Doctors Reach for Remote Control to Improve Cancer Care

Cancer treatment has come a long way in the last 150 years. From strictly surgical methods and folk remedies, to the development of chemotherapy, endoscopy, cryosurgery, laser treatments, and more, today’s cancer patients and their doctors have access to a broader array of options, with new techniques like immunotherapy and genetic therapies coming online each month.

But even these advanced treatments are far from perfect.

Today, for example, there is a big push around the engineering of T cells (or T lymphocytes, a type of white blood cell that is critical in immune response) to improve the performance of immunotherapy treatments. This involves collecting T cells from a patient’s blood, genetically engineering those cells so that they express certain cancer-killing antibodies, and then re-injecting them back into the patient. The hope is that the tumors in the patient’s body will then activate these engineered T cells, triggering them to release their toxic payload and killing the tumor.

But there’s a problem with this approach. There is no perfect antigen or antibody that works for every person and every situation. No matter how targeted the antibody in an engineered T cell, particularly when treating solid tumors,  there will always be some normal tissue and organs near the tumor that will trigger the release of the antibody, thereby damaging otherwise healthy parts of the body. This can lead to ineffective treatments, internal bleeding, and death.

That’s why Dr. Peter Yingxiao Wang, a bioengineering professor at the University of California, San Diego, and a team of researchers are developing a noninvasive, ultrasound-based system that would enable doctors to remotely control the genetic processes in engineered T cells from outside a patient’s body, triggering them to recognize and kill cancer cells while leaving healthy tissues alone.

Other researchers on the project include Dr. Shu Chien, also a bioengineering professor at UC San Diego; Dr. Kirk Shung with the Institute for Biomedical Therapeutics at the University of Southern California; and Dr. Michel Sadelain from the Memorial Sloan Kettering Cancer Center in New York.

“When you engineer a T cell and put it back into the patient, it has to go through the whole circulatory system, so there’s not much control of the cells,” Wang says. “So we thought, can we use an external signal to control them to only specifically attack a tumor?”

The process relies on mechanogenetics, which is the study of how physical force can be used to change the genetic expression of cells. In this case, Wang and his team developed a way to genetically alter chimeric antigen receptor (CAR) T cells to target cancer cells, engineering mechano-sensors and genetic transducing modules into the T cells themselves, and then remotely activating them with ultrasound outside the body.

Through the process, any engineered T cells that miss their target and end up getting trapped in normal organ tissue wouldn’t cause any problems for the patient, because the cells wouldn’t be activated.

“It’s also a sort of homing system for the T cells,” Wang explains. “When they are put back into the patient and recognize a specific surface protein or antigen that triggers their response that also sends a signal to us to identify the tumor site in the body. With that, we can use the external control to only activate those T cells that have successfully reached the target tumor site. Therefore we have very precise control and are less likely to activate T cells accidentally that are trapped in normal organ tissue.”

Broad Applications

While the research around this technology right now is focused on CAR T cells and leukemia treatments, the team believes their ultrasound manipulation technique has the potential to treat a wide variety of diseases, including other cancers and non-tumor conditions.

“It gives us a little bit hope knowing that we’ve actually demonstrated that we can do it in the lower frequency range,” says Shung, co-author on the study. “Low-frequency ultrasounds have been used in ultrasonic imaging for very many years. And the intensity of ultrasound used by this group is actually in the ballpark of diagnostic ultrasound, so we know that it's not going to create any kind of harms to the human body.”

What’s more, these low-frequency ultrasound beams only have to be applied locally to certain tissues where tumors are located. That benefit further reduces the change of affecting neighboring tissues and expands the usefulness of the technology.

“Actually, using ultrasound for this kind of study was started quite a few years ago,” Shung says. “But what Peter did is introduce cell manipulation to genetic engineering. It’s one more tool in the whole arsenal.”

As part of the larger world of cell therapy treatments and research, this work has the potential to add a powerful new option to modern medicine. Doctors are already using high-frequency ultrasound and other devices for cell manipulation, cell interrogation and more. The new method is simply way for them to do this work with a higher level of targeting and precision.

The next step for the technology will be clinical trials, though all involved admit the final goal is still a few years away.

“At this point, we're working only on cell lines, but this is an important premise that the group is working on,” Shung says. “The lower-frequency approach opens up the possibility of allowing this to be done on animals and perhaps on human beings soon. That’s why Peter started this work, and I think that we can be there in a year or two.”

Read more about cell therapy on AABME.org. 

Tim Sprinkle is an independent writer.