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ID-KD vaccine induced T-cell cytotoxicity

Fighting lethal cancer with a one-two punch

The immune system is the ultimate yin and yang, explains Anthony D. Sandler, M.D., senior vice president and surgeon-in-chief of the Joseph E. Robert Jr. Center for Surgical Care at Children’s National in Washington, D.C. With an ineffective immune system, infections such as the flu or diarrheal illness can run unchecked, causing devastating destruction. But on the other hand, excess immune activity leads to autoimmune diseases, such as lupus or multiple sclerosis. Thus, the immune system has “checks and balances” to stay controlled.

Cancer takes advantage of “the checks and balances,” harnessing the natural brakes that the immune system puts in place to avoid overactivity. As the cancer advances, molecular signals from tumor cells themselves turn on these natural checkpoints, allowing cancers to evade immune attack.

Several years ago, a breakthrough in pharmaceutical science led to a new class of drugs called checkpoint inhibitors. These medicines take those proverbial brakes off the immune system, allowing it to vigorously attack malignancies. However, Dr. Sandler says, these drugs have not worked uniformly and in some cancers, they barely work at all against the cancer.

One of these non-responders is high risk neuroblastoma, a common solid tumor found outside the skull in children. About 800 U.S. children are diagnosed with this cancer every year. And kids who have the high-risk form of neuroblastoma have poor prognoses, regardless of which treatments doctors use.

However, new research could lead to promising ways to fight high-risk neuroblastoma by enabling the immune system to recognize these tumors and spark an immune response. Dr. Sandler and colleagues recently reported on these results in the Jan. 29, 2018, PLOS Medicine using an experimental model of the disease.

The researchers created this model by injecting the preclinical models with cancer cells from an experimental version of neuroblastoma. The researchers then waited several days for the tumors to grow. Samples of these tumors showed that they expressed a protein on their cell surfaces known as PD-L1, a protein that is also expressed in many other types of human cancers to evade immune system detection.

To thwart this protective feature, the researchers made a cancer vaccine by removing cells from the experimental model’s tumors and selectively turning off a gene known as Id2. Then, they irradiated them, a treatment that made these cells visible to the immune system but blocked the cells from dividing to avoid new tumors from developing.

They delivered these cells back to the experimental models, along with two different checkpoint inhibitor drugs – antibodies for proteins known as CLTA-4 and PD-L1 – over the course of three treatments, delivered every three days. Although most checkpoint inhibitors are administered over months to years, this treatment was short-term for the experimental models, Dr. Sandler explains. The preclinical models were completely finished with cancer treatment after just three doses.

Over the next few weeks, the researchers witnessed an astounding turnaround: While experimental models that hadn’t received any treatment uniformly died within 20 days, those that received the combined vaccine and checkpoint inhibitors were all cured of their disease. Furthermore, when the researchers challenged these preclinical models with new cancer cells six months later, no new tumors developed. In essence, Dr. Sandler says, the preclinical models had become immune to neuroblastoma.

Further studies on human patient tumors suggest that this could prove to be a promising treatment for children with high-risk neuroblastoma. The patient samples examined show that while tumors with a low risk profile are typically infiltrated with numerous immune cells, tumors that are high-risk are generally barren of immune cells. That means they’re unlikely to respond to checkpoint inhibiting drugs alone, which require a significant immune presence in the tumor microenvironment. However, Dr. Sandler says, activating an immune response with a custom-made vaccine from tumor cells could spur the immune response necessary to make these stubborn cancers respond to checkpoint inhibitors.

Dr. Sandler cautions that the exact vaccine treatment used in the study won’t be feasible for people. The protocol to make the tumor cells immunogenic is cumbersome and may not be applicable to gene targeting in human patients. However, he and his team are currently working on developing more feasible methods for crafting cancer vaccines for kids. They also have discovered a new immune checkpoint molecule that could make this approach even more effective.

“By letting immune cells do all the work we may eventually be able to provide hope for patients where there was little before,” Dr. Sandler says.

In addition to Dr. Sandler, study co-authors include Priya Srinivasan, Xiaofang Wu, Mousumi Basu and Christopher Rossi, all of the Joseph E. Robert Jr. Center for Surgical Care and The Sheikh Zayed Institute for Pediatric Surgical Innovation (SZI), at Children’s National in Washington, D.C.

Financial support for research described in this post was provided by the EVAN Foundation, the Catherine Blair foundation, the Michael Sandler Research Fund and SZI.

