Taking Aim at Molecular Targets for Meningiomas & Pituitary Tumors

black and white image of DNA double helix
Image courtesy of Wenya Linda Bi, MD, PhD

Meningiomas and pituitary tumors traditionally have been regarded as surgically treated disease. However, some patients with these tumors face recurrence, premature morbidity and mortality. This challenge has motivated researchers at Brigham and Women’s Hospital to zero in on molecular targets that shed light on prognosis and suggest novel pathways for biological treatments.
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At the Forefront of Immunotherapy for Glioblastoma

E. Antonio Chiocca headshotPhysician-investigators in the Department of Neurosurgery at Brigham and Women’s Hospital are leading clinical trials of cutting-edge approaches for treating glioblastoma. Clinical trials are currently underway for patients with recurrent, progressive glioblastoma as well as patients newly diagnosed with high-grade gliomas as investigators pursue new treatment options to stimulate a patient’s immune system to recognize and eliminate cancer in the brain.

A Study of the Treatment of Recurrent Malignant Glioma with rQNestin34.5v.2

In a phase 1 clinical trial led by E. Antonio Chiocca, MD, PhD, chair of the Department of Neurosurgery at the Brigham, investigators are evaluating the investigational drug rQNestin34.5v.2, an oncolytic viral vector engineered from the herpes simplex virus type 1 (HSV1).

The virus has been rendered incapable of making copies of itself outside of glioma cells, and the vector is designed to preferentially infect, replicate and lyse within rapidly dividing tumor cells. Once the tumor cells are lysed, the viral particles they release can infect neighboring tumor cells, continuing the process of cancer cell destruction.

The current study is designed to test the safety of the drug and will also analyze the appropriate dosage as a possible treatment for recurrent or progressive glioblastoma. While several pharmaceutical companies are developing their own oncolytic viruses for targeting various forms of cancer, Chiocca’s team is the first to begin clinical trials in patients with glioblastoma utilizing this particular oncolytic virus. So far, the team has tested this approach in 16 patients with promising results.

“Oncolytic viral vectors are the new frontier of tumor treatment, and we are at the forefront of this trend. We are hoping to see the successes we had in the laboratory translate into marked improvements for our patients with brain tumors,” said Chiocca. “This clinical trial is the culmination of over a decade of research and testing.”

GMCI, Nivolumab, and Radiation Therapy in Treating Patients With Newly Diagnosed High-Grade Gliomas

Enrollment has recently begun for another study led by investigators at Brigham/Dana-Farber Cancer Institute will test the safety of a new combination therapeutic approach to treat patients with newly diagnosed high-grade gliomas. The approach combines the use of an immunostimulator, an immune checkpoint inhibitor and standard of care therapy.

The immunostimulatory approach known as Gene Mediated Cytotoxic Immunotherapy (GMCI) involves the use of aglatimagene besadenovec (AdV-tk) injection into the tumor site and oral valacyclovir to kill tumor cells and stimulate the immune system. Patients undergo tumor resection and receive AdV-tk injection into the wall of the resection cavity. The trial combines GMCI with nivolumab, an immune checkpoint inhibitor that may also stimulate the immune system by blocking the PD-1 immune suppressive pathway. Patients also receive radiation therapy and the chemotherapeutic drug temozolomide.

A Study of Ad-RTS-hIL-12 With Veledimex in Combination With Nivolumab in Subjects With Glioblastoma

In a third clinical trial, investigators will be testing the effectiveness of a gene therapy approach in combination with a checkpoint inhibitor for treating glioblastoma. Patients enrolled in the study will initially receive nivolumab, which is currently FDA-approved to treat other forms of cancer. Patients will undergo craniotomy and tumor resection and, on the day of surgery, will receive a single tumoral injection of Ad-RTS-hIL-12 given with oral veledimex. Ad-RTS-hIL-12 is an inducible vector that encodes interleukin-12, which can activate the immune system in the presence of veledimex. This gene therapy approach, accompanied with low-dose steroids, has been tested in a phase 1 clinical trial and found to have encouraging patient survival, when compared to the historical rate of 5 to 8 months for patients with recurrent glioblastoma. The phase 1 trial combining gene therapy with nivolumab began enrollment this summer and is actively recruiting.

