Three-way brain tumor therapy sparks immune system with radiation

Johns Hopkins researchers have found that combining radiation with two therapies that activate the immune system allow mice with brain tumors (glioblastoma) to survive longer than mice who did not receive the combo treatment. INBT affiliated faculty member Michael Lim, M.D., an associate professor of neurosurgery, oncology at the Johns Hopkins University School of Medicine, said the radiation may act “as kind of kindling, to try to induce an immune response.”

brainRead the full press release from Johns Hopkins regarding the publication in PLoS One journal below:

A triple therapy for glioblastoma, including two types of immunotherapy and targeted radiation, has significantly prolonged the survival of mice with these brain cancers, according to a new report by scientists at the Johns Hopkins Kimmel Cancer Center.

Mice with implanted, mouse-derived glioblastoma cells lived an average of 67 days after the triple therapy, compared with mice that lasted 24 days when they received only the two immunotherapies. Half of the mice who received the triple therapy lived 100 days or more and were protected against further tumors when new cancer cells were re-injected under the animals’ skins.

The combination treatment described in the July 11 issue of PLOS One consists of highly focused radiation therapy targeted specifically to the tumor and strategies that lift the brakes and activate the body’s immune system, allowing anti-cancer drugs to attack the tumor. One of the immunotherapies is an antibody that binds to and blocks an immune checkpoint molecule on T cells called CTLA-4, allowing the T-cells to infiltrate and fight tumor cells. The second immunotherapy, known as 4-1BB, supplies a positive “go” signal, stimulating anti-tumor T cells.

None of the treatments are new, but were used by the Johns Hopkins team to demonstrate the value of combining treatments that augment the immune response against glioblastomas, the most common brain tumors in human adults. The prognosis is generally poor, even with early treatment.

“We’re trying to find that optimal balance between pushing and pulling the immune system to kill cancer,” said Charles Drake, M.D., Ph.D., an associate professor of oncology, immunology and urology, and medical oncologist at the Johns Hopkins Kimmel Cancer Center.

The researchers speculate that when radiation destroys tumor cells, the dead tumor cells may release proteins that help train immune cells to recognize and attack the cancer, said Michael Lim, M.D., an associate professor of neurosurgery, oncology at the Johns Hopkins University School of Medicine and member of Johns Hopkins’ Institute of NanoBiotechnology.

“Traditionally, radiation is used as a definitive therapy to directly kill cancer cells,” said Lim, who also serves as director of the Brain Tumor Immunotherapy Program and director of the Metastatic Brain Tumor Center at Johns Hopkins Medicine. “But in this situation we’re using radiation as kind of kindling, to try to induce an immune response.”

Lim says if further studies affirm the value of the triple therapy in animals and humans, the radiation could be delivered a few days before or after the immunotherapies and still achieve the same results. Lim said this leeway “could make applications of this therapy in patients possible.”

The researchers say they were also encouraged to see that the triple therapy created “immune memory” in mice that were long-term survivors. When brain tumor cells were re-introduced under the skin of the animals, their immune systems appeared to protect them against the development of a new brain tumor.

Drake said since the immune system usually doesn’t generate a memory when foreign (tumor) cells are still present in the body. “But the idea that this combination treatment was successful at generating immunological memory really suggests that we could do this in patients and generate some long-term responses.”

The researchers are developing a variety of clinical trials to test combination therapies against brain tumors.

Other researchers on the study include Zineb Belcaid, Jillian A. Phallen, Alfred P. See, Dimitrios Mathios, Chelsea Gottschalk, Sarah Nicholas, Meghan Kellett, Jacob Ruzevick, Christopher Jackson, Xiaobu Ye, Betty Tyler, and Henry Brem of the Department of Neurosurgery at Johns Hopkins University School of Medicine; Jing Zeng, Phuoc T. Tran, and John W. Wong of the Department of Radiation Oncology and Molecular Radiation Sciences at the Johns Hopkins Kimmel Cancer Center;  and Emilia Albesiano, Nicholas M. Durham, and Drew M. Pardoll at the Kimmel Center’s Department of Oncology and Medicine, Division of Immunology.

