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Novel cancer vaccine targets oncogenes known to evade immunity in melanoma and neuroblastoma models

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"Neuroblastoma of the Adrenal Gland (2)" by euthman is licensed under CC BY 2.0

“Neuroblastoma of the Adrenal Gland (2)” by euthman is licensed under CC BY 2.0.

A personalized tumor cell vaccine strategy targeting Myc oncogenes combined with checkpoint therapy creates an effective immune response that bypasses antigen selection and immune privilege, according to a pre-clinical study for neuroblastoma and melanoma. The neuroblastoma model showed a 75% cure with long-term survival, researchers at Children’s National Hospital found.

Myc is a family of regulator genes and proto-oncogenes that help manage cell growth and differentiation in the body. When Myc mutates to an oncogene, it can promote cancer cell growth. The Myc oncogenes are deregulated in 70% of all human cancers.

Myc mutations, like the amplification of c-MYC and MYCN, are associated with host immune suppression in melanoma and neuroblastoma tumors, according to the study published in The Journal for Immunotherapy of Cancer.

“Paradoxically, from an immunotherapeutic perspective, a lack of an immune response may offer an opportunity to target those tumors [melanoma and neuroblastoma] that would be less resistant to host immunity assuming potent cellular immunity can be generated against the tumor,” said the authors.

The findings suggest that small molecule inhibitors — I-BET726 and JQ1 — suppress Myc’s uncontrolled cellular proliferation and enhance the immune response against tumor cells themselves, enabling their use as a tumor cell vaccine. The combination of cell vaccine and available therapies that keep the immune responses in check, also known as checkpoint inhibitor therapy, can help inform a personalized therapeutic tumor vaccine in the future.

“The work is pre-clinical and although we have seen excellent responses in these models, we need to determine whether this will also be effective in humans,” said Xiaofang Wu, staff scientist III at Sheikh Zayed Institute for Pediatric Surgical Innovation and lead author.  “For this purpose we have started laboratory testing in human cells. Our eventual hope is to translate these basic science findings to clinical application.”

There is a need for more effective therapies for neuroblastoma and melanoma, given the poor outcome of patients experiencing high-risk or advanced disease through traditional chemotherapy methods.  While the field has developed tumor vaccines and immune-based therapies, c-MYC and MYCN seem to protect the tumor against an immune response, so they often evade cure.

The researchers cautioned that both models induced potent immunity but draw different results, which means that this novel therapeutic vaccine is more effective in the neuroblastoma model than in the melanoma model. The neuroblastoma model resulted in a remarkable 75% cure and significantly improved long-term survival despite a larger initial tumor challenge.

“In contrast, the melanoma tumor gained adaptive resistance that is associated with an imbalance between tumor cell growth and cytotoxic killing and thus the vaccine failed to eradicate the tumor,” said the authors. “Despite potent immune effects from the vaccine, other immunosuppressive molecules will need to be targeted to see the full effects of the vaccine protocol in the melanoma model.”

The study proposes a framework that could be translated for therapeutic patient-specific vaccines for MYCN-amplified neuroblastoma tumors resistant to available therapies.

To understand the exact role of c-Myc and MYCN amplification and their association with immune suppression, the researchers examined 21 human neuroblastoma samples — the majority with metastatic disease — and 324 melanoma samples where only 30 were categorized as MYC amplified. Based on the oncogene’s capability to suppress the immune response, the researchers combined checkpoint inhibitors with pharmacologic molecules — I-BET726 and JQ1 — to target Myc oncogenes in mouse neuroblastoma and melanoma models. They also tested for the effects of different doses, drug combinations and incubation times on tumor cell proliferation, differentiation and gene alteration.

Authors on the study from Children’s National Hospital include: Xiaofang Wu, Ph.D., Marie Nelson, M.D., Mousumi Basu, Priya Srinivasan, Ph.D., Christopher Lazarski, Ph.D., and Anthony Sandler, M.D.

ID-KD vaccine induced T-cell cytotoxicity

Fighting lethal cancer with a one-two punch

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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

Anthony Sandler

Anthony Sandler, M.D., Named Director of Sheikh Zayed Institute

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Anthony Sandler

Children’s National Health System is pleased to announce that Anthony Sandler, M.D., current senior vice president and surgeon-in-chief of the Joseph E. Robert Jr. Center for Surgical Care at Children’s National, will now additionally assume the title of director, Sheikh Zayed Institute for Pediatric Surgical Innovation. He will succeed Peter Kim, M.D., the founding vice president of the Sheikh Zayed Institute, who is leaving to pursue other career opportunities after seven years at the helm of our surgical innovation center.

Dr. Sandler will be in a unique position, leading both in the research and clinical enterprises of Children’s National and will help to forge a stronger link between them, especially in the surgical subspecialties.

Internationally known for his work on childhood solid tumors and operative repair of congenital anomalies, Dr. Sandler is the Diane and Norman Bernstein Chair in Pediatric Surgery and is a professor of surgery and pediatrics at the George Washington University School of Medicine & Health Sciences. He is currently on the Board of Examiners for the Pediatric Surgery Qualifying Examination and has served on multiple committees for the American Pediatric Surgical Association and for the Children’s Oncology Group.

Dr. Sandler’s research interests focus on solid tumors of childhood and he’s presently studying tumor immunology and investigating immunotherapeutic vaccine strategies. He has co-developed a surgical polymer sealant that is R01 funded by the National Institutes of Health and is currently in pre-clinical trials. Dr. Sandler has over 120 peer-reviewed publications in clinical and scientific medical journals.

Anthony Sandler

Treatment of neuroblastoma with immunotherapy and vaccine combination shows promise

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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

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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.