ID-KD vaccine induced T-cell cytotoxicity

Mechanism of Id2kd Neuro2a vaccination combined with α-CTLA-4 and α-PD-L1 immunotherapy in a neuroblastoma model. During a vaccine priming phase, CTLA-4 blockade enhances activation and proliferation of T-cells that express programmed cell death 1 (PD1) and migrate to the tumor. Programmed cell death-ligand 1 (PD-L1) is up-regulated on the tumor cells, inducing adaptive resistance. Blocking PD-L1 allows for enhanced cytotoxic effector function of the CD8+ tumor-infiltrating lymphocytes. Artist: Olivia Abbate

PICU room

How to help bereaved families

PICU room

To help clinicians provide better care to families after children die, Tessie W. October, M.D., MPH, and colleagues recently published an article on this topic in a special supplement to Pediatric Critical Care Medicine on death and dying.

Death and dying are always difficult topics to discuss at hospitals. They’re especially hard conversations when they occur within pediatric intensive care units (PICUs), says Tessie W. October, M.D., MPH, a critical care specialist at Children’s National.

“It’s almost easier to pretend that children don’t die in the ICU. But they do,” Dr. October says.

Tragically, some children do die in ICUs. However, even when pediatric patients die, Dr. October adds, the pediatric care team’s relationship with the bereaved family continues. Knowing how to help vulnerable families during these trying times and ensuring they have needed resources can be critical to lessening the health and social consequences of grief. To help clinicians provide better care to families after children die, Dr. October and colleagues recently published an article on this topic in a special supplement to Pediatric Critical Care Medicine on death and dying.

The multi-institutional research team performed a narrative literature review for this budding field. They pored through more than 75 papers to better understand the health outcomes of parents whose child died within a PICU and the different ways that hospitals help families cope with these tragedies.

The researchers found a range of detrimental health outcomes, from a significantly increased risk of parental death in the aftermath of a child’s death to higher rates of myocardial infarction, cancer and multiple sclerosis. Bereaved parents used more health care resources themselves, took more sick days and had more sleep problems than parents who weren’t bereaved.

Likewise, parents whose child died were at a high risk of experiencing mental health conditions including complicated grief, anxiety, depression and posttraumatic stress disorder. Divorce was eight times higher among bereaved parents compared with the general population, and financial crises were common after voluntary or involuntary unemployment.

Knowing which risks parents could face can help the care team respond better if a child dies, Dr. October explains. Their review highlighted simple ways to support families in the immediate aftermath of a child’s death and beyond, such as:

  • Giving parents the opportunity to spend time alone with the child’s body
  • Allowing friends, family and others to visit at the parents’ discretion and
  • Providing easy access to professional support, such as chaplains, social workers and grief coordinators.

Even simple acts such as closing doors and blinds to provide privacy can be helpful, Dr. October says.

An ongoing relationship with health care providers is also important for helping parents grieve, she adds. Children’s National is among hospitals across the country to set up meetings for parents and other family members within weeks of a child’s death. This gives parents a chance to ask questions about what happened in the confusing blur of the PICU and to gather resources for themselves and surviving siblings. Children’s National also provides ongoing support through periodic calls, sending sympathy cards, attending funeral services and in a special annual memorial during which surviving family members release butterflies.

“Our role doesn’t end when a child dies,” Dr. October says. “To help parents through bereavement, we need to maintain that strong connection.”

Another way to help bereaved families is to make sure they have adequate information, she adds, particularly about the confusing subject of brain death. In a different study recently published in Chest Journal, Dr. October and Children’s colleagues sought to understand which information the public typically accesses about this topic.

The team searched Google and YouTube using “brain dead” and “brain death” as search terms. They evaluated the top 10 results on both sites, assessing the accuracy of information using 2010 guidelines released by the American Academy of Neurology. They also assessed the reading level of websites and evaluated comments about the YouTube videos for content accuracy and tone.

They found that there was inaccurate information on four of the 10 websites, six of the 10 videos and within 80 percent of the YouTube comments. Most of these inaccuracies dealt with using terms like brain death, coma and persistent vegetative state interchangeably. “These conditions are very different and affect how we treat patients,” Dr. October says.

The average reading level of the websites was 12th grade, far too sophisticated for much of the public to comprehend, she adds. And the majority of comments on the YouTube videos were negative, often disparaging clinicians and deriding organ donation.

“It’s really important for providers to recognize that this is an emotionally laden topic, and a lot of times, families come to us with information that’s not always true,” she says. “That’s why it’s especially important for the field to respond with empathy and care.”

In addition to Dr. October, co-authors of the Pediatric Critical Care Medicine study include Karen Dryden-Palmer, R.N., MSN, Ph.D., The Hospital for Sick Children; Beverley Copnell, Ph.D., BAppSc, R.N., Monash University; and Senior Author Kathleen L. Meert, M.D., FCCM, Children’s Hospital of Michigan. Dr. October’s co-authors for the Chest Journal article include Lead Author, Amy H. Jones, M.D., and co-author Zoelle B. Dizon, BA, both of Children’s National.