A novel anti-tumor vaccine for neuroblastoma and melanoma developed by scientists and clinicians at Children’s National Medical Center in collaboration with investigators from the University of Iowa is showing significant impact on tumor growth in mice, according to new research published in the October edition of the research journal Cancer Immunology, Immunotherapy.  The vaccine uses the tumor’s own protein to induce an immune system response, allowing for a personalized approach to treatment.

The vaccine and delivery system, developed in the laboratory of Children’s National Chief of General and Thoracic Surgery Anthony Sandler, MD, involves the creation of synthetic microparticles known as “immune stimulatory antigen loaded particles” (ISAPs), that consist of tumor antigens (proteins) from the specific tumor to be targeted, as well as immune stimulatory agents.  The ISAPs are detected and engulfed by specialized immune cells and sensed to be immune-stimulating “foreign bodies.”

The study shows that ISAPs are effective at blocking the growth of tumors in mice by inducing activation of immune cells that then stimulate the immune system to specifically target the tumor whose antigens match those that are loaded in the particles – known as tumor specific immunity.

The research team also discovered, however, that the impact of ISAPs on tumor growth was partially mitigated by an increased presence of regulatory t-cells (T-reg) when ISAPs are introduced into the body.  The researchers believe that T-regs play a key role in how the vaccine impacts tumor growth by suppressing the development of the specific immune cells needed to combat the tumor.  By adding a T-reg suppressor such as cyclosphosphamide or anti-CD25 antibody, the scientists were able to have a greater impact on preventing tumor growth using the ISAP approach.

“For tumors like neuroblastoma, reduction to minimal residual disease with standard therapies like chemotherapy and/or surgical resection and subsequent treatment with this vaccine could quite possibly cure the patient of the disease in the not too distant future,” said Dr. Sandler, lead author of the study.  “Creation of ISAPs allows us to target our treatments to the specific tumor of interest, a capability that will more effectively combat a wide range of these tumors in a personalized fashion.”

Among patients with castration-resistant prostate cancer, the addition of hormone therapy following vaccine treatment improved overall survival compared with either treatment alone or when the vaccine followed hormone treatment, according to recent data published in the July 15 Clinical Cancer Research, a journal of the American Association for Cancer Research.

Philip M. Arlen, M.D., director of the Clinical Research Group for the Laboratory of Tumor Immunology and Biology, Center for Cancer Research, at the National Cancer Institute, said the findings have important implications for guiding treatment decisions for prostate cancer patients.

“Vaccines, if and when they are approved, can be safely and effectively combined with other therapies, including hormones,” said Arlen.  “There appears to be an advantage in overall survival.”

Arlen and colleagues enrolled 42 patients who had castration-resistant prostate cancer.  These patients were randomly assigned to receive either a poxvirus-based prostate-specific antigen vaccine or hormone therapy with nilutamide.  At progression, patients received the other therapy and continued to receive their original therapy.

For all the patients enrolled in the study, the three-year survival probability was 71 percent and the median overall survival was 4.4 years.  Patients randomized to the vaccine had a three-year survival probability of 81 percent and an overall survival of 5.1 years, while patients taking nilutamide had a three-year survival probability of 62 percent and an overall survival of 3.4 years.

Of the 42 patients in the study, 12 patients who were originally assigned to vaccine switched to nilutamide plus vaccine and eight patients who were originally assigned to nilutamide switched to vaccine plus hormone, due to rising levels of prostate-specific antigen with no evidence of metastasis.  For patients who received vaccine and then nilutamide, the three-year survival probability was 100 percent with a median overall survival of 6.2 years.  For patients who switched to the vaccine after hormone, the three-year survival probability was 75 percent with a median overall survival of 3.7 years.

Arlen said the hormone therapy in combination with the vaccine works in two ways.

“By using hormone therapy in prostate cancer you can help enhance your T-cell response to where the cancer is in the prostate gland, and you are also more likely to achieve a better immune response,” said Arlen.

Building on the results of this phase II study, researchers have developed another generation of this vaccine by adding molecules which boost T-cell responses.

Based on the current pace of vaccine research overall, Arlen predicts that men with prostate cancer could potentially see an effective, new treatment vaccine within the next several years.

“Phase II trials such as this one are adding to our knowledge, and other phase III trials are getting ready to publish their data,” said Arlen.  “If the phase II data hold up in phase III trials, we could see a new treatment vaccine within a few years.”

Microspheres carrying targeted nucleic acid molecules fabricated in the laboratory have been shown to prevent and even reverse new-onset cases of type 1 diabetes in animal models. The results of these studies were reported by diabetes researchers at the John G. Rangos Sr. Research Center at Children’s Hospital of Pittsburgh of UPMC and Baxter Healthcare Corporation.

In a research study at Children’s Hospital, the scientists injected the microspheres under the skin near the pancreas of mice with autoimmune diabetes. The microspheres were then captured by white blood cells known as dendritic cells which released the nucleic acid molecules within the dendritic cells. The released molecules reprogrammed these cells, and then migrated to the pancreas. There, they turned off the immune system attack on insulin-producing beta cells. Within weeks, the diabetic mice were producing insulin again with reduced blood glucose levels.

Results of the microsphere study are published in the June issue of Diabetes, the journal of the American Diabetes Association.

