New immunotherapy for malignant brain tumors

It is relatively easy to treat cancer in the early stages. However, it is far more difficult to successfully treat advanced cancer. Treatment of brain tumors is particularly challenging because regulatory T-cells accumulate in brain tumors and suppress an immune attack.

In several steps using a new strategy and a novel drug, Burkhard Becher’s team from the Institute of Experimental Immunology at the University of Zurich has now succeeded in doing exactly this in the case of glioblastoma, one of the most dangerous brain tumors. First step, they stimulated the body’s own immune system in such a way that it recognised and then killed the brain tumor cells even in advanced stages of the disease.

The initial objective of their new study was to break through the tumor’s protective shield. “We wanted to establish whether we can actually elicit an immune response to a tumor growing within the brain”, explains Burkhard Becher. To this end, the team used the immune messenger substance, Interleukin-12. When Interleukin-12 is produced in the tumor, immune cells are stimulated locally in such a manner that the tumor is attacked and rejected. Once this procedure had worked well in the early stages of the tumor, the researchers waited in the next stage until the tumor was very large and the life expectancy of the untreated test animals was less than three weeks. “We only began treatment when it was, in fact, already too late”, says the first author of the study Johannes vom Berg. The success rate was low, Berg adds. “We then injected biopharmaceutical Interleukin-12 into the large brain tumor. This did induce an immune response but only led to tumor rejection in one-quarter of the animals.”

From 25 to 80 percent: combined treatment leads to success

The researchers were successful when they drew on a new development in skin cancer treatment. They combined intra-tumoral Interleukin-12 treatment with the intravenous administration of a novel immunostimulating drug that suppresses the regulatory T-cells. The rejection of the tumor then worked in 80 percent of the test animals. “I have rarely seen such convincing data in preclinical glioma treatment”, says Michael Weller, neurooncologist and Director of the Clinic for Neurology at the University Hospital Zurich. He added, “That’s why this development should be tested as soon as possible in clinical trials.”

In a joint trial, the team then tested the treatment in a further tumor model which mimics the clinical situation of the brain tumor patient even better. And once again they were successful.

The next step: a clinical trial as soon as possible

The findings of the current research work have been published in the Journal of Experimental Medicine. Their promising results do not mean that the treatment can already be as effective in brain tumor patients. This has to be examined in the next phase for which the team now actively seek commercial partners. Burkhard Becher puts it like this, “We are cautiously optimistic but it’s time that we adopted completely new strategies to really get to grips with this fatal tumor”

vom Berget et al.,(2013). Intratumoral IL-12 combined with CTLA-4 blockade elicits T cell mediated glioma rejection. J. Exp. Med., EPub Ahead of Print, doi: 10.1084/jem.20130678 [Abstract]

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Dysfunctional mitochondria may underlie resistance to radiation therapy

New role discovered for gene
The resistance of some cancers to the cell-killing effects of radiation therapy may be due to abnormalities in the mitochondria – the cellular structures responsible for generating energy, according to an international team of researchers. Their findings are published in the Nov. 25 issue of Developmental Cell.

Maxim Frolov, associate professor of biochemistry and molecular genetics at the University of Illinois at Chicago, and colleagues investigated the effects of a mutation in a gene called E2F, which controls other genes responsible for initiating programmed cell death, a normal function in most cells. Cells undergo programmed cell death — or apoptosis — when they are no longer needed, as a normal part of aging, or in response to environmental factors like radiation that damage cellular DNA.

When Frolov and colleagues exposed fruit flies carrying a mutant E2F gene to radiation, genes that initiate apoptosis were activated, but the flies did not die.

“Something else was preventing the flies from dying, even though the genes needed to undergo cell death were turned on,” Frolov said.

A closer look within the cells of the flies revealed that their mitochondria were misshapen and produced less energy than normal mitochondria. Flies with the most severely deranged mitochondria were the most resistant to radiation-induced cell death.

The observation in fruit flies suggested a previously unknown role for the E2F transcription factor — the protein encoded by E2F that regulates expression of other genes — in mitochondrial function.

“It seems their mitochondria were also affected by the E2F mutation and were not functioning at full strength,” said Frolov. “You need properly functioning mitochondria to carry out programmed cell death.”

Turning to human cells, the researchers found the same effects: those that lacked the E2F gene were resistant to the effects of radiation. Frolov said the similarity in the findings shows that basic cellular functions do not change much across the vast evolutionary distance between fruit flies and humans.