“I’ve had a long-standing interest in immunotherapy and gene therapy. We’ve conducted the research and have studied these therapies in preclinical models, but my interest in moving these treatments into humans is why I am at the Brigham,” said Chiocca. “The strength of research and our close connections with the Dana-Farber Cancer Institute make the Brigham a fertile environment in which to figure out the best approach for patients.”

New Research in Nature: Neoantigen Vaccine for Glioblastoma
Chiocca and other investigators from Brigham and Women’s Hospital and Dana-Farber Cancer Institute recently published in Nature the results from a phase 1/1b trial designed to assess feasibility and safety of a personalized neoantigen vaccine for glioblastoma. The vaccine was extremely safe with no significant side effects. Co-authors from the Brigham Department of Neurosurgery extracted tumor tissue from which the personalized vaccines were developed.
“This personalized approach to creating a vaccine that can reinvigorate a patient’s immune system represents the culmination of a collaboration between experts in neurosurgery and neuro-oncology,” said Chiocca. “We’re thrilled to have played a role in this innovative work.”

Building a Discovery Engine for Genetic Stratification and Precision Treatment of Parkinson’s Disease

microscope image of neuronsVikram (Vik) Khurana, MD, PhD, chief of the Division of Movement Disorders in the Department of Neurology at Brigham and Women’s Hospital, with colleagues and collaborators around the world, is building a research engine poised to deliver therapies that precisely target specific disease mechanisms in individual patients with Parkinson’s disease and related disorders.
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Focused Ultrasound: Noninvasive Surgery Stops Tremor in its Tracks

Image courtesy of INSIGHTEC

Each week, two or three patients with medically refractive essential tremor undergo  MRI-Guided Focused Ultrasound (MRgFUS) Thalamotomy at Brigham and Women’s Hospital, with often-life-changing results – fulfilling the promise of a technology that dawned here 20 years ago.

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Just the Right Dose: Antiepileptic Drug Clearance Changes Early in Pregnancy

Young pregnant woman with doctor in ambulance.New research from Brigham and Women’s experts in women’s epilepsy provides guidance on whether and when effectiveness of antiepileptic drugs (AEDs) may be altered by the metabolic changes of pregnancy. The results suggest a need for therapeutic drug monitoring as soon as pregnancy is known.
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Precision Neurology Program Aims at Disease Drivers

How do genetic variants disrupt brain cells and cause abnormal movements and memory loss? Can addressing these molecular glitches before disease advances lead to better outcomes?

The new Precision Neurology Program (PNP) at Brigham and Women’s Hospital (BWH) and Harvard Medical School addresses these key questions.

Researchers in the program, based in the BWH Department of Neurology, are drawing upon the full spectrum of basic research, clinical work, and discovery of targeted treatment for movement and memory disorders.

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NeuroTechnology Studio Offers New Resource to Neuroscience Researchers

To speed innovation, a new NeuroTechnology Studio at Brigham and Women’s Hospital (BWH) now offers investigators access to advanced instrumentation, tools and expert support.

The goal of the NeuroTechnology Studio is to leverage advances in a range of technologies including microscopy, cell sorting and informatics to speed research and drive new understanding of brain function and of mechanisms underlying nervous system disorders. The Studio’s first two instruments for advanced imaging are installed and in use: a GE IN Cell Analyzer 2200 (a widefield high-content imaging system) and a Zeiss LSM880 + AiryScan confocal/super-resolution microscope.

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New Executive Director Appointed for the Ann Romney Center for Neurologic Diseases and the Program for Interdisciplinary Neuroscience at Brigham and Women’s Hospital

Charles G. Jennings, PhD, has been appointed the executive director of the Ann Romney Center for Neurologic Diseases and the Program for Interdisciplinary Neuroscience at Brigham and Women’s Hospital (BWH).

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Spinal Tumor Program: Multidisciplinary Care for Patients with Spinal Tumors

If your patient has been diagnosed with a spinal tumor, there are many treatment options, including surgery, radiation and chemotherapy. Determining the most appropriate treatment plan can be challenging, and often requires the collective opinion of multiple physicians across several specialties. Our team in the Spinal Tumor Program can assist in the care of your patients.

“The Spinal Tumor Program is a unique program that offers consultative services to physicians who are caring for patients with tumors of the spine. Our physicians work as a multidisciplinary team to create individualized treatment plans for each patient,” said John H. Chi, MD, director of neurosurgical spine cancer at the Brigham and Women’s Hospital.

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