In type 1 diabetes, T cells from the immune system travel to the pancreas and destroy beta cells, which produce insulin. The scientists – led by Massimo Trucco, MD, and Nick Giannoukakis, PhD – found that the microspheres reprogram dendritic cells to block the signaling mechanism that sends T cells to destroy beta cells. The microsphere research builds on previous research by Drs. Giannoukakis and Trucco in which they used dendritic cells delivered to the pancreas in another method to turn off the immune system’s attack on insulin-producing beta cells, thereby allowing the cells of the pancreas to recover and begin producing insulin again.

Drs. Trucco and Giannoukakis anticipate that the latest research involving microspheres represents a significant improvement over their previous approach to extract (through a process known as leukapheresis) and reprogram the dendritic cells.

“The microspheres prevented the onset of type 1 diabetes and, most importantly, exhibited a capacity to reverse hyperglycemia, suggesting a potential to reverse type 1 diabetes in new-onset patients,” said Dr. Trucco, chief of the Division of Immunogenetics at Children’s. “This novel microsphere approach represents for the first time a vaccine with the potential to suppress and reverse diabetes. This finding holds true promise for clinical testing in people with type 1 diabetes.”

Currently, Drs. Trucco and Giannoukakis are conducting a clinical trial of their leukapheresis-based dendritic cell approach in humans at Children’s. This Phase 1 clinical trial has been approved by the U.S. Food and Drug Administration (FDA).

“Our ultimate goal is to offer this dendritic cell vaccine or microsphere-based therapy to children at risk for or newly diagnosed with type 1 diabetes. We want to make the procedure as safe and comfortable as possible,” Dr. Giannoukakis said.

The trial began late last year and enrollment is ongoing. The study, which plans to enroll a total of 15 adults over age 18 with type 1 diabetes, is expected to conclude later this year.

If the leukapheresis-based approach continues to show exceptional safety, the researchers hope to launch a national clinical trial that will assess the effectiveness of the dendritic cells in pediatric patients to prevent diabetes or reverse the disease right after it is clinically confirmed. At a later date, it is anticipated that Baxter Healthcare will collaborate with Drs. Trucco and Giannoukakis in a clinical trial utilizing the unique microsphere-based approach.

Leukapheresis is a process that allows for the collection of dendritic cell precursors from the patients in the study, which takes two to four hours. After the precursors are collected, they are treated in the lab with specific growth factors that turn them into dendritic cells. The growth factors are also combined with short DNA sequences that specifically block the expression of molecules that are found at the surface of dendritic cells known as CD40, CD80 and CD86. Once these reprogrammed dendritic cells are tested in the lab, they are injected back into the patient. They then orchestrate an anti-diabetic effect by suppressing the activity of T-cells which are responsible for the impairment and destruction of the pancreatic insulin-producing cells.

“Using microspheres will be much less invasive for the patient and much more efficient for clinicians. We wouldn’t need to harvest a patient’s dendritic cells, and it would eliminate the need to genetically reprogram the dendritic cells in a sterile, off-site facility. Instead, the patient would receive the microsphere injection with a small needle in a clinic setting in a matter of minutes,” Dr. Giannoukakis said.

BIRMINGHAM, Ala. – A significant drop in abnormal Pap test results happened after girls and women were given a vaccine to prevent cervical cancer, according to a researcher at the University of Alabama at Birmingham (UAB).The findings show the vaccine, named GARDASIL, appears to prevent the development of cell changes that lead to cervical disease, the researcher said.

In testing GARDASIL reduced abnormal Pap test results by 43 percent compared to women not given the vaccine. The 43 percent reduction was for tests that found pre-cancerous changes called high-grade squamous intraepithelial lesions (HSIL) more than three years after women were given the vaccine.

GARDASIL reduced other abnormal Pap results, including milder pre-malignant cell changes, by 16 to 35 percent compared to women not given the vaccine.

While the findings are not definitive that GARDASIL prevents cancer, they do signal the vaccine will spare thousands of women a diagnosis of cell abnormality or malignant changes that may lead to more tests and possibly surgery, said Warner Huh, M.D., associate professor in the UAB Division of Gynecologic Oncology and the doctor chosen to present the data.

“Clearly the vaccine’s benefits include something that can be appreciated by women and daughters fairly quickly,” Huh said. “This is a positive first sign, and it will take many more years to know definitively if the vaccine prevents cancer.”

The findings were presented March 10 at the annual meeting of the Society of Gynecological Oncologists held in Tampa.

The results are a compilation of three separate trials involving more than 18,000 women, ages 16 to 26, in the United States, Europe and Asia. All test subjects had normal Pap smear readings at the start of the trial.

In addition to the drop in unwanted Pap results, the study found invasive procedures like cervical biopsies were performed up to 42 percent less in GARDASIL recipients compared to women not given the vaccine, Huh said.

GARDASIL is approved to fight the human papilloma virus (HPV) strains believed to cause 70 percent of cervical cancers and more than 90 percent of genital warts.

For many unvaccinated women HPV infections clear up naturally without causing any cervical problems, as do many pre-malignant lesions. In other cases, HPV prompts cell changes that can gradually put women at greater risk of cervical cancer.

Nearly 25 million U.S. women between the ages of 14 and 59 are infected with HPV, and the annual cost of screening and treating cervical abnormalities is about $4 billion, according to a statement from the Society of Gynecologic Oncologists. “Dr. Huh’s study concludes that the trials covered in this paper indicate an overall benefit of vaccination,” the society’s statement said.