Pennsylvania: Investigational “hunter” immune cells engineered to seek out and attack a deadly brain cancer known as glioblastoma (GBM) infiltrated patients’ tumors and triggered thousands of more T cells once inside, researchers from Penn Medicine reported in a late breaking abstract at the AACR Annual Meeting 2017 (Abstract LB-053). The findings are among the results from three studies being presented on chimeric antigen receptor (CAR) therapy with T cells and a newer approach known as CARMA, which successfully pitted engineered macrophages against breast and ovarian tumors.
The GBM results, presented by Donald M. O’Rourke, MD, an associate professor of Neurosurgery at the Perelman School of Medicine at the University of Pennsylvania,
fall under a phase I trial testing immune cells made from patients’ own
T cells engineered in a specialized laboratory to target a
tumor-specific protein known as EGFRvIII, which is found in about 30
percent of GBM tumors.
Last year, O’Rourke and his colleagues reported that these CAR T
cells successfully migrated to and infiltrated GBM tumors in nine
patients, which has been an ongoing challenge in the treatment of many
solid tumors with CAR because of an unfavorable tumor microenvironment.
The new results showed a dramatic increase (nearly 20-fold) in the
number of tumor-infiltrating (TIL) T cells in patients’ tumors following
that infusion, suggesting that the infused cells can recruit and expand
other T cells once in the tumor. To determine this, researchers
sequenced the T cell receptor chain of TIL cells from the tumor
specimens of five patients before and after their infusion.
Penn is the first institution to open a trial utilizing in this type
of CAR T cell therapy for GBM, which is diagnosed in more than 22,000
Americans each year. One of the next steps in the research is to
determine whether these tumor-infiltrating cells can initiate a tumor
The GBM clinical trial is sponsored by Novartis. In 2012, the
University of Pennsylvania and Novartis announced an exclusive global
research and licensing agreement to further study and commercialize
novel cellular immunotherapies using CAR technologies.
Another hurdle for CAR T cell therapy in solid tumors is immune
inhibitory receptors, such as PD-1 and CTL4A, which can inhibit T cell
In a new preclinical study, presented by Edmund K. Moon, MD,
an assistant professor of medicine in the division of Pulmonary,
Allergy, and Critical Care at Penn, researchers modified a CAR T cell to
quiet one of those molecules, known as SHP1, to help overcome that
resistance in certain solid tumors. (Abstract 3749).
Moon and colleagues modified CAR T cells to target the specific
protein mesothelin on cancer cells and inserted a genetically engineered
SHP1 inhibitor to block PD-1-mediated immune suppression.
The team, which also includes Steven M. Albelda, MD,
the William Maul Measey Professor of Medicine at Penn, showed that mice
that received the mesoCAR/dnSHP1 T cells had a 60 percent greater
decrease in tumor growth compared to mice that only received mesoCARs.
TIL infiltration was also significantly higher in tumors harvested from
mice that received the mesoCAR/dnSHP1 T cells.
“DnSHP-1 engineering is a powerful and novel way of blocking the
suppression of CAR T cells by PD1 and other inhibitory receptors,” the
Results from a preclinical study using a newer CAR therapy approach from the lab of Saar Gill, MD, PhD, an assistant professor of Medicine at Penn, known as CARMA , or chimeric receptor antigen macrophages, were also presented (Abstract 4575).
Macrophages are a type of white blood cell that engulfs and digests
cell debris and bacteria. Under some circumstances, macrophages can also
promote cancer, which is perhaps one of the reasons this cell type has
not yet been intensively studied for adoptive cellular therapy.
“When you look at solid tumors, you can see that they are very much
infiltrated with macrophages,” Gill said. “We reasoned that a cell
already predisposed to trafficking to tumors might be a good one to
genetically engineer to be a cancer killer, instead of what it normally
does, which is act as an accomplice to help the tumor grow. We also
wanted to make them more powerful and specific.”
The team engineered CAR macrophages to target specific proteins on
cancer cells (including mesothelin and HER2, which is found in some
breast and ovarian cancers) using the viral vector Ad5f35, an
The abstract was presented by Michael Klichinsky, PharmD, a PhD candidate in the department of Systems Pharmacology and Translational Therapeutics at Penn.
Anti-HER2 CARMA demonstrated targeted phagocytosis and killed
significantly more HER2 expressing ovarian and breast cancer cells
compared to cell lines treated with the drug trastuzumab, the
researchers showed in laboratory experiments. In an ovarian cancer
mouse model, CARMA significantly decreased tumor burden (by 100 fold)
and demonstrated a 30-day survival benefit compared to untreated mice,
the researchers found.
“CARMA exhibited targeted anti-tumor function in both in vitro and in vivo
preclinical models,” the authors said. “A platform that makes
macrophages recognize and kill tumor cells while simultaneously making
them resistant to tumor-mediated subversion would represent a major
advance in the field to treat solid tumors.”
Editor’s Note: The University of Pennsylvania has licensed
some technologies involved in these studies to Novartis. Some of the
scientists involved in these trials are inventors of these technologies.
As a result of the licensing relationship with Novartis, the University
of Pennsylvania receives significant financial benefit, and these
inventers have benefitted financially and/or may benefit financially in
the future. Additional disclosure information is available in the
meeting abstracts. In addition, some Penn faculty have equity in the
start-up company CARMA Therapeutics, LLC, which has an option to license
the CARMA technology.