By engineering cancer-killing T cells that can be manipulated noninvasively by remote control, researchers have added a potentially powerful feature to an already promising type of immunotherapy known as CAR T cell therapy.

A report on the study, led by the University of California, San Diego (UCSD), is due to be published in the Proceedings of the National Academy of Sciences.

Immunotherapy, a relatively new approach to fighting cancer, manipulates and strengthens the patient's own immune system to eliminate tumors.

One type of immunotherapy that is emerging rapidly is chimeric antigen receptor T cell (CAR T cell) therapy.

In CAR T cell therapy, immune cells called T cells are taken from a person and genetically modified in the laboratory so that they can recognize and kill cancer cells more effectively. The engineered cells are then multiplied and put back into the person.
 
Designed to kill cancer cells

The genetically modified part of the T cell is the chimeric antigen receptor (CAR). It contains various synthetic elements, including one that can recognize unique features of tumor cells known as tumor-associated antigens, and another that activates the T cell to kill the target.

As new generations of CAR T cell therapy have been developed, the CAR has become increasingly sophisticated and acquired more features, including some that boost the anti-tumor power and persistence of the modified T cells.

Two CAR T cell therapies have recently been approved in the United States: one for the treatment of acute lymphoblastic leukemia in children, and another for the treatment of advanced lymphoma in adults.

However, there are now concerns surrounding whether this type of immunotherapy can be used effectively to treat cancers with solid tumors, such as those of the breast and colon.

One concern is whether or not the engineered T cells can be made powerful enough to overcome the resistance that the microenvironment inside a solid tumor has to immune responses.

Renier J. Brentjens, a medical oncologist and an early pioneer of CAR T cell therapy, says that what is needed is a "super T cell."

He and his team at Memorial Sloan Kettering Cancer Center in New York City, NY, are working on a solution to the microenvironment resistance problem that they call an "armored CAR T cell."
 
Mechanogenetic features added to T cells

Another concern that poses a challenge to therapy developers is that the "non-specific targeting of CAR T cells against nonmalignant tissues can be life-threatening," says Peter Yingxiao Wang, a bioengineering professor at UCSD and one of the senior investigators on the new study.

In their journal report, Prof. Wang and the rest of the study team describe how they added new features to CAR T cell therapy in which the T cells carry modules that can be manipulated to produce gene and cell changes through remotely controlled and noninvasive ultrasound.

They believe that the new features potentially make CAR T cell therapy more powerful at fighting cancer and less likely to produce adverse side effects.

They say that there is a "critical need" for tools that can work in this way, particularly when translating new experimental treatments into animals and humans.

The new approach is an example of mechanogenetics, which is a new field that manipulates mechanical properties at the level of cells to alter gene expression and cell functions.
 
'Unprecedented precision and efficiency'

The team engineered the CAR on the T cells to carry mechano-sensors loaded with microbubbles that vibrate when exposed to ultrasound waves.

The microbubbles activate a protein encoded by a gene called Piezo Type Mechanosensitive Ion Channel Component 1 (PIEZO1). The PIEZO1 protein is a "mechanically activated ion channel that links mechanical forces to biological signals."

Once activated, the PIEZO1 channel allows calcium ions to enter the T cell. This action triggers a cascade of molecular reactions that switch on genes that help the T cell to recognize and kill cancer cells.

"This work," Prof. Wang says, "could ultimately lead to an unprecedented precision and efficiency in CAR T cell immunotherapy against solid tumors, while minimizing off-tumor toxicities."

"CAR T cell therapy is becoming a paradigm-shifting therapeutic approach for cancer treatment."