“This result highlights a remarkable degree of conservation between fruit flies and humans and illustrates the advantages of using model organisms in cancer research,” said Frolov, whose laboratory is part of the UIC Cancer Center.

Frolov and his colleagues think that dysfunctional mitochondria might underlie the differences in how patients respond to radiation therapy. Previous studies have suggested that the inability of some patients’ mitochondria to support apoptosis might account for differences in their response to chemotherapy for acute myelogenous leukemia.

“If we could develop a small-molecule drug that could enhance mitochondrial function in these patients, we may be able to improve the effectiveness of radiation therapy,” Frolov said.

Ambrus et al., (2013). Loss of dE2F compromises mitochondrial function. Develop. Cell27, 438-451 [Abstract]

Nurse navigators help cancer patients cope early in care

Randomized controlled trial, now in practice at Group Health

When Group Health patients received support from a nurse navigator, or advocate, soon after a cancer diagnosis, they had better experiences and fewer problems with their care—particularly in health information, care coordination, and psychological and social care—according to a randomized controlled trial in the Journal of Clinical Oncology.

Patients with a nurse navigator reported feeling better supported emotionally and more involved in their care. They also said they were better informed and more prepared for the future. And they tended to feel that the health care team had gone out of their way to make them feel better emotionally.

“Hearing that you have cancer is so difficult,” said lead author Ed Wagner, MD, MPH, a senior investigator at Group Health Research Institute and director emeritus of the Institute’s MacColl Center for Health Care Innovation. Right after a cancer diagnosis, patients and their families often need extra help: with information, translating medical jargon, psychological and social support, and coordinating care from various health providers. That’s what Dr. Wagner learned earlier from studying the perspectives of patients, families, providers, and experts around the country.

“It makes sense that patients would benefit from having a single point person devoted to providing support and coordination of services,” said Dr. Wagner’s coauthor Ruth McCorkle, PhD, RN, the Florence Schorske Wald professor of nursing at Yale School of Nursing and a professor of epidemiology at Yale School of Public Health. “Oncology nurse navigator programs are proliferating across the country, but they are highly variable because there hasn’t been much rigorous evidence.”

In this randomized controlled trial, half of the 251 adult patients newly diagnosed with cancer were assigned to an oncology nurse navigator to help them for four months. Starting two weeks after the diagnosis, the nurse navigator initiated weekly phone calls and contacted each patient an average of 18 times, including meeting in person at least once with each patient: for instance, accompanying them to a doctor’s appointment.

The other group of the patients received “enhanced usual care” consisting of educational material designed by a patient advisory committee. Most (190) of the patients had breast cancer, but 30 had lung and 31 had colon or rectal cancer. Patient-reported outcomes were measured at baseline, four months, and one year.

Some of the differences between the groups persisted for eight months after patients’ last contact with a nurse navigator. “That suggests that the nurse navigators helped patients to develop the confidence and skills to manage their illness and treatment more effectively,” Dr. Wagner said. “This is important because it’s crucial for patients to be involved in their care and self-care.”

Overall costs of health care, including the costs of the intervention, didn’t rise at all with the nurse navigator intervention—and in lung cancer patients, they might have actually declined. No overall changes were detected in patients’ quality of life or depression. “That might have been because our patients had high quality of life to start with,” Dr. Wagner said, “and our way of measuring that might not have been sensitive enough.”

The oncology nurse navigators had experience with cancer patients, received special training to deal with psychosocial distress, and were familiar with the Group Health system. “Our system tends to be better coordinated than average in the United States,” Dr. Wagner said. “Further research is needed to see how well nurse navigation works in more fragmented care systems—and whether it can reduce the costs of cancer care.”

Group Health was so impressed with this work that it has already incorporated an oncology nurse navigator into usual care for women newly diagnosed with breast cancer at its Capitol Hill campus—even before the research was published.

Also, the Group Health Foundation has awarded a Partnership for Innovation grant to Drs. Wagner and McCorkle’s coauthor Evette J. Ludman, PhD, a senior research associate at Group Health Research Institute, to implement and evaluate a peer support program for women with breast cancer.

Wagner et al., (2013). Nurse navigators in early cancer care: A randomized, controlled trial. J. Clin. Oncol., EPub Ahead of Print [Abstract]