including cancer biology and focused ultrasound engineering. Lessons learned from this landmark study have the potential to transform the cancer care for patients afflicted with glioblastomas. As we transform the natural history of this deadly disease, we will not only palliate human suffering but also maximize our ability to meaningfully influence our collective destiny.

Clark C. Chen, MD, PhD, is the Lyle French Chair in Neurosurgery and head of the Department of Neurosurgery at the University of Minnesota Medical School. He is also a University of Minnesota Physicians neurosurgeon and member of the Masonic Cancer Center.