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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

T cell

Clinical Trial Spotlight: Is more really better? Dose escalation of multi-antigen targeted T cells to illicit a more robust response

T cell

As the promise of immunotherapy in treating patients with cancer becomes more evident, physician researchers at Children’s National are pushing the needle further along. Holly Meany, M.D., is leading a Phase 1 dose-escalation trial to determine the safety and efficacy of administering rapidly generated tumor multi-antigen associated specific cytotoxic T lymphocytes (TAA CTL) to patients who have undergone allogeneic hematopoietic stem cell transplantation (HSCT) or traditional therapy for a high-risk solid tumor due to the presence of refractory, relapsed and/or residual detectable disease.

“In the escalation portion of our trial, we found that the highest dose evaluated did not have unfavorable toxicity in these patients and is our recommended dose,” Dr. Meany said. “Our next step is an expansion of the trial in five distinct disease categories – Wilms tumor, neuroblastoma, rhabdomyosarcoma, adenocarcinoma and esophageal carcinoma – to examine efficacy on a broader level at the recommended dose.”

Dr. Meany and fellow research clinicians at Children’s National will evaluate not only what happens to the patients when given the additional dosage, but also what happens to the cells – How long will they last? Will they remain targeted against the same antigens or will they shift to target other proteins?

This novel trial is currently enrolling patients at Children’s National Health System in Washington, D.C.

  • PI: Holly Meany, M.D.
  • Title: Research Study Utilizing Expanded Multi-antigen Specific Lymphocytes for the Treatment of Solid Tumors (REST)
  • Status: Currently enrolling

For more information about this trial, contact:

Holly Meany, M.D.
202-476-5697
hmeany@childrensnational.org 

Click here to view Open Phase 1 and 2 Cancer Clinical Trials at Children’s National.

The Children’s National Center for Cancer and Blood Disorders is committed to providing the best care for pediatric patients. Our experts play an active role in innovative clinical trials to advance pediatric cancer care. We offer access to novel trials and therapies, some of which are only available here at Children’s National. With research interests covering nearly aspect of pediatric cancer care, our work is making great advancements in childhood cancer.

Catherine Bollard

Engineering TGFB receptor to enhance NK cells and fight neuroblastoma

Catherine Bollard

“In this study, we have genetically engineered cord blood derived NK cells so that they are not only resistant to the devastating effects of TGFb, but they are not able to become activated in the presence of TGFb,” said, Catherine Bollard, M.B.Ch.B., M.D.

Catherine Bollard, M.B.Ch.B., M.D., and her research team published results showing potential efficacy of a novel cell therapy for treatment of pediatric patients with relapsed/refractory neuroblastoma.

The research paper, entitled, “Engineering the TGFβ receptor to Enhance the Therapeutic Potential of Natural Killer Cell as an Immunotherapy for Neuroblastoma,” was published on April 29, 2019 by Clinical Cancer Research and is being recognized for the potential efficacy of the “off the shelf” treatment for patients with relapsed/refractory neuroblastoma.

The researcher’s approach allows them to manipulate Natural Killer (NK) cells, expand and reinfuse them within a patient so they can fight cancer and disease.

“In this study, we have genetically engineered cord blood derived NK cells so that they are not only resistant to the devastating effects of TGFb, but they are not able to become activated in the presence of TGFb,” said, Dr. Bollard, who is the senior corresponding author of the study and director of the Center for Cancer and Immunology Research at the Children’s Research Institute. “In other words, turning the negative effects of TGFb into positive effects enhances the persistence and anti-tumor activity of these tumor-killing NK cells in vivo.”

NK cells are highly cytolytic, and their potent antitumor effects can be rapidly triggered by a lack of human leukocyte antigen (HLA) expression on interacting target cells, as in the case for a majority of solid tumors, including neuroblastoma. With neuroblastoma being a leading cause of pediatric cancer-related deaths, it presents as an ideal candidate for NK cell therapy.

“This manuscript encompasses a significant portion of work, in which we generated genetically-modified NK cells as an enhanced form of immunotherapy for neuroblastoma,” said Rachel Burga, Ph.D., lead author and graduate of the Institute for Biomedical Sciences at George Washington and Children’s National Health System.  “We’re very excited to share our pre-clinical findings which demonstrate the efficacy of approaches to “hijack” the TGFb receptor and target TGFb in the tumor microenvironment.”

She added that the approach will allow for the NK cells to simultaneously resist the immune suppression in the microenvironment and initiate activation to increase their ability to target tumor cells.

Pre-clinical testing and research for this trial began in 2016 and ended in 2019. “The idea came from a Department of Defense award given to Dr. Bollard and Dr. Cruz and they took the idea and reduced it to practice and showed feasibility for pre-clinical trial,” said Rohan Fernandes, Ph.D., assistant professor in the Department of Medicine at George Washington University and senior author on the manuscript.

Fernandes added that the timeframe to start the clinical trial is within the next two to four years at Children’s National.