Funding for the study was provided by the WW Smith Charitable Foundation and individual patient donations.

Michael Lim is a consultant for Accuray and receives research funding from Accuray, Bristol-Meyers Squibb, Celldex and Aegenus. Charles Drake has served as a consultant for Amplimmune, Bristol-Meyers Squibb, Compugen, Dendreon, ImmunExcite and Roche/Genentech and is on the Scientific Advisory Board of Compugen. He receives research funding from Bristol-Meyers Squibb, Aduro and Janssen and has stock ownership in Compugen. Drew Pardoll is a consultant/advisor for Jounce Therapeutics, Bristol-Meyers Squibb, ImmuneXcite and Aduro and receives research funding from Bristol-Meyers Squibb. Jing Zeng, Michael Lim, Charles Drake and Drew Pardoll hold a patent for the work related to this study.

The authors declare that they have a patent relating to material pertinent to this article; this international patent application (PCT/US2012/043124) is entitled “Use of Adjuvant Focused Radiation Including Stereotactic Radiosurgery for Augmenting Immune Based Therapies Against Neoplasms.” These relationships are being managed by The Johns Hopkins University in accordance with its conflict of interest policies.

For all press inquiries regarding INBT, its faculty and programs, contact Mary Spiro, mspiro@jhu.edu or 410-516-4802.

INBT launches Johns Hopkins Center of Cancer Nanotechnology Excellence

Martin Pomper and Peter Searson will co-direct INBT’s new Center of Cancer Nanotechnology Excellence (Photo: Will Kirk/Homewood-JHU)

Faculty members associated with the Johns Hopkins Institute for NanoBioTechnology have received a $13.6 million five-year grant from the National Cancer Institute to establish a Center of Cancer Nanotechnology Excellence. The new Johns Hopkins center brings together a multidisciplinary team of scientists, engineers and physicians to develop nanotechnology-based diagnostic platforms and therapeutic strategies for comprehensive cancer care. Seventeen faculty members will be involved initially, with pilot projects adding more participants later.

The Johns Hopkins Center of Cancer Nanotechnology Excellence, which is part of the university’s Institute for NanoBioTechnology, is one of several NCI-supported centers launched through a funding opportunity started in 2005. According to the NCI, the program was established to create “multi-institutional hubs that integrate nanotechnology across the cancer research continuum to provide new solutions for the diagnosis and treatment of cancer.”

Peter Searson, who is the Joseph R. and Lynn C. Reynolds Professor of Materials Science and Engineering in the Whiting School of Engineering and director of the Institute for NanoBioTechnology, will serve as the center’s director. The co-director will be Martin Pomper, professor of radiology and oncology at the School of Medicine and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins.

“A unique feature of the center is the integration of research, education, training and outreach, and technology commercialization,” Searson said.

To move these new technologies toward use by physicians, a Cancer Nanomedicine Commercialization Working Group will be established and headed by John Fini, director of intellectual property for the university’s Homewood campus. This group will be responsible for managing and coordinating the translational process.

Another special feature of the center will be its Validation Core, led by Pomper, who is also associate director of the Johns Hopkins In Vivo Cellular and Molecular Imaging Center and director of the Johns Hopkins Small Animal Imaging Resource Program.

“Validation is about assuring that the experimental products and results we generate are on target and able to measure the biological effects for which they’re intended,” he said.

Searson and Pomper said the center will consist of four primary research projects.

One project will seek methods to screen bodily fluids such as blood or urine for indicators of cancer found outside of the genetic code, indicators called epigenetic markers. Led by Tza-Huei “Jeff” Wang, associate professor of mechanical engineering in the Whiting School of Engineering; Stephen Baylin, the Virginia and Daniel K. Ludwig Professor of Cancer Research in the School of Medicine; and James Herman, a professor of cancer biology in the School of Medicine, this project will use semiconductor nanocrystals, also known as quantum dots, and silica superparamagnetic particles to detect DNA methylation. Methylation adds a chemical group to the exterior of the DNA and is a biomarker frequently associated with cancer.

