Lisa Feldman, MD, PhD, received the 2015-16 William P. Van Wagenen Fellowship. Dr. Feldman gave NREF the following update on her career and research:
In 2015, I was deeply honored to be awarded the Van Wagenen Fellowship. I took a leave of absence from my home Neurosurgery training program at Virginia Commonwealth University, to spend one year in New Zealand. As a fellow, I developed multiple international and multi-institutional studies involving Virginia Commonwealth University, Washington University in St. Louis, Malaghan Institute of Medical Research in New Zealand, and New Zealand Universities: University of Otago, Victoria University of Wellington, and University of Auckland. One major study that came out of this collaboration was to identify the very early changes seen in mouse brain following cerebral radiation necrosis with Gamma Knife™ stereotactic radiation. Immunohistochemistry was used to study vascular, inflammatory, astrocytic and neuronal changes as soon as 1 hour and up to days after radiation.
In a separate study, we used immunohistochemistry to assess the degree of hypoxia in a murine model of high-grade glioma using GL261 cells. We subsequently showed that perflourocarbons, nanoparticles that carry 50 times more oxygen than hemoglobin, and supplemental oxygen completely abrogated any trace of hypoxia in tumors. Finally, we showed that by removing any hypoxia, cerebral radiation therapy became significantly more effective and resulted in tumor- bearing animals significantly longer after radiation therapy.
After completing my Van Wagenen year and finishing residency, I pursued a surgical fellowship in neuro-oncology at City of Hope in Duarte, California. Not only did I finesse my surgical skills, but I continued my collaborative relationships to explore our findings further. I also learned about chimeric antigen receptor T (CAR T-cell) therapy for glioblastoma. More specifically, City of Hope employs a team of world-renown expert physicians and scientists who develop chimeric antigen receptor T cells by collecting patients' autologous T cells and genetically modifying them to target and destroy tumor cells. Interleukin 13 receptor alpha 2 (IL13Rα2) is a protein expressed on about 60% of GBM tumors and not expressed in healthy brain. Our team generates IL13Rα2-targeted CAR T cells and are delivering them loco-regionally in clinical trial to treat GBM and high-grade gliomas. I had the privilege of working closely with patients with GBM patients who were enrolled into IL13Rα2- and HER2-targeted CAR T cell clinical trials.
After my surgical fellowship, I began my position as an Assistant Clinical Professor of Neurosurgery at City of Hope in August 2019, and three weeks later was awarded a K12 award to pursue my research using IL13Rα2-targeted CAR T cells to treat leptomeningeal disease (LMD), a very late stage of GBM. During my first year on staff, I implemented a clinical trial recruiting patients with LMD from high-grade glioma and am studying exosomes from patients' CSF blood to monitor CAR T efficacy as well as treatment response. In my laboratory, I am exploring how hypoxia and oxygenation alter the GBM tumor microenvironment, and how these changes impact CAR T cell survival and efficacy.
In parallel, I became the PI for two observational “Legacy” clinical trials. The City of Hope Division of
Precision Medicine successfully implemented a rapid post-mortem tissue collection program called The Legacy
Project, in which samples of biopsied/resected tissues as well as biofluids are collected from enrolled
patients while under treatment, and large volumes of healthy and diseased tissue as well as biofluids, are
rapidly collected within 6 hours of death. Samples are sent to multiple labs throughout City of Hope,
including my own, as well as to multiple labs in collaboration with University of Southern California (USC).
Our first Legacy project collects tumor samples, plasma and CSF from patients with leptomeningeal disease
due to metastatic breast cancer. The second Legacy project enrolls patients with glioma. Both projects aim
to study heterogeneity with and across tumors and identify novel biomarkers such as cell-free DNA and
extracellular vesicles. We hope to map out tumor progression based on tumor markers, genomic dissection of
structural mutations within tumors, molecular geolocation and liquid biopsies as novel methods of tumor
burden tracking.
Most recently, I also become the PI of the Patient, Partner & Providers Working Together: A Strengths-based
Brain Cancer Program, which is a unique integrated, interdisciplinary program for GBM patients, their
partners and caregivers. This intervention by Neurosurgery, Neuro-Oncology and Supportive Care medicine
provides psychosocial support for patients and their partner, utilizing both in person supportive social
support by a social worker, in personal and through phone app that collects real time data monitoring
overall wellbeing. This program focuses on optimizing symptom management, psychological services, and
spiritual care. We hypothesize this intervention will not only ease coping and psychological distress for
patients and their caregivers, but also result in shorter and fewer hospitalizations for patients resulting
in improved overall wellbeing.
“My experience as a Van Wagenen fellow provided for me the unique opportunity to expand scientific knowledge through international cooperative teamwork. I attribute much of my current success as an independent neurosurgeon-scientist to the skills I accrued as a research fellow, and to the sustained ongoing research collaborations with my fellowship mentors and co-scientists.”