Additional authors include Rachel A. Burga, Ph.D., Eric Yvon, Rohan Fernandes, Conrad Russell Cruz, and Catherine M. Bollard, M.B.Ch.B., M.D.

Anthony Sandler

Treatment of neuroblastoma with immunotherapy and vaccine combination shows promise

Anthony Sandler

“Treatment options like these that help the body use its own immune system to fight off cancer are incredibly promising, and we look forward to continuing this work to understand how we can best help our patients and their families,” said Anthony Sandler, M.D.

Despite being the most common extracranial solid tumor found in children and having multiple modes of therapy, neuroblastoma continues to carry a poor prognosis. However, a recent cutting-edge pre-clinical study, PD-L1 checkpoint inhibition and anti-CTLA-4 whole tumor cell vaccination counter adaptive immune resistance: A mouse neuroblastoma model that mimics human disease, published in PLOS Medicine shows the first signs of success in treating high-risk neuroblastoma, a promising step not only for neuroblastoma patients, but potentially for other types of cancer and solid tumors as well. While the research was conducted on mouse models and is in the early stages, the lead author of the study, Anthony Sandler, M.D., senior vice president and surgeon-in-chief of the Joseph E. Robert, Jr., Center for Surgical Care at Children’s National, believes these findings are an encouraging development for the field.

The treatment method combines a novel personalized vaccine and a combination of drugs that target checkpoint inhibitors enabling the immune system to identify and kill cancer cells. When these checkpoints are blocked, it’s similar to taking the brakes off the immune system so that the body’s T cells can be primed by the vaccine, identify the tumor and allow for targeted tumor cell killing. The vaccine then brings in reinforcements to double down on the attack, helping to eradicate the tumor. The vaccine could also be used as a way to prevent recurrence of disease. After a patient has received the vaccine, the T cells would live in the body, remembering the tumor cells, and attack reemerging cancer in a similar way that a flu vaccine helps fight off the flu virus.

“Treatment options like these that help the body use its own immune system to fight off cancer are incredibly promising, and we look forward to continuing this work to understand how we can best help our patients and their families,” said Dr. Sandler.

A vaccine approach to tumor cure

Anthony Sandler

Anthony Sandler, M.D, is trying to understand how cancer cells can change their behavior and activate the immune system – enlisting the patients’ own defenses to fight the tumor.

Building on their groundbreaking research that found a method to cure neuroblastoma tumors in mice, researchers at Children’s National have been working in recent months on a personalized tumor-specific vaccine approach for neuroblastoma and other solid tumors.

The possibility that such a vaccine could non-invasively cure one of the most common childhood cancers is part of Children’s innovative efforts to address some of the most critical medical research challenges facing the field. Anthony Sandler, M.D., Senior Vice President, the Joseph E. Robert, Jr. Center for Surgical Care, and the Diane and Norman Bernstein Professor in Pediatric Surgery, is leading the research that followed an initial publication in PLOS ONE. Sandler’s team seeks to understand how cancer cells can change their behavior and activate the immune system – enlisting the patients’ own defenses to fight the tumor.

Their research is particularly significant because neuroblastoma, most commonly centered in the adrenal glands, is the third most common tumor in childhood, and the most common cancer in babies younger than one year old. It accounts for six percent of all childhood cancers in the United States, with about 700 children younger than 15 diagnosed each year.

“Historically, tumor vaccines held much promise, but demonstrated little clinical success,” Dr. Sandler and his team wrote in their study. “Thus, the task of establishing an effective anti-tumor response in neuroblastoma has been daunting.” However, with this most recent study finding, Dr. Sandler says this failed promise is changing.

The study revealed that “knockdown’” of a DNA-protein inhibitor, known as ID-2, in aggressive high-risk solid tumors resulted in activation of T-cells, which are white blood cells that have figured significantly in immunity research. Gene knockdown refers to a technique in which the expression of one or more of a cell’s genes is reduced.

The research also focused on using “checkpoint blockade,” a therapy in clinical use that allows for expansion of the immune response against tumors. “The combination of selective gene knock-down in tumor cells and checkpoint blockade produced a novel, potent T-cell triggered tumor vaccine strategy,” Dr. Sandler says.

As Children’s researchers examined the impact of the knockdown of ID-2 protein on a tumor, they implanted N2a, a fast growing mouse neuroblastoma cell line, in the mice. Unexpectedly, Sandler said, “Most of the mice rejected the tumor cells and subsequently were protected against further tumor challenges.”

The researchers also noted that a “massive influx” of T-cells infiltrated the shrinking tumor, indicating that T-cells are necessary for antitumor immunity in this vaccination protocol.

The ultimate goal for Sandler’s team is to work toward potential clinical trials to make further progress in neuroblastoma research, with immunotherapy playing a key role.

Dr. Sandler is the Principal Investigator of the Immunology initiative of the Sheikh Zayed Institute for Pediatric Surgical Innovation, and has worked in immunology research related to childhood cancers for more than 20 years.