A second project, led by Anirban Maitra, associate professor of pathology and oncology at the School of Medicine and the Johns Hopkins Kimmel Cancer Center, will focus on curcumin, a substance found in the traditional Indian spice turmeric. In preclinical studies, curcumin has demonstrated anti-cancer properties but, because of its physical size, it is not readily taken up into the bloodstream or into tissues. Engineered curcumin nanoparticles, however, can more easily reach tumors arising in abdominal organs such as the pancreas, Maitra said. This team will try to determine whether nanocurcumin, combined with chemotherapeutic agents, could become a treatment for highly lethal cancers, such as pancreatic cancer.

Hyam Levitsky, professor of oncology at the Johns Hopkins Kimmel Cancer Center, will lead a third project, which will seek to use a noninvasive method to monitor the effectiveness of vaccines for cancer and infectious diseases.

A final project will build on the work of Justin Hanes and Craig Peacock, professors in the School of Medicine, to deliver therapies directly to small cell lung cancer tissue via mucus-penetrating nanoparticles.

All research efforts will be supported by a nanoparticle engineering core, led by Searson, which will make and characterize a variety of nanomaterials. Another core, centering on bioinformatics and data sharing, will be led by Rafael Irizarry, professor of biostatistics at the Johns Hopkins Bloomberg School of Public Health.

Johns Hopkins Institute for NanoBioTechnology

Sidney Kimmel Comprehensive Cancer Center

EOC leader Gregg Semenza wins Canada Gairdner Award

Gregg Semenza

Gregg Semenza, associate director of Johns Hopkins Engineering in Oncology Center (EOC), has been named among seven 2010 winners of Canada’s international prize for medical research–the Canada Gairdner Award. The award is among the most prestigious for medical research and comes with a $100,000 cash prize.

The Canada Gairdner Award recognized Semenza for his work on how cells respond to oxygen availability in the body. He was the first to identify and describe hypoxia-inducible factor-1 (HIF-1), which switches genes on or off in response to oxygen levels.

Semenza leads a research project related to this topic for EOC with Sharon Gerecht, an assistant professor of chemical and biomolecular engineering. Their work focuses on analyzing the makeup and physical properties of the extracellular matrix, the three-dimensional scaffold in which cells live.

“Normal cells live in a flexible scaffold, but cancer cells create a rigid scaffold that they climb through to invade normal tissue,” Semenza said. “We will study how this change occurs and how it is affected by the amount of oxygen to which cancer cells are exposed. Our studies have shown that cancer cells are deprived of oxygen, which incites them to more aggressively invade the surrounding normal tissues where oxygen is more plentiful. Hypoxia-inducible factor 1 controls the responses of cancer cells to low oxygen, and we have recently identified drugs that block the action of HIF-1 and inhibit tumor growth in experimental cancer models.”

Semenza is the C. Michael Armstrong Professor in Medicine and founding director of the Vascular Biology program at  Johns Hopkins Institute for Cell Engineering at the School of Medicine. He also is a member of the McKusick-Nathans Institute of Genetic Medicine, is an affiliated faculty member of Johns Hopkins Institute for NanoBioTechnology, and has ties to the Department of Biological Chemistry and the Sidney Kimmel Comprehensive Cancer Center, both at the Johns Hopkins School of Medicine.

The Johns Hopkins Engineering in Oncology Center, launched October 2009, is one of 12 funded by the National Cancer Institute to bring a new cadre of theoretical physicists, mathematicians, chemists and engineers to the study of cancer. During the five-year initiative, the NCI’s Physical Sciences-Oncology Centers (PS-OC) will take new, nontraditional approaches to cancer research by studying the physical laws and principles of cancer; evolution and evolutionary theory of cancer; information coding, decoding, transfer and translation in cancer; and ways to deconvolute cancer’s complexity.

Read more about Gregg Semenza winning the Canada Gairdner Award in the Johns Hopkins Gazette story by Audrey Huang here.

Johns Hopkins Engineering in Oncology Center