FEB 26, 2015 4:45 PM PST

Personalized Cellular Therapy for Brain Cancer

WRITTEN BY: Ilene Schneider
A study published in Science Translational Medicine showed that immune cells engineered to seek out and attack a type of deadly brain cancer can be both safe and effective at controlling tumor growth in mice reated with these modified cells. A team from the Perelman School of Medicine at the University of Pennsylvania and the Novartis Institutes for BioMedical Research has paved the way for a newly opened clinical trial for glioblastoma patients at Penn.

"Penn trials that began in 2010 have found that engineered T cells have an effect in treating some blood cancers, but expanding this approach into solid tumors has posed challenges," said the study's senior author, Marcela Maus, MD, PhD, an assistant professor of hematology/oncology in Penn's Abramson Cancer Center. "A challenging aspect of applying engineered T cell technology is locating the best targets that are found on tumors but not normal tissues. This is the key to making this kind of T cell therapy both effective and safe."

Conducted in collaboration with Hideho Okada, MD, PhD, and his colleagues at the University of Pittsburgh, the preclinical study details the design and use of T cells engineered to express a chimeric antigen receptor (CAR) that targets a mutation in the epidermal growth factor receptor protein called EGFRvIII, which is found on about 30 percent of glioblastoma patients' tumor cells. More than 22,000 Americans are diagnosed with glioblastoma each year. Patients whose tumors express the EGFRvIII mutation tend to have more aggressive glioblastomas. Their tumors are less likely to respond favorably to standard therapies and more likely to recur following those treatments.

According to M. Sean Grady, MD, the Charles Harrison Frazier Professor and chair of the department of Neurosurgery, "Patients with this type of brain cancer have a very poor prognosis. Many survive less than 18 months following their diagnosis. We've brought together experts in an array of fields to develop an innovative personalized immunotherapy for certain brain cancers."

The new trial is led by Donald M. O'Rourke, MD, an associate professor of Neurosurgery. He oversees an interdisciplinary collaboration of neurosurgeons, neuro-oncologists, neuropathologists, immunologists and transfusion medicine experts.

Maus called the genesis of the new results as a "tour de force," in terms of the range of experiments performed to characterize the EGFRvIII CAR T cell. First, the team developed and tested multiple antibodies, or what immunologists call single-chain variable fragments (scFv), which bind to cells expressing EGFRvIII on their surface. The scFvs recognizing the mutated EGFRvIII protein must be rigorously tested to confirm that they do not also bind to normal, non-mutated EGFR proteins, which are widely expressed on cells in the human body.

The researchers then generated a panel of humanized scFvs and tested their specificity and function in CAR modified T cells. (Humanized scFvs are molecularly changed from their origins in non-human species to increase their similarity to human antibodies.) Out of the panel of humanized scFvs that were tested, the researchers selected one scFv to explore further based on its binding selectivity for EGFRvIII over normal non-mutated EGFR. They also evaluated the EGFRvIII CAR T cells in an assay utilizing normal EGFR-expressing skin cells in mice grafted with human skin. They found that the engineered EGFRvIII CAR T cells did not attack cells with normal EGFR in this model.

The lead scFv was then tested for its anti-cancer efficacy. Using human tumor cells, the scientific team determined that the EGFRvIII CAR T cells could multiply and secrete cytokines in response to tumor cells bearing the EGFRvIII protein. Importantly, the researchers found that the EGFRvIII CAR T cells controlled tumor growth in several mouse models of glioblastoma, as measured by magnetic resonance imaging (MRI) and luminescence of tumors in the mouse brains. In the mouse model, the EGFRvIII CAR T cells caused tumor shrinkage when measured by MRI and were also effective in eliminating tumors when administered in combination with temozolomide chemotherapy that is used to treat patients with glioblastoma.
About the Author
  • Ilene Schneider is the owner of Schneider the Writer, a firm that provides communications for health care, high technology and service enterprises. Her specialties include public relations, media relations, advertising, journalistic writing, editing, grant writing and corporate creativity consulting services. Prior to starting her own business in 1985, Ilene was editor of the Cleveland edition of TV Guide, associate editor of School Product News (Penton Publishing) and senior public relations representative at Beckman Instruments, Inc. She was profiled in a book, How to Open and Operate a Home-Based Writing Business and listed in Who's Who of American Women, Who's Who in Advertising and Who's Who in Media and Communications. She was the recipient of the Women in Communications, Inc. Clarion Award in advertising. A graduate of the University of Pennsylvania, Ilene and her family have lived in Irvine, California, since 1978.
You May Also Like
DEC 08, 2019
Cancer
DEC 08, 2019
Is there an association between smoking marijuana and cancer?
The controversy with marijuana is only likely to continue as research studies try to understand if marijuana use is associated to an increased risk of canc...
JAN 02, 2020
Cancer
JAN 02, 2020
Early onset stomach cancer in young people
New research from Mayo Clinic published recently in the journal Surgery details a distinction in the types of stomach cancer that affects particularly youn...
JAN 15, 2020
Clinical & Molecular DX
JAN 15, 2020
Laser microchip picks up cancer markers in urine
A future where patients no longer need to endure expensive, painful and complicated cancer tests could soon become a reality. Researchers have developed a...
JAN 03, 2020
Drug Discovery & Development
JAN 03, 2020
New Drug Combo Reverses Breast Cancer
Researchers from Georgetown University have found that combining a drug used for epilepsy, bipolar disorder, and migraines with a drug used to ease blood p...
JAN 13, 2020
Cell & Molecular Biology
JAN 13, 2020
Disrupting Leukemia's Deadly Reliance on Vitamin B6
Acute Myeloid Leukemia is a cancer of the blood that starts in the bone marrow, where the stem cells that produce blood cells reside, and rapidly moves to the blood....
FEB 11, 2020
Cancer
FEB 11, 2020
Could we be over-diagnosing cancer?
Roughly one in every two people are estimated to receive a cancer diagnosis at some point in their lives, but are all of those diagnoses valid? New researc...
Loading Comments...