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
SEP 22, 2021
Cancer
Whole Genome Sequencing for Cancer Diagnostics
SEP 22, 2021
Whole Genome Sequencing for Cancer Diagnostics
The human genome consists of genetic material known as DNA.  We all have unique DNA sequences made up of four bases ...
OCT 14, 2021
Cancer
Mechanism of Resistance to Colorectal Cancer Treatment Uncovered
OCT 14, 2021
Mechanism of Resistance to Colorectal Cancer Treatment Uncovered
Colorectal cancer develops when a series of changes occur across multiple genes.  While researchers have paid signi ...
OCT 25, 2021
Cell & Molecular Biology
The Labroots 2021 Cell Biology Virtual Event Poster Winner: 5-Azacytidine Treatment & Lung Cancer
OCT 25, 2021
The Labroots 2021 Cell Biology Virtual Event Poster Winner: 5-Azacytidine Treatment & Lung Cancer
Labroots virtual events are a great place to share research and learn about others work. These events feature participan ...
NOV 23, 2021
Clinical & Molecular DX
Scientists Enter Uncharted Territory of the Cancer Genome, Emerge Victorious
NOV 23, 2021
Scientists Enter Uncharted Territory of the Cancer Genome, Emerge Victorious
Cancer is a genetic disease—it stems from specific changes in the DNA sequences of the cancer cell genome. Over th ...
DEC 15, 2021
Health & Medicine
Limonene: The Terpene to Deploy against Cancer
DEC 15, 2021
Limonene: The Terpene to Deploy against Cancer
Limonene is one of the most well-known cannabis terpenes, and it’s getting increased attention in the medical prof ...
DEC 18, 2021
Cell & Molecular Biology
How the HTLV-1 Virus Can Turn Immune Cells Cancerous
DEC 18, 2021
How the HTLV-1 Virus Can Turn Immune Cells Cancerous
In some cases, viruses have been linked to cancer. For example, HPV, which is now preventable with a vaccine, can lead t ...
Loading